Experimental

General Remarks

1H NMR and 13C NMR spectra were recorded at 300 MHz and 75.5 MHz, respectively, with a Bruker AC-300 in deuterated solvent (CDCl₃, DMSO-d₆, D₂O, CD₃OD etc.), with TMS as internal standard. The following abbreviations are used in the splitting pattern of ¹H NMR: s (singlet), br (broad single), d (doublet), dd (double doublet), t (triplet), q (quartet), m (multiplet).

EI-Mass spectra (MS) (HP-5995 A) and EI-high resolution mass(HRMS) spectra (MAT 711, Varian) were measured at 70 eV.

Elemental analysis was measured at CHNS-932 (Leco) in the microanalytical lab of institute of chemistry.

Melting points were determined on a Boetius hot-stage apparatus and were reported uncorrected.

TLC analysis was performed on Merck silica gel 60 F₂₅₄ plates or Merck Al₂O₃ 60F₂₅₄ neutral (Typ E) plates and visualized with UV illumination.

Column chromatography was conducted with Merck silica gel 60 (400-639 mesh) or Merck neutral Al₂O₃ gel (90 standard). The normal solvents hexane, cyclohexane, ethyl acetate, dichloromethane were redistilled before use.

The cross-coupling reactions were carried out under argon in oven-dried glasswares. Solvents were dried and deoxygenated by standard procedures.

Starting materials were purchased from Aldrich, Lancaster, Acros, and Merck, except compounds S1-S11 (see Scheme7.1 to 7.4).

3-amino-5-arylpyrazoles S2 were prepared according to literatures [223, 224], 3-amino-4-arylpyrazoles S4 were prepared as described in the literatures [225, 226]. (Scheme 7.1)

Scheme 7.1

1-(4-chloro-phenyl)-butane-1,3-dione S5 was prepared according to literature [227] (Scheme 7.2).

Scheme 7.2

Allyl-trityl-amine S-6, allyl trityl ether S-7,allyl-phthalamide S-8,andpropargyl phthalamide S-9 were prepared according to literatures [228-231], respectively (Scheme 7.3).

Scheme 7.3

4-Ethynyl-phenyl)-dimethylamine S-11 was prepared according to literature procedures [232]. (Scheme 7.4).

Scheme 7.4

Synthesis of pyrazolo[1,5-a]pyrimidine derivatives Synthesis of pyrazolo[1,5-a]pyrimidines by ring closure Synthesis of 2, 5, 7-tri-substituted pyrazolo[1,5-a]pyrimidines

General procedure:

A 50 ml round flask was chargedwithappropriate5-substituted 3-aminopyrazole (20 mmol), appropriate 1,3-diketone (22 mmol) and 37 % hydrochloric acid (15 ml). The mixture was heated at reflux for 3 h. After the reaction was complete (from TLC), the mixture was cooled, neutralized with aq. Na₂CO₃ and extracted with CHCl₃ (3 × 40 ml). The combined organic layers were dried with anhydrous MgSO₄. The solvent was evaporated and the crude product was purified by recrystallization or column chromatography on silica gel.

5-Methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine(88a)

The crude product was purified by recrystallization with ethanol as solvent, and provided a light yellow solid, yield 89 %, mp 185-6 °C.

1H-NMR(CDCl₃), δ(ppm): 2.62 (s, 3 H, CH₃), 6.74 (s, 1 H, H-3), 6.90 (s, 1 H, H-6), 7.43-8.14 (m, 10 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 24.79 CH₃, 92.54 CH(C-3), 108.15CH(C-6), 126.58 CH, 128.50 CH, 128.64 CH, 129.45 CH, 129.70 CH, 130.90 CH, 131.15 C, 133.10 C, 145.73 C, 150.82 C, 155.72 C, 158.65 C.

HRMS(EI) calcd for C₁₉H₁₅N₃(M⁺) 285.12660, found 285.12656.

Anal. Calcd. for C₁₉H₁₅N₃: C, 79.98; H, 5.30; N, 14.73.

Found: C, 79.81; H, 5.34; N, 14.78.

2-(4-Chloro-phenyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidine(88b)

The crude product was purified by recrystallization with ethanol as solvent, and provided a light yellow solid, yield 66 %, mp 156-8 °C.

1H-NMR (CDCl3), δ(ppm): 2.64 (s, 3 H, CH₃), 6.78 (s, 1 H, H-3), 6.88 (s, 1 H, H-6), 7.37-8.12 (m, 9 H, Ar-H).

13C-NMR (CDCl3), δ(ppm): 24.79 CH3, 92.50CH(C-3), 108.36 CH(C-6), 127.78 CH, 128.53 CH, 128.78 CH, 129.41 CH, 130.97 CH, 131.00 C, 131.49 C, 134.60 C, 145.74 C, 150.84 C, 154.49 C, 158.87 C.

Anal. Calcd. for C₁₉H₁₄ClN₃: C, 71.36; H, 4.41; Cl, 11.09; N, 13.41.

Found: C, 71.52; H, 4.50; Cl, 11.10; N, 13.24.

2-Methyl-5,7-diphenylpyrazolo[1,5-a]pyrimidine(88c)

The crude product was purified by recrystallization with ethanol as solvent, and provided a light yellow solid, yield 74 %, mp 113-4 °C.

1H-NMR(CDCl₃), δ(ppm): 2.53 (s, 3 H, CH₃), 6.58 (s, 1 H, H-3), 7.24 (s, 1 H, H-6), 7.49-8.09 (m, 10 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 14.92 CH₃, 96.47 CH( C-3), 104.42 CH(C-6), 127.20 CH, 128.68 CH, 128.87 CH, 129.26 CH, 130.09 CH, 130.87 CH, 131.66 C, 137.73 C, 146.15 C, 150.65 C, 155.44 C, 155.82 C.

Anal. Calcd. for C₁₉H₁₅N₃: C, 79.98; H, 5.30; N, 14.73.

Found: C, 79.83; H, 5.36; N, 14.74.

7-(4-Chloro-phenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine(88d)

The crude product was purified by recrystallization, using ethanol as solvent, and afforded a light yellow solid, yield 77 %, mp 155-7 °C.

1H-NMR(CDCl₃), δ(ppm): 2.63 (s, 3 H, CH₃), 6.74 (s, 1 H, H-3), 6.92 (s, 1 H, H-6), 7.37-8.13 (m, 9 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 24.80 CH₃, 92.69 CH(C-3), 107.95 CH(C-6), 126.53 CH, 128.69 CH, 128.80 CH, 128.91 CH, 129.50 C, 130.78 CH, 132.91 C, 137.02C, 144.49 C, 150.78 C, 155.79 C, 158.62 C.

Anal. Calcd. for C₁₉H₁₄ClN₃: C, 71.36; H, 4.41; Cl, 11.09; N, 13.41.

Found: C, 71.16; H, 4.58; Cl, 11.17; N, 13.09.

2,5-Dimethyl-7-phenylpyrazolo[1,5-a]pyrimidine(88e)

The crude product was purified by recrystallization, using ethanol as solvent, and provided a light yellow solid, yield 78 %, mp 81-2 °C.

1H-NMR(CDCl₃), δ(ppm): 2.50(s, 3 H, CH₃), 2.60(s, 3H, CH₃), 6.41(s, 1 H, H-3), 6.67(s, 1H, H-6), 7.52-8.03 (m, 5 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 14.83 CH₃, 24.69 CH₃, 95.18 CH(C-3), 107.50 CH(C-6), 128.60 CH, 129.20 CH, 130.80 CH, 131.13 C, 145.56 C, 150.37 C, 154.85 C, 158.29 C.

Anal. Calcd. for C₁₄H₁₃N₃: C, 75.31; H, 5.87; N, 18.82.

Found: C, 75.19; H, 5.98; N, 18.83.

2,5,7-Trimethylpyrazolo[1,5-a]pyrimidine(88f)

The crude product was purified by recrystallization, using diethyl ether/hexane (1/2) as solvent, and provided a light brown solid, yield 68 %, mp 69-70 °C.

1H-NMR(CDCl₃), δ(ppm): 2.52 (s, 3 H, CH₃), 2.54 (s, 3 H, CH₃), 2.71 (s, 3 H, CH₃), 6.36 (s, 1 H, H-3), 6.48(s, 1 H, H-6).

13C-NMR(CDCl₃), δ(ppm): 14.67 CH₃, 17.17 CH₃, 24.43 CH₃, 95.09 CH(C-3), 107.54 CH(C-6), 144.90 C, 149.08 C, 154.63 C, 157.98 C.

Anal. Calcd. for C₉H₁₁N₃: C, 67.06; H, 6.88; N, 26.07.

Found: C, 66.81; H, 7.01; N, 26.14.

2,5,7-Triphenylpyrazolo[1,5-a]pyrimidine(88g)

The crude product was purified by recrystallization with ethanol as solvent, and provided a light yellow solid, yield 77 %, mp 154-5 °C.

1H-NMR(CDCl₃), δ(ppm): 7.09 (s, 1 H, H-3), 7.24 (s, 1 H, H-3), 7.35-8.22 (m, 15 H, Ar-H).

13C NMR(CDCl₃), δ(ppm): 93.76 CH(C-3) , 105.04 CH(C-6), 126.61 CH, 127.22 CH, 128.57 CH, 128.68 CH, 128.88 CH, 128.93 CH, 129.52 CH, 130.25 CH, 131.46 C, 133.05 C, 137.61 C, 146.37 C, 151.15 C, 156.09 C, 156.26 C.

Anal. Calcd. for C₂₄H₁₇N₃: C, 82.97; H, 4.93; N, 12.09.

Found: C, 82.89; H, 4.99; N, 11.99.

5,7-Diphenylpyrazolo[1,5-a]pyrimidine(88h)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate(4/1) as eluting solvent, and provide a yellow solid, yield 89 %, mp 85-6 °C.

1H-NMR(CDCl₃), δ(ppm): 6.30 (d, 1 H, J = 2.3, H-3), 7.28( s, 1 H, H-3), 7.44-8.08 (m, 10 H, Ar-H), 8.11 (d, 1H, J = 2.3, H-2).

13C-NMR(CDCl₃), δ(ppm): 97.19 CH(C-3), 105.22 CH(C-6), 127.29 CH, 128.74 CH, 128.95 CH, 129.24 CH, 130.31 CH, 130.97 CH, 131.51 C, 137.52 C, 145.21 CH(H-2), 146.85 C, 149.86 C, 156.22 C.

Anal. Calcd. for C₁₈H₁₃N₃: C, 79.68; H, 4.83; N, 15.49.

Found: C, 79.34; H, 5.06; N, 15.54.

Synthesis of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines

A 50 ml flask was chargedwith3-amino-4-phenylpyrazole S-4a (3.18 g, 20 mmol), appropriate 1,3-diketone (22 mmol) and 37 % hydrochloric acid (15 mL). The mixture was heated at reflux for 10 hours. After the reaction was complete (check TLC), the mixture was cooled, neutralized with aq. Na₂CO₃ and extracted with CHCl₃ (3 × 40 ml). The combined organic layers were dried with anhydrous MgSO₄. The solvent was evaporated and the crude product was purified by recrystallization

5,7-Dimethyl-3-phenylpyrazolo[1,5-a]pyrimidine (89a)

The crude product was purified by recrystallization with ethanol:hexane(4/1) as solvent and provided a yellow solid, yield 75 %, mp 91-92 °C.

1H-NMR(CDCl₃), d(ppm): 2.54 (s, 3 H, CH₃), 2.67 (s, 3 H, CH₃), 6.52 (s, 1 H, H-6), 7.17-8.02 (m, 5 H, Ph-H), 8.32 (s, 1 H, H-2).

13C-NMR(CDCl₃),d(ppm): 17.08 CH₃(C-7), 24.93 CH₃(C-5), 108.74 CH(C-6), 109.54 C, 125.94 CH, 126.19 CH, 128.69 CH, 132.50 C, 142.14 CH(C-2), 144.81 C, 145.22 C, 158.74 C.

Anal. Calcd. for C₁₄H₁₃N₃ (223.28): C, 75.31; H, 5.87; N, 18.82.

Found: C, 75.25; H, 5.94; N, 18.84.

5-methyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine(89b)

The crude product was purified by recrystallization with ethanol to provide a yellow solid, yield 86 %, mp 124-5°C.

1H-NMR(CDCl₃), d(ppm): 2.61 (s, 3 H, CH₃), 6.70 (s, 1 H, H-6), 7.17-8.04 (m, 10 H, Ph-H), 8.32 (s, 1 H, H-2).

13C-NMR (CDCl₃), d(ppm): 25.06 CH₃, 108.71 CH(C-6), 109.57 C, 126.05 CH, 126.34 CH, 128.69 CH, 128.76 CH, 129.21 CH, 130.90 CH, 131.20 C, 132.41 C, 142.56 CH(C-2), 145.84 C, 146.24 C, 159.06 C.

Anal. Calcd. for C₁₉H₁₅N₃ (285.34): C, 79.98; H, 5.30; N, 14.73.

Found: C, 79.98; H, 5.41; N, 14.76.

3,5,7-Triphenylpyrazolo[1,5-a]pyrimidine(89c):

The crude product was purified by recrystallization with ethanol as solvent, and provided a yellow solid, yield 86 %, mp 163-4 °C.

1H-NMR(CDCl₃),d(ppm): 7.17 (s, 1 H, H-6), 7.31-8.18 (m, 15 H, Ph-H), 8.41 (s, 1 H, H-2).

13C-NMR (CDCl₃),d(ppm): 105.17 CH(C-6), 110.70 C, 126.14 CH, 126.37 CH, 127.35 CH, 128.74 CH, 128.78 CH, 129.95 CH, 129.28 CH, 130.43 CH, 131.01 CH, 131.39 C, 132.41 C, 137.38 C, 142.96 CH(C-2), 145.95 C, 147.02 C, 155.91 C.

Anal. Calcd. for C₂₄H₁₇N₃ (347.4): C, 82.97; H, 4.93; N, 12.10.

Found: C, 82.92; H, 5.01; N, 12.13.

Hydroxy-substituted pyrazolo[1,5-a]pyrimidines
7-hydroxy-3,5-diphenylpyrazolo[1,5-a]pyrimidine (90)

A mixture of 4-phenyl-3-aminopyrazole (3.18 g, 0.02 mol) and ethylbenzoyacetate (4.55 g, 0.022 mol) in acetic acid 5 ml was heated at reflux for 20 h, the solution was evaporated to dryness in vacuo and treated with diethyl ether, white solid was obtained, the crude product was recrystallized with ethanol, and 4.26 g white solid was obtained, yield 74 %, mp 250-2 °C.

1H-NMR(DMSO-d₆), d(ppm): 6.06 (s, 1 H, H-6), 7.28-7.85 (m, 10 H, Ph-H), 8.22 (s 1 H, H-2), 12.28 (br, 1 H, OH).

13C-NMR(DMSO-d₆), d(ppm): 95.22 CH,106.23 C, 126.56 CH, 127.67 CH, 128.05 CH, 128.21 Ch, 128.72 CH, 130.88 CH, 132.92 C, 136.23 C, 142.35 CH(C-2), 144,20 C, 150.67 C, 156.32 C.

Anal. Calcd. for C₁₈H₁₃N₃O(287.32): C, 75.25; H, 4.56; N, 14.63.

Found: C, 75.31; H, 4.68; N, 14.59.

5,7-dihydroxy-3-phenylpyrazolo[1,5-a]pyrimidine (91)

4-Phenyl-3-aminopyrazole S-4a (3.20 g, 0.02 mol) and diethyl malonate (3.23 g, 0.20 mol) were added to a solution of sodium (1.8g, 0.077mol) in 200 ml dry ethanol, the mixture was heated at reflux for 16 hours, after cooled the precipitate was collected by filter and washed with ethanol, and dried in vacuum, the solid (sodium salt) was dissolved in 150 ml water and the aqueous phase was acidified with 6 N HCl, the precipitate was collected and dried, the crude product was dissolved in 6N aqueous NaOH, and acidified the solution with 6N HCl, and provided a pure white solid 2.2 g, yield 50 %, mp 308-310 °C.

Anal. Calcd. for C₁₂H₉N₃O₂(227.22): C, 63.43; H, 3.99; N, 18.49.

Found: C, 63.20; H, 4.18; N, 18.32.

7-hydroxy-3,5-diphenylpyrazolo[1,5-a]pyrimidine(92)

A mixture of 3-amino-2-methylpyrazole (1.95 g, 0.02 mol) and ethyl acetoactate (3.12 g, 0.024 mol) in 8 ml acetic acid was heated at reflux for 3 hours, after cooled, 40 ml water was added, the solution was cooled and the white solid was collected, washed with cold water and provided a white solid 2.32 g, yield 71 %, mp 226-8 °C.

1H-NMR(DMSO-d₆), d(ppm): 2.44 (s, 3H; CH₃), 2.49 (s, 3 H, CH₃), 5.27 (br, 1 H, OH), 5.69 (s, 1 H, H-3), 6.09 (s, 1 H, H-6).

13C-NMR(DMSO-d₆), d(ppm): 14.20 CH₃, 19.68 CH₃, 88.52 CH(C-2), 94.14 CH(C-6), 144.21 C, 151.33 C, 151.47 C, 156.58 C.

Anal. Calcd. for C₈H₉N₃O(163.18): C, 58.88; H, 5.56; N, 25.75.

Found: C, 58.78; H, 5.87; N, 25.64.

5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrimidine (93)

3-Amino-5-methylpyrazole (5.03 g, 51 mmol), diethyl malonate (9.60 g, 60 mmol) was added to a solution of sodium (3.2 g,0.14 mol) in 100 ml dry ethanol, the mixture was heated at reflux for 16hours, after cooled the precipitate was collected by filter and washed with ethanol, and dried in vacuum, the solid (sodium salt) was dissolved in 20ml water and the solution was acidified with 10 % HCl ( to pH value <2), the solution was then cooled and the precipitate was collected, washed with cold 1 N HCl and dried, and provided a light yellow solid 6.9 g, yield 82 %, mp 244-6 °C.

Anal. Calcd. for C₇H₇N₃O₂(165.15): C, 50.91; H, 4.27; N, 24.55.

Found: C, 50.75; H, 4.48; N, 24.29.

Synthesis of halogen substituted pyrazolo[1,5-a]pyrimidines Synthesis of 6-bromopyrazolo[1,5-a]pyrimidines
(a) 6-Bromo-5-methyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine(95)

Scheme 7.5

A solution of bromine (6.10 g, 0.038 mol) in 40 ml CCl₄ was added dropwise in 45 min to a vigorously stirring dispersion of benzoylacetone (6.16 g, 0.037 mol) in CCl₄ 40 ml and water 40 ml at 0 °C, the mixture was continue to stir for 1 h, the mixture was separated and the aqueous layer was extracted with CCl₄(2 × 30 ml), the combined organic phase was washed with brine (2 × 30 ml) and dried with anhydrous MgSO₄, the solvent was evaporated in high-vacuum and provide 9.30 g oily crude 2-bromo-1-phenyl-butane-1,3-dione 94.

A 50 ml round flask was chargedwith4-phenyl-3-aminopyrazole S-2a (3.18 g, 20 mmol), crude 2-bromo-1-phenyl-butane-1,3-dione 94 (5.8 g, >22 mmol) and conc. hydrochloric acid 15 ml. The mixture was heated at reflux for 10 h. After the reaction was complete, the mixture was cooled, neutralized with aq Na₂CO₃ and the orange precipitate was collected, washed with 1 N HCl and water, the crude product was purified by recrystallization from ethanol and 5.10 g orange solid was obtained, yield 70 %, mp.129-130 °C.

1H-NMR(CDCl₃), δ(ppm): 2.73 (s, 3 H, CH₃), 7.35-8.00 (m, 10 H, Ph-H), 8.25 (s, 1 H, H-2).

13C-NMR(CDCl₃), δ(ppm): 24.47 CH₃, 108.50 C, 126.32 CH, 126.57 CH, 128.76 CH, 129.08 CH, 129.61 CH, 130.70 CH, 131.09 C, 131.84 C, 142.92 CH(C-2), 146.24 C, 147.16 C, 157.45 C.

Anal. Calcd for C₁₉H₁₄BrN₃ (364.40): C, 62.63; H, 3.87; Br, 21.93; N, 11.53.

Found: C, 62.31; H, 4.09; Br, 22.02; N, 11.64.

(b)6-Bromo-2,5,7-trimethylpyrazolo[1,5-a]pyrimidine (97)

Scheme 7.6

A soution of acetylacetone (2.02 g, 0.020 mol), NBS (3.60 g, 0.020 mol) in 20 ml CCl₄ was heated at reflux for 5 h, then filtered and the filtrate was evaporated to dryness and gave 3.4 g oily crude 3-bromo-acetylacetone 96.

A mixture of 3-amino-2-methylpyrazole (1.65 g, 0.017 mol) and crude 3-bromo-acetylacetone 97 (3.10 g, 0.018 mol) in acetic acid 10 ml was heated at reflux for 3 h, after the mixture was cooled, 10 ml water was added, the solution was neutralized with 6 N NaOH, and extracted with diethyl ether (2 × 40 ml), the extract was washed with water 30 ml, dried with anhydrous MgSO₄.the solvent was evaporated, the crude product was recrystallized with water and provided 3.64 g light brown solid, yield 89 %, mp 83-4 °C.

1H-NMR(CDCl₃), δ(ppm): 2.42 (s, 3 H, CH₃), 2.62 (s, 3 H, CH₃), 2.84 (s, 3 H, CH₃), 6.28 (s, 1 H, H-2).

13C-NMR(CDCl₃), δ(ppm): 14.63 CH₃, 17.30 CH₃, 26.17 CH₃, 95.64 CH(C-2), 105.73 C, 143.97 C, 147.27 C, 154.96 C, 156.50 C.

Anal. Calcd for C₉H₁₀BrN₃ (240.10): C, 45.02; H, 4.42; Br, 33.28; N, 17.50.

Found: C, 44.96; H, 4.42; Br, 33.49; N, 17.65.

Synthesis of 7-halo-3,5-diphenylpyrazolo[1,5-a]pyrimidine

7-Chloro-3,5-diphenylpyrazolo[1,5-a]pyrimidine(98)

A solution of 7-hydroxy-5,7-diphenylpyrazolo[1,5-a]pyrimidine 90 (4.60 g, 16 mmol), POCl₃ (5 ml, 53 mmol) and N, N-dimethylaniline (0.4 ml, 3.1 mmol) was heated at reflux for 3 h. After the mixture was cooled to RT, ice (about 30 ml) was added slowly and carefully. The mixture was extracted with chloroform (3 × 30 ml), the combined organic layers were dried with anhydrous MgSO₄ and concentrated. The crude product was recrystallized with a mixture solvent of acetone and pentane, and a yellow crystal 4.81 g was obtained, yield 98 %, mp 159-60 °C.

1H-NMR(CDCl₃), δ(ppm): 7.49 (s, 1 H, H-6), 8.53 (s, 1 H, H-2), 7.28-8.17 (m, 10 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 105.59 CH(C-6),112.31 C, 126.43 CH, 126.63 CH, 127.40 CH, 128.81CH, 129.06 CH, 130.88 CH, 131.66 C, 136.29 C, 139.03 C, 143.54 CH(C-2), 145.81 C, 155.65 C.

Anal. Calcd for C₁₈H₁₂ClN₃ (305.77): C, 70.71; H, 3.96; Cl, 13.74; N, 11.60.

Found: C, 70.78; H, 3.94; Cl, 11.86; N, 13.77.

7-Bromo-3,5-diphenylpyrazolo[1,5-a]pyrimidine(99)

A solution of 7-hydroxy-5,7-diphenylpyrazolo[1,5-a]pyrimidine 90 (2.87 g, 10 mmol), POBr₃ (4.59 g, 16 mmol), and N, N-dimethylaniline (0.3 ml, 2.3 mmol) in dry toluene (10 mL) was heated at reflux for 3 h. After the solvent was evaporated, ice 30 g was added inside slowly and the mixture was extracted with CHCl₃ (3 × 30 ml). The combined organic layers were dried with anhydrous MgSO₄ and concentrated. The crude product was recrystallized with a mixture solvent of acetone and pentane to give a yellow crystal 3.35 g, yield 96 %, mp 164-5 °C.

1H-NMR(CDCl₃), δ(ppm): 6.77 (s, 1 H, H-6), 8.52 (s, 1 H, H-2 ), 7.27-8.16 (m, 10 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 109.72 CH ( C-6 ), 112.46 C, 126.42 CH, 126.60 CH, 127.41 CH, 128.79 CH, 128.99 C, 129.04 CH, 130.84 CH, 131.77 C, 136.12 C, 143.28 CH (C-2), 145.30 C, 155.16 C.

Anal. Calcd for C₁₈H₁₂BrN₃ (350.21): C, 61.73; H, 3.45; Br, 22.82; N, 12.00.

Found: C, 61.71; H, 3.49; Br, 22.82; N, 12.00.

7-Iodo-3,5-diphenylpyrazolo[1,5-a]pyrimidine(100)

A mixture of 7-chloro-5,7-diphenylpyrazolo[1,5-a]pyrimidine (98) (1.53 g, 5 mmol) and 57 % aq HI (20 ml) was stirred at room temperature for 3 days, the mixture was diluted with H₂O (40 ml) and the mixture was extracted with CHCl₃ (3 × 40ml): The combined organic layers were washed with saturated aq Na₂S₂O₃ (2 × 30ml), 10 % aq Na₂CO₃ (2 × 30ml) and brine (30 ml). After dryed with anhydrous MgSO₄ and evaporated the solvent,1.90 g yellow crystal was obtained, yield 95 %, mp 172-3 °C.

1H-NMR(CDCl₃), δ(ppm): 7.86 (s, 1 H, H-6), 8.51 (s, 1 H, H-2), 7.27-8.51 (m, 10 H, Ar-H).

13C-NMR ( CDCl₃ ), δ(ppm): 103.94 C, 112.79 C, 117.45 CH(C-6), 126.40 CH, 126.52 CH, 127.43 CH, 128.79 CH, 128.78 CH, 129.02 CH, 130.72 CH, 132.09 C, 135.90 C, 142.60 CH (C-2), 143.90 C, 154.47 C.

Anal. Calcd for C₁₈H₁₂IN₃ (397.21): C, 54.43; H, 3.05; I, 31.95; N, 10.58.

Found: C, 54.64; H, 2.89; I, 31.90; N, 10.66.

Synthesis of 5,7-dichloro-pyrazolo[1,5-a]pyrimidines
5,7-dichloro-3-phenylpyrazolo[1,5-a]pyrimidines(101)

To a solution of 5,7-dihydroxy-2-phenylpyrazolo[1,5-a]pyrimidine 91 (2.20 g, 10 mmol) in phosphoryl chloride 30 ml, N,N-dimethylaniline 3 ml (as catalyst) was added, the resulting solution was heated at reflux for 20 hours, the mixture was evaporated in vacuum, 30 ml ice was added in the residue slowly and carefully, the mixture was extracted with ethyl acetate (3 × 40 ml), the combined organic phase was then washed with saturated aqueous sodium bicarbonate (2 × 30 ml), and dried with anhydrous MgSO₄, the solvent was evaporated, and the crude product was purified by recrystallization with hexane as solvent, and a yellow needle crystal 1.40 g was obtained, yield 53 %, mp 153-155 °C

1H-NMR (CDCl₃), δ(ppm): 6.91 (s, 1 H, H-6), 7.20-7.91 (m, 5 H, Ph-H), 8.44 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm):108.80 CH(C-6), 112.51 C, 126.46 CH, 127.16 CH, 128.89 CH, 130.46 C, 140.03 C, 144.10 CH(C-2), 149.18 C.

Anal. Calcd. for C₁₂H₇Cl₂N₃: C, 54.57; H, 2.67; Cl, 26.85; N, 15.91.

Found: C, 54.80; H, 2.69; Cl, 26.99; N, 15.83.

5,7-dichloro-2-methylpyrazolo[1,5-a]pyrimidines(102)

To a solution of 5,7-dihydroxy-3-methylpyrazolo[1,5-a]pyrimidine (6.60 g, 40 mmol) in phosphoryl chloride 60 ml, N,N-dimethylaniline 5 ml was added, the resulting red solution was refluxed for 20 hours, the mixture was evaporated in vacuum, 100ml ice was added in the residue slowly, and extracted with ethyl acetate (5 × 60 ml), the combined organic phase was then washed with saturated aqueous sodium bicarbonate (4 × 50 ml), and dried with anhydrous Na₂SO₄, the solvent was evaporated, and the crude product was purifed by recrystallization with hexane as solvent, and provided a yellow needle crystal 4.57 g, yield 57 %, mp 93-95 °C.

1H-NMR (CDCl₃), δ(ppm): 2.56 (s, 3 H, CH₃), 6.52 (s, 1 H, H-6), 6.89 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm):14.47 CH3, 98.08 CH(C-6), 107.49 CH(C-2), 139.15 C, 148.74 C, 148.94 C, 157.12 C

Anal. Calcd. for C₇H₅ClN₃: C, 41.61; H, 2.49; Cl, 35.09; N, 20.80.

Found: C, 41.65; H, 2.57; Cl, 35.14; N, 20.72.

Synthesis of 3-halo-2,5,7-trisubstituted-pyrazolo[1,5-a]pyrimidines
3-Bromo-5-methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine(103)

A solution of 5-methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine 88a (2.85 g, 10 mmol), NBS (1.98 g, 11.0 mmol) in 30 ml CCl₄ was stirred at 50 °C for 0.5 h. After cooled, the solution was filtered and petroleum ether was added to the filtrate, causing precipitation of 7. The product 3.15 g was collected as a light yellow crystal, yield 87 %, mp 136-138 °C.

1H-NMR(CDCl₃), δ(ppm): 2.64 ( s, 3 H, CH₃), 6.77 (s, 1 H, H-6), 7.36-8.44 (m, 10 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 25.01 CH₃, 81.97 C, 109.29 CH(C-6), 128.41 CH, 128.63 CH, 128.92 CH, 129.03 CH, 129.45 CH, 130.29 C, 131.20 CH, 132.08 C, 146.08 C, 147.50 C, 152.44 C, 160.12 C.

Anal. Calcd for C₁₉H₁₄BrN₃ (364.24): C, 62.63; H, 3.87; Br, 21.93; N, 11.53.

Found: C, 62.65; H, 4.01; Br, 22.63; N, 11.66.

3-iodo-2,5,7-substituted-pyrazolo[1,5-a]pyrimidine(104a-104h)

General Procedure:

A 50ml round flask was chargedwith10 mmolappropriate pyrazolo[1,5-a]pyrimidine 88, N-iodosuccinimide, NIS (2.48 g, 11.0 mmol) and 20 ml dry THF. The mixture was heated at reflux 24 h. After the mixture was cooled, satd. aq. Na₂S₂O₃ (20 ml) was added and stirred for 30 min, then the mixture was extracted with AcOEt (4 × 40 ml). The combined organic layer was dried with anhydrous MgSO₄, the solvent was evaporated and the crude products purified by column chromatography on silica gel using hexane-ethyl acetate (4/1) as eluting solvent and provided a pure yellow or orange product.

3-Iodo-5-methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine(104a)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (8/1→3/1) as eluting solvent, and provided a light yellow solid, yield 70 %, mp 164-6 °C.

1H-NMR(CDCl₃), δ(ppm): 2.72 (s, 3 H, CH₃), 6.84 (s, 1 H, H-6), 7.55-8.09 (m, 10 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 25.03 CH₃, 49.02 C, 109.40CH(C-6), 126.58 CH, 128.88 CH, 128.96 CH, 129.41 CH, 129.65 CH, 130.33 CH, 131.13 C, 133.21 C, 146.24 C, 150.06 C, 155.50 C, 160.42 C.

HRMS(EI) calcd for C₁₉H₁₄IN₃ (M⁺) 411.02325, found 411.02322.

Anal. Calcd. for C₁₉H₁₄IN₃: C, 55.49; H, 3.43; I, 30.86; N, 10.22.

Found: C, 55.87; H, 3.52; I, 30.56; N, 10.18.

3-Iodo-2-(4-chlorophenyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidine(104b)

The crude product was purified by column chromatography on silica gel, eluenting with hexane:ethyl acetate (8/1→3/1), and a light yellow solid was obtained, yield 69 %, mp 166-8 °C.

1H-NMR(CDCl₃),δ(ppm): 2.71 (s, 3 H, CH₃), 6.84 (s, 1 H, H-6), 7.41-8.04 (m, 9 H, Ar-H).

13C-NMR(CDCl₃),δ(ppm): 25.03 CH₃, 48.90 C, 109.60CH(C-6), 128.53 CH, 128.91 CH, 129.39 CH, 130.07 CH, 131.21 CH, 131.32 C, 135.03 C, 137.50 C, 146.24 C, 150.10 C, 154.28 C, 160.61 C.

Anal. Calcd. for C₁₉H₁₃ClIN₃: C, 51.20; H, 2.94; N, 9.43.

Found: C, 50.98; H, 3.15; N, 9.43.

3-Iodo-2-Methyl-5,7-diphenylpyrazolo[1,5-a]pyrimidine(104c)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (8/1→3/1) as eluting solvent, and a yellow solid was obtained, yield 78 %, mp 138-40 °C.

H NMR(CDCl₃), δ(ppm): 2.53 (s, 3 H, CH₃), 7.30 (s, 1 H, H-6), 7.49-8.18 (m, 10 H, Ar-H).

13C NMR(CDCl₃), δ(ppm): 15.34 CH₃, 53.24 C, 105.20 CH(C-6), 127.36 CH, 128.73 CH, 128.92 CH, 129.46 CH, 130.46 CH, 130.85 C, 131.13 CH, 137.06 C, 146.80 C, 149.46 C, 156.54 C, 156.75 C.

Anal. Calcd. for Calcd. for C₁₉H₁₄IN₃: C, 55.49; H, 3.43; I, 30.86; N, 10.22.

Found: C, 55.52; H, 3.64; I, 31.23; N, 10.27.

3-Iodo-7-(4-Chloro-phenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine(104d)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (8/1→3/1) as eluting solvent and a light yellow solid was obtained, yield 83 %, mp 63-5 °C.

1H-NMR(CDCl₃), δ(ppm): 2.70 (s, 3 H, CH₃), 6.80 (s, 1 H, H-6), 7.45-8.05 (m, 9 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 25.02 CH₃, 49.26 C, 109.20 CH(C-6), 128.33 CH, 128.80 CH, 128.90 CH, 129.06 CH, 130.61 C, 130.75 CH, 132.67 C, 137.30 C, 144.96 C, 150.02 C, 155.54 C, 160.37 C

Anal. Calcd. for C₁₉H₁₃ClIN₃: C, 51.20; H, 2.94; N, 9.43.

Found: C, 50.96; H, 3.09; N, 9.46.

3-Iodo-2,5-dimethyl-7-phenylpyrazolo[1,5-a]pyrimidine(104e)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (8/1→3/1) as eluenting solvent; and a yellow solid was obtained, yield 63 %, mp 90-1 °C.

1H-NMR(CDCl₃), δ(ppm): 2.49 (s, 3 H, CH₃), 2.67 (s, 3 H, CH₃) , 6.73 (s, 1 H, H-6), 7.54-7.99 (m, 5H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 15.24 CH₃, 24.91 CH₃, 51.52 C, 108.69 CH(C-6), 128.64 CH, 129.23 CH, 130.85 C, 131.06 CH, 146.08 C, 149.27 C, 156.10 C, 160.09 C.

Anal. Calcd. for C₁₄H₁₂IN₃: C, 48.16; H, 3.46; I, 36.34; N, 12.03.

Found: C, 48.23; H, 3.50; I, 36.38; N, 12.14.

3-Iodo-2,5,7-trimethylpyrazolo[1,5-a]pyrimidine(104f)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (8/1→3/1) as eluting solvent; and a brown solid was obtained, yield 45 %, mp 132-3°C.

1H-NMR(CDCl₃), δ(ppm): 2.51 (s, 3 H, CH₃), 2.60 (s, 3 H, CH₃), 2.70 (s, 3 H, CH₃), 6.53 (s, 1 H, H-6).

13C-NMR(CDCl₃), δ(ppm): 15.09 CH₃, 16.62 CH₃, 24.79 CH₃, 51.10 C, 108.77 CH(C-6) , 144.85 C, 148.73 C, 155.24 C, 160.01 C.

Anal. Calcd. for C₉H₁₀IN₃: C, 37.65; H, 3.51; I, 44.20; N, 14.64.

Found: C, 37.48; H, 3.72; I, 43.63; N, 14.60.

3-Iodo-2,5,7-triphenylpyrazolo[1,5-a]pyrimidine(104g)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (8/1→3/1)as eluting solvent; and a yellow solid was obtained, yield 81 %, mp 202-3 °C.

1H-NMR(CDCl₃), δ(ppm): 7.24 (s, 1 H, H-6), 7.24-8.24 (m, 15 H, Ar-H).

13C-NMR(CDCl3), δ(ppm): 50.67 C(C-3), 105.91 CH(C-6), 127.40 CH, 128.65 CH, 128.86 CH, 128.92 CH, 129.52 CH, 130.57 CH,130.82 C, 131.18 CH, 132.83 C, 136.99 C, 146.93 C, 150.2 C, 155.98 C, 156.99 C.

Anal. Calcd. for C₂₄H₁₆IN₃: C, 60.90; H, 3.41; I, 26.81; N, 8.88.

Found: C, 60.64; H, 3.45; I, 27.01; N, 8.82.

3-Iodo-5,7-diphenylpyrazolo[1,5-a]pyrimidine(104h)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (10/1→4/1)as eluting solvent, and a yellow solid was obtained, yield 90 %, mp 160-1 °C.

1H NMR(CDCl₃), δ(ppm): 7.31 (s, 1 H, H-6), 7.44-8.15 (m, 10 H, Ar-H), 8.09 (s, 1 H, H-2).

13C NMR(CDCl₃), δ(ppm): 50.24 C(C-3), 105.74 CH(C-6), 127.46 CH, 128.80 CH, 128.98 CH,129.03 CH, 129.26 CH, 130.69 CH, 131.24 C, 136.90 C, 147.43CH(C-2), 149.01 C, 149.18 C, 157.22 C.

Anal. Calcd. for C₁₈H₁₂IN₃: C, 54.43; H, 3.05; I, 31.95; N, 10.58.

Found: C, 54.54; H, 3.18; I, 31.34; N, 10.39.

Synthesis of 5-bromomethyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine (105)

To a solution of 5-methyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine (89b) (1.43 g, 5 mmol), NBS (1.07 g, 6.0 mmol) in 20 ml CCl₄, catalytic amount of AIBN (80 mg) was added, the mixture was heated at reflux for 3 h, after the mixture was cooled, then filtered, petroleum ether (40-60 °C) was added to the filtrate, the precipitate was collected and washed with petroleum ether, 1.05 g orange solid was obtained, yield 58 %, mp 131-3 °C.

1H-NMR(CDCl₃), δ(ppm): 4.57 (s, 2 H, CH₂), 7.00 (s, 1 H, H-6), 7.16-8.04 (m, 10 H, Ar-H), 8.40 (s, 1 H, H-2).

13C-NMR(CDCl₃), δ(ppm): 33.31 CH₂, 107.58 CH(C-6), 111.11 C, 126.53 CH, 128.71 CH, 128.78 CH, 129.21 CH, 129.27 CH, 130.82 C, 131.26 CH, 131.82 C, 143.11 CH(C-2), 145.24 C, 147.48 C, 156.29 C.

Anal. Calcd for C₁₉H₁₄BrN₃ (364.24): C, 62.63; H, 3.87; Br, 21.93; N, 11.53.

Found:C, 62.65; H, 4.03; Br, 21.83; N, 11.60.

Synthesis of 3-alkenylpyrazolo[1,5-a]pyrimidines (Heck cross-coupling reactions)
Substituted 3-alkenylpyrazolo[1,5-a]pyrimidines 106a-h, 107a-c, 108, 109, 110, 111;

General Procedure:

A 50 ml round flask was chargedwith3-iodopyrazolo[1,5-a]pyrimidine 104 (0.5 mmol), Pd(PPh₃)₂Cl₂(18 mg, 0.025 mmol), MeCN (15 mL), triethylamine (203 mg, 2 mmol) and the corresponding alkene (1.5 mmol). The mixture was refluxed under argon for 24 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel.

Substituted pyrazolo[1,5-a]pyrimidin-3-yl-acrylic acid methyl ester (106a-h)

3-(5-Methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylic acid methyl ester(106a)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (2/1) as eluting solvent; and a yellow solid was obtained, yield 91 %, mp 155-6 °C.

1H-NMR(CDCl₃), δ(ppm): 2.73 (s, 3 H, CH₃), 3.80 (s, 3 H, CH₃), 6.92 (s, 1 H, H-6), 7.31 (d, 1 H, J = 16Hz, =C-H), 7.98 (d, 1 H, J = 16Hz, =C-H), 7.47-8.10 (m, 10 H, Ar-H).

13C-NMR(CDCl₃), δ(ppm): 25.08 CH₃, 51.97 CH₃, 102.97 C, 109.74 CH(C-6), 116.20 CH(=CH), 128.66 CH, 128.73 CH, 128.88 CH, 129.05 CH, 129.52 CH, 130.60 C, 131.19 CH, 132.40 C, 135.15 CH(=CH), 146.26 C, 148.56 C, 157.15 C, 160.80 C, 168.81C(C=O).

HRMS( EI ) calcd for C₂₃H₁₉N₃O₂ (M⁺) 369.14773, found 369.14773.

Anal. Calcd. for C₂₃H₁₉N₃O₂: C 74.78; H, 5.18; N, 11.37.

Found: C, 74.89; H, 5.33; N, 11.17.

3-[2-(4-Chloro-phenyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-3-yl]-acrylic acid methyl ester(106b)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (2/1) as eluting solvent , and a yellow solid was obtained, yield 93 %, mp 149-51 °C.

1H-NMR(CDCl₃), δ(ppm): 2.73 (s, 3 H, CH₃), 3.81 (s, 3 H, CH₃), 6.93 (s, 1 H, H-6), 7.30 (d, 1 H, J = 15.4Hz, =C-H), 7.92 (d, 1 H, J = 15.4Hz, =C-H), 7.48-8.21 (m, 9 H, Ar-H)

13C-NMR(CDCl₃),δ(ppm): 25.08 CH₃, 51.44 CH₃, 102.99 C, 106.38 CH(C-6), 116.59 CH(=CH), 128.70 CH, 128.83 CH, 129.49 CH, 130.73 CH, 130.90 C, 131.27 CH, 134.58 CH(=CH), 135.28 C, 146.28 C, 148.25 C, 155.86 C, 161.00 C, 168.68 C(C=O).

Anal. Calcd. for C₂₃H₁₉ClN₃O₂: C, 68.40; H, 4.49; Cl, 8.78; N, 10.40.

Found: C, 68.41; H, 4.56; Cl, 9.15; N, 10.34.

3-(2-Methyl-5,7-diphenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylic acid methyl ester(106c)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (3/1) as eluting solvent; and a orange solid was obtained, yield 89 %, mp 164-5 °C.

1H-NMR(CDCl₃), δ(ppm): 2.60(s, 3H, CH₃), 3.85(s, 3 H, CH₃), 7.11(d, 1H, J =16Hz, =C-H), 7.26(s, 1H, H-6), 7.97(d, 1H, J =16 Hz, =C-H), 7.40-8.24(m, 10H, Ar-H)

13C-NMR(CDCl₃),δ(ppm): 13.63 CH₃, 51.44 CH₃, 104.76 C, 105.50 CH(C-6), 114.87 CH(=CH), 127.47 CH, 128.79 CH, 129.42 CH, 129.63 CH, 130.79 CH, 131.00 C, 131.29 CH, 134.48 CH(=CH), 136.87 C, 146.85 C, 148.50 C, 156.54 C, 157.25 C, 168.76 C(C=O).

Anal. Calcd. for C₂₃H₁₉N₃O₂: C, 74.78; H, 5.18; N, 11.37.

Found: C, 74.30; H, 5.31; N, 11.35.

3-[7-(4-Chloro-phenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl]-acrylic acid methyl ester(106d)

The crude product was purified by column chromatography on silica gel, using hexane:ethyl acetate (2/1) as eluting solvent; and a yellow solid was obtained, yield 94 %, mp 162-4 °C;

1H-NMR(CDCl₃), δ(ppm): 2.72 (s, 3 H, CH₃), 3.80 (s, 3 H, CH₃), 6.89 (s, 1 H, H-6), 7.30 (d, 1 H, J = 16 Hz, =C-H), 7.97 (d, 1 H, J = 16 Hz, =C-H), 7.47-8.06 (m, 9 H, Ar-H).

13C-NMR(CDCl₃),δ(ppm): 25.07 CH₃, 51.40 CH₃, 103.09 C, 109.50 CH(C-6), 116.48 CH(=CH), 128.77, 128.97, 128.90, 129.14, 129.46, 130.86, 132.25, 134.94 (=CH), 137.41, 144.99, 148.48, 157.16, 160.75, 168.74 (C=O).

Anal. Calcd. for C₂₃H₁₉ClN₃O₂: C, 68.40; H, 4.49; Cl, 8.78; N, 10.40.

Found: C, 68.44; H, 4.64; Cl, 8.53; N, 10.28.

3-(2,5-Dimethyl-7-phenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylic acid methyl ester(106e)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate(4/1) as eluting solvent; and a yellow solid was obtained, yield 90 %, mp 194-6 °C.

1H-NMR(CDCl₃), δ(ppm): 2.57 (s, 3 H, CH₃), 2.58 (s, 3 H, CH₃), 3.82 (s, 3 H, CH₃), 6.81 (s, 1 H, H-6), 7.01 (d, 1 H, J = 16 Hz, =C-H ), 7.91 (d, 1 H, J = 16Hz, =C-H), 7.57-8.01 (m, 5 H, Ar-H).

13C-NMR(CDCl₃),δ(ppm): 13.58 CH₃, 24.96 CH₃, 51.39 CH₃, 103.68 C, 109.11 CH(C-6), 114.43 CH(=C-H), 128.71CH, 129.35 CH, 130.83 C, 131.16 CH, 134.56 CH(=C-H), 146.04 C, 148.37 C, 155.36 C, 160.70 C, 168.85 C(C=O).

Anal. Calcd. for C₁₈H₁₇N₃O₂: C, 70.34; H, 5.58; N, 13.67.

Found: C, 70.23; H, 5.57; N, 13.76.

3-(2,5,7-Trimethylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylic acid methyl ester(106f)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (4/1) as eluting solvent; and a light yellow solid was obtained, yield 62 %, mp 171-3 °C;

1H-NMR(CDCl₃), δ(ppm): 2.58 (s, 3 H, CH₃), 2.60 (s, 3 H, CH₃), 2.70 (s, 3 H, CH₃), 3.81 (s, 3 H, CH₃), 6.60 (s, 1 H, H-6), 6.98 (d, 1 H, J = 16 Hz, =C-H), 7.86 (d, 1 H, J = 16 Hz, =C-H).

13C-NMR(CDCl₃), δ(ppm): 13.38 CH₃, 17.06 CH₃, 24.80 CH₃, 51.37 CH₃, 103.71 C, 109.27 CH(C-6), 114.30 CH(=C-H), 134.60 CH(=C-H), 145.29 C, 147.43 C, 155.06 C, 160.40 C, 168.83 C(C=O).

Anal. Calcd. for C₁₃H₁₅N₃O₂: C, 63.66; H, 6.16; N, 17.13.

Found: C, 63.40; H, 6.21; N, 17.05.

3-(2,5,7-Triphenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylic acid methyl ester(106g)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (2/1) as eluting solvent; and a yellow solid was obtained, yield 90 %, mp 215-6 °C;

1H-NMR(CDCl₃), δ(ppm): 3.83 (s, 3 H, CH₃), 7.26 (s, 1H, H-6), 7.54 (d, 1 H, J = 19Hz, =C-H), 8.05 (d, 1 H, J = 19 Hz, =C-H), 7.59-8.27 (m, 15 H, Ar-H).

13C-NMR(CDCl₃),δ(ppm): 51.43 CH₃, 104.03 C(C-3), 106.16 CH(C-6), 116.66 CH(=CH), 127.90 CH, 128.76 CH, 128.80 CH, 129.20 CH, 129.55 CH, 129.58 CH, 129.81 CH, 130.41 CH, 130.64 C, 130.91 CH, 132.34 C, 135.04 CH(=CH), 136.86 C, 147.07 C, 148.71 C, 157.34 C, 157.40 C, 168.82 C(C=O).

Anal. Calcd. for C₂₈H₂₁N₃O₂: C, 77.94; H, 4.91; N, 9.74.

Found: C, 77.33; H, 5.01; N, 9.58.

3-(5,7-Diphenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylic acid methyl ester (106h)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate(6/1) as eluting solvent, and a yellow solid was obtained, yield 86 %, mp.134-5 °C.

1H-NMR(CDCl₃), δ(ppm): 3.77 (s, 3 H, CH₃), 6.87 (d, 1 H, J = 16 Hz, =C-H), 7.39 (s, 1H, H-6), 7.95 (d, 1 H, J = 16 Hz, =C-H), 7.47-8.15 (m, 10 H, Ar-H), 8.23 (s, 1 H, H-2).

13C NMR(CDCl3), δ(ppm): 51.50 CH₃, 106.11 CH(H-6), 107.20 C(C-3), 105.74 CH(C-6), 115.49 CH(=CH), 127.52 CH, 128.84 CH, 129.07 CH, 129.11 C, 129.34 CH, 130.95 CH, 131.34 CH, 134.42 CH(=CH), 136.70 C, 145.58 CH(C-2), 147.55 C, 157.55 C, 168.39 C(C=O).

Anal. Calcd. for C₂₂H₁₇N₃O₂: C, 74.35; H, 4.82; N, 11.82.

Found: C, 74.17; H, 4.92; N, 11.71.

Substituted pyrazolo[1,5-a]pyrimidin-3-yl-acrylonitrile (107a-107c)

3-(5-Methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylonitrile(107a)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (2/1) as eluting solvent; and a yellow solid was obtained, yield 52 %, mp 206-8 °C.

1H-NMR(CDCl₃), δ(ppm): 2.73( s, 3 H, CH₃), 6.85(d, 1H, J =16.2 Hz, =C-H ), 6.96 (s, 1 H, H-6 ), 7.59 (d, 1 H, J = 16.2 Hz, =C-H), 7.48-8.10 (m, 10 H, Ar-H).

13C-NMR(CDCl₃),δ(ppm): 25.06 CH₃, 93.95 C, 102.56 CH(=CH), 110.04 CH(C-6), 120.26 C, 127.49 C, 128.72 CH, 128.84 CH, 129.38 CH, 129.41 CH, 129.54 CH, 130.29 C, 131.39 CH, 140.48 CH(=CH), 146.56 C, 148.62 C, 156.68 C, 161.44 C(CN).

HRMS( EI ) calcd for C₂₂H₁₆N₄ (M⁺) 336.13750, found 369.13753.

Anal. Calcd. for C₂₂H₁₆N₄: C, 78.55; H, 4.79; N, 16.66.

Found: C, 78.80; H, 4.82; N, 16.38.

3-[2-(4-Chloro-phenyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-3-yl]-acrylonitrile (107b)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (2/1) as eluting solvent, and a yellow solid was obtained, yield 43 %, mp180-2 °C.

1H-NMR(CDCl₃), δ(ppm): 2.74(s, 3 H, CH₃), 6.86(d, 1 H, J =15.6 Hz, =C-H), 6.98(s, 1H, H-6), 7.49(d, 1 H, J = 15.6 Hz, =C-H), 7.46-8.07 (m, 9 H, Ar-H).

13C-NMR(CDCl₃),δ(ppm): 25.08 CH₃, 94.46 CH(=CH), 102.56 C, 110.23 CH (C-6), 120.08 C, 128.77 CH, 129.13 CH, 129.52 CH, 130.19 C, 130.3, 130.62 CH, 131.49 CH, 135.67 C, 139.96 CH(=CH), 146.61C, 148.62 C, 155.41 C, 161.67 C(CN).

Anal. Calcd. for C₂₂H₁₅ClN₄: C, 71.75; H, 4.08; Cl, 9.56; N, 15.11.

Found: C, 72.29; H, 4.17; Cl, 9.21; N, 14.92.

3-(2-Methyl-5,7-diphenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylonitrile(107c)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (2/1) as eluting solvent; and a orange solid was obtained, yield 79 %, mp 164-5 °C.

1H-NMR(CDCl₃), δ(ppm): 2.56 (s, 3 H, CH₃), 6.73 (d, 1 H, J = 16.2 Hz, =C-H), 7.44 (s, 1 H, H-6), 7.54 (d, 1 H, J = 16.2 Hz, =C-H), 7.56-8.19 (m, 10 H, Ar-H).

13C-NMR(CDCl₃),δ(ppm): 13.15 CH₃, 92.75 CH(=CH), 104.41 C, 105.83 CH(C-6), 120.33 C, 127.45 CH, 128.86 CH, 129.13 CH, 129.46 CH, 130.71 C, 131.10 CH, 131.49 CH, 136.59 C, 139.71CH(=CH), 147.18 C, 148.48 C, 155.45 C, 157.88 C(CN).

Anal. Calcd. for C₂₂H₁₆N₄: C, 78.55; H, 4.79; N, 16.66.

Found: C, 78.71; H, 4.86; N, 16.52.

5,7-Diphenyl-3-styrylpyrazolo[1,5-a]pyrimidine(108)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate(4/1) as eluting solvent , and a red solid was obtained, yield 36 %, mp 174-6 °C.

1H-NMR(CDCl₃), δ(ppm): 7.30 (s, 1 H, H-6), 7.41 (d, 1 H, J = 16.2 Hz, =C-H), 7.55 (d, 1 H, J = 16.2 Hz, =C-H), 7.19-8.21 (m, 15 H, Ar-H), 8.29 (s, 1 H, H-2).

¹³C-NMR(CDCl₃),δ(ppm): 105.26 CH(C-6), 109.68 C(C-3), 117.68(=CH), 126.03 CH, 126.87 CH, 127.25 CH, 128.57 CH, 128.70 CH, 128.89 CH, 129.20 CH, 130.39 CH, 130.98CH(=CH), 131.25 CH, 137.20 C, 138.19 C, 143.13 CH (C-2) , 143.15 C, 146.22 C, 146.84 C, 155.71 C

Anal. Calcd. for C₂₆H₁₉N₃: C, 83.62; H, 5.13; N, 11.25.

Found: C, 83.84; H, 5.15; N, 11.07.

3-(5,7-Diphenylpyrazolo[1,5-a]pyrimidin-3-yl)-acrylic acid 2-dimethylamino-ethyl ester(109)

The crude product was purified by column chromatography on silica gel, using ethyl acetate:methanol (5/1) as eluting solvent and provided a yellow glass material, yield 57 %.

1H-NMR(CDCl₃), δ(ppm):2.26(s, 3H, CH₃), 2.61(t,2H, J=5.9 Hz), 4.25 (t, 2H, J=5.9 Hz , CH₂), 6.81(d, 1H, J=15.8Hz, =CH), 7.30(s, 1H, H-6), 7.39-7.48(m, 6H, Ph-H), 7.89-7.92(dd, 2H, Ph-H), 7.91(d, 1H, J=15.8Hz, =CH), 8.16(s, 1H, H-2).

13C-NMR(CDCl₃), δ(ppm): 45.00 CH₃, 57.83 CH₂, 61.83 CH₂, 105.97 CH, 107.16 C, 115.45 CH, 127.43 CH, 128.73 CH, 128.95 CH, 129.31 CH, 130.87 CH, 131.26 CH, 134.46 CH, 136.54 C, 145.35 C, 145.37 CH, 147.36, 147.53 C, 157.39 C, 167.84 C.

HRMS (EI) calcd for C₁₉H₁₅N₃(M⁺) 412.18993, found 412.18964.

3-(2,5-Dimethyl-7-phenylpyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-acrylic acid methyl ester (110)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (4/1) as eluting solvent; and provided a yellow solid, yield 27 %, mp. 122-3 °C;

1H-NMR(CDCl₃), δ(ppm): 2.08 (d, 3 H, J = 1.5Hz, =C-CH₃), 2.43 (s, 3 H, CH₃), 2.61 (s, 3 H, CH₃), 3.80 (s, 3 H, O-CH₃), 6.72 (s, 1 H, H-6), 7.51-7.54(m, 3 H, Ph-H), 7.71 (d, 1 H, J = 1.5 Hz, =C-H), 7.98 (dd, 2 H, Ph-H).

13C-NMR(CDCl₃), δ(ppm):13.95CH₃, 15.79 CH₃, 24.95 CH₃, 51.87 CH₃, 10438 C, 108.33 CH(C-6), 128.17 C, 128.66 CH, 128.71 CH, 129.29 CH, 130.99 CH(=C-H), 131.27 C, 145.76 C, 146.93 C, 154.24 C, 159.04 C, 169.12 C.

Anal. Calcd. for C₁₉H₁₉N₃O₂: C, 71.01; H, 5.96; N, 13.08.

Found: C, 71.13; H, 6.00; N, 13.00.

2-(5,7-Diphenylpyrazolo[1,5-a]pyrimidin-3-ylmethylene)-succinic acid dimethyl ester(111)

The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (6/1) as eluting solvent; and get yellow solid, yield: 14 %, mp. 128-9 °C;

1H-NMR(CDCl₃), δ(ppm): 3.63 (s, 3 H, CH₃), 3.80 (s,3 H, CH₃), 3.82 (s, 2 H, CH₂), 7.39 (s, 1H, H-6), 7.46-7.54 (m, 6 H, Ph-H), 7.96 (dd, 2 H, Ph-H), 8.12 (dd, 2 H, Ph-H), 8.27 (s, 1H, =C-H), 8.29 (s, 1H, H-2).

13C-NMR(CDCl₃), δ(ppm):34.45 CH₂, 52.15 CH₃, 52.21 CH₃, 106.36 CH(C-6), 106.98 C, 120.71C, 127.50 CH, 128.83 CH, 129.02 CH, 129.32 CH, 130.76 C, 130.94 CH, 131.13 CH, 131.36 CH(=C-H), 136.74 C, 144.90 CH(C-3), 147.37 C, 148.20 C, 157.39 C, 168.37 C, 171.62 C.

Anal. Calcd. for C₂₅H₂₁N₃O₄: C, 70.25; H, 4.95; N, 9.83.

Found: C, 70.38; H, 5.09; N, 9.75.

Synthesis of 3-alkynylpyrazolo[1,5-a]pyrimidines and related compounds (Sonogashira cross-coupling reaction)
(1) Pd/C catalyzed Sonogashira reaction

Synthesis of substituted 3-alkynylpyrazolo[1,5-a]pyrimidines (113a-k, 114)

General Procedure:

A 25ml Schlenk flask was charged with 3-iodopyrazolo[1,5-a]pyrimidine (104a-d,or 104h) (0.5 mmol), K₂CO₃ (166 mg, 1.2 mmol), CuI (10 mg, 0.05 mmol), 10% Pd/C (22 mg, 0.02 mmol ), and PPh₃ (21 mg, 0.08 mmol) in DME (5 ml) and water (5 ml). Argon was passed through the flask 3 times and the mixture was stirred at 25 °C for 0.5 h, then the alkyne (0.6 mmol) was added via syringe. The mixture was heated at 80 °C for 24 h, then cooled to RT, and filtered through a pad of celite, washing with EtOAc, the combined crude solution was washed with water (2 × 30 ml) twice. The organic layer was dried with anhydrous MgSO₄, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with EtOAc:MeOH (1:0→6:1) for products 113a-113e, with hexane:EtOAc (1:1→0:1) for products 113f-113k.

3-(5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-prop-2-ynyl]-dimethylamine(113a)

Yellow solid, yield 91 %, mp 102-3 °C

1H-NMR (CDCl₃), δ(ppm): 2.41 (s, 6 H, 2CH₃), 3.58 (s, 2 H, CH₂), 7.32 (s, 1 H, H-6), 7.43-8.13 (m, 10 H, Ph-H), 8.15 (s, 1H, H-2).

13C-NMR (CDCl₃), δ(ppm):44.15 CH₃, 49.03 CH₂,76.23 C, 87.69 C, 93.99 C, 105.89 CH(H-6), 127.50 CH, 128.79 CH, 128.93 CH, 129.26 CH, 129.36 C, 130.71 CH,130.92 C, 131.24 CH, 136.93 C, 147.34 CH(C-2), 150.11 C, 157.01 C.

Anal. Calcd. for C₂₃H₂₀N₄(352.43): C, 78.38; H, 5.72; N, 15.66.

Found: C, 78.50; H, 5.94; N, 15.66.

Dimethyl-[3-(2-methyl-5,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-prop-2-ynyl]-amine(113b)

Yellow solid, yield 76 %, mp 109-11 °C

1H NMR (CDCl₃), (ppm): 2.50 (s, 3 H, CH₃), 2.64 (s, 6 H, 2CH₃), 3.87(s, 2 H, CH₂), 7.27 (s, 1 H, H-6), 7.43-7.52 (m, 6 H, Ph-H), 7.96-8.00 (dd, 2 H, Ph-H), 8.08-8.11 (dd, 2 H, Ph-H).

13C NMR (CDCl₃) (ppm): 13.87 CH₃, 42.91 CH₃, 48.62 CH₂, 85.26 C, 92.14 C, 105.58 CH (C-6), 127.41 CH, 128.78 CH, 128.94 CH, 129.33 CH, 130.70 CH, 130.91 C, 131.29 CH, 136.95 C, 146.91 C, 150.94 C, 157.10 C, 157.65 C .

Anal. Calcd. for C₂₄H₂₂N₄(366.46): C, 78.68; H, 6.05; N, 15.29.

Found: C, 78.44; H, 6.25; N, 15.01.

Dimethyl-[3-(5-methyl-2,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-prop-2-ynyl]-amine(113c):

Yellow solid, yield 70 %, mp 152-4 °C

1H-NMR (CDCl₃), δ(ppm): 2.44 (s, 6 H, 2CH₃), 2.63 (s, 3 H, CH₃), 3.70 (s, 2 H, CH₂), 6.77 (s, 1 H, H-6), 7.35-7.51 (m, 6 H, Ph-H), 8.04 (dd, 2 H, Ph-H), 8.21 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):25.03 CH₃, 43.96 CH₃, 49.18 CH₂, 77.93 C, 88.79 C, 89.93 C, 109.50 CH(H-6), 127.81 CH, 128.41 CH, 128.59 CH, 129.18 CH, 129.47 CH, 130.53 C, 131.19 CH, 132.52 C, 146.09 C, 151.75 C, 155.56 C, 160.22 C.

HRMS (EI) calcd for C₂₄H₂₂N₄ (M⁺) 366.18445, found, 366.18447.

Anal. Calcd. for C₂₄H₂₂N₄(366.46): C, 78.68; H, 6.05; N, 15.29.

Found: C, 78.65; H, 6.28; N, 15.05.

{3-[7-(4-Chloro-phenyl)-5-methyl-2-phenyl-pyrazolo[1,5-a]pyrimidin-3-yl]-prop-2-ynyl}-dimethylamine(113d)

Yellow solid, yield 54 %, mp 177-8 °C;

1H-NMR (CDCl₃), δ(ppm): 2.44 (s, 6 H, 2CH₃), 2.71 (s, 3 H, CH₃), 3.68 (s, 2 H, CH₂), 6.84 (s, 1 H, H-6), 7.40-7.59 (m, 5 H, Ph-H), 8.09 (dd, 2 H, Ph-H), 8.26 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):25.03 CH₃, 44.35 CH₃, 49.26 CH₂, 76.50 C, 90.34 C, 90.66 C, 109.62 CH(H-6), 128.58 CH, 128.61 CH, 129.03 CH, 129.43 CH, 130.51 C, 131.16 C, 131.20 CH, 134.98 C, 146.04 C, 151.65 C, 154.20 C, 160.23 C.

Anal. Calcd. for C₂₄H₂₁ClN₃(400.90): C, 71.90; H, 5.28; Cl, 8.84; N, 13.86.

Found: C, 71.82; H, 5.42; Cl, 8.89; N, 13.58.

{3-[2-(4-Chloro-phenyl)-5-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidin-3-yl]-prop-2-ynyl}-dimethylamine(113e)

Yellow solid, yield 69 %, mp 80-2 °C

1H-NMR (CDCl₃), δ(ppm): 2.50 (s, 6 H, 2CH₃), 2.68 (s, 3 H, CH₃), 3.79 (s, 2 H, CH₂), 6.81 (s, 1 H, H-6), 7.43-7.54 (m, 5 H, Ph-H), 8.06 (dd, 2 H, Ph-H), 8.26 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):24.97 CH₃, 43.12 CH₃, 48.32 CH₂, 77.94 C, 88.41 C, 90.03 C, 109.30 CH(H-6), 127.74 CH, 128.45 CH, 128.88 CH, 129.27 CH, 130.70 C, 130.79 CH, 132.33 C, 137.32 C, 144.82 C, 151.68 C, 155.59 C, 160.21 C.

Anal. Calcd. for C₂₄H₂₁ClN₃(400.90): C, 71.90; H, 5.28; Cl, 8.84; N, 13.86.

Found: C, 72.18; H, 5.38; Cl, 9.02; N, 13.57.

3-(2-Methyl-5,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-prop-2-yn-1-ol(113f)

Yellow solid, yield 78 %, mp 152-4 °C;

1H-NMR (CDCl₃), δ(ppm): 4.58 (s, 2 H, CH₂), 7.37 (s, 1 H, H-6), 7.50-7.61 (m, 6 H, Ph-H), 8.01 (dd, 2 H, Ph-H), 8.17 (dd, 2 H, Ph-H), 8.22(s, 1H, H-2).

13C-NMR (CDCl₃), δ(ppm):51.99 CH₂, 76.10 C, 91.51 C, 93.48 C, 106.13 CH(H-6), 127.58 CH, 128.77 CH, 128.93 CH, 129.29 CH, 130.77 CH, 131.29 CH, 136.83, 147.45 CH(C-2), 150.04 C, 157.45 C.

Anal. Calcd. for C₂₁H₁₅N₃O (325.30):C, 77.52; H, 4.65; N, 12.91.

Found: C, 77.40; H, 4.80; N, 12.67.

3-(5-Methyl-2,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-prop-2-yn-1-ol(113g)

Yellow solid, yield 72 %, mp 85-6 °C

1H-NMR (CDCl₃), δ(ppm): 2.56 (s, 3 H, CH₃), 4.56 (s, 2 H, CH₂), 6.67 (s, 1 H, H-6), 7.33-7.48 (m, 6 H, Ph-H), 7.96 (dd, 2 H, Ph-H), 8.15 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):24.78 CH3, 51.94 CH₂, 77.17 C, 89.56 C, 93.58 C, 109.52 CH(H-6), 127.58 CH, 128.43 CH, 128.59 CH, 129.19 CH, 129.50 CH, 130.36 C, 131.22 CH, 132.33 C, 146.14 C, 151.62 C, 155.17 C, 160.32.

Anal. Calcd. for C₂₂H₁₇N₃O_{(339.39):C, 77.86; H, 5.05; N, 12.38.}

Found: C, 77.64; H, 5.20; N, 12.11

4-(5-Methyl-2,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-but-3-yn-1-ol(113h)

Yellow solid, yield 71 %, mp 182-3 °C

1H-NMR (CDCl₃), δ(ppm): 2.66 (s, 3 H, CH₃), 2.86 (t, 2 H, J = 6.4 Hz, CH₂), 3.91 (t, 2 H, J = 6.4 Hz, CH₂), 7.06 (s, 1 H, H-6), 7.31-7.44 (m, 6 H, Ph-H), 8.05 (dd, 2 H, Ph-H), 8.22 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 24.68 CH₂, 24.91 CH_3, 61.18 CH₂, 74.25 C, 91.47 C, 92.37 C, 106.08 CH(C-6), 127.48 CH; 127.59 CH, 128.52 CH, 128.87 CH, 129.14 CH, 130.47 CH, 132.69 C, 137.02 C, 146.24 C, 150.72 C, 155.49 C, 156.49 C.

Anal. Calcd. for C₂₃H₁₉N₃O_{(353.42):C, 73.16; H, 5.42; N, 11.89.}

Found: C, 73.28; H, 5.59; N, 11.68.

4-(5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-but-3-yn-1-ol(113i)

Yellow solid, yield 75 %, mp 132-3 °C

1H-NMR (CDCl₃), δ(ppm): 2.74 (t, 2 H, J = 6.4 Hz, CH₂), 3.80 (t, 2 H, J = 5.7 Hz, CH₂), 7.30 (s, 1 H, H-6), 7.44-7.52 (m, 6 H, Ph-H), 7.94 (dd, 2 H, Ph-H), 8.10 (dd, 2 H, Ph-H), 8.13 (s, 1H, H-2).

13C-NMR (CDCl₃), δ(ppm): 24.42 CH₂, 61.18 CH₂, 72.75 C, 90.35 C, 94.26 C, 105.94 CH(C-6), 127.54 CH; 128.78 CH, 128.96 CH, 129.28 CH, 130.71 CH, 130.94 C, 131.24 CH, 136.94 C, 147.17 CH(C-2), 147.36 C, 150.01 C, 157.07 C.

Anal. Calcd. for C₂₂H₁₇N₃O_{(339.39):C, 77.86; H, 5.05; N, 12.38.}

Found: C, 77.91; H, 5.19; N, 12.23

4-(2-Methyl-5,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-but-3-yn-1-ol(113j)

Yellow solid, yield 70 %, mp 128-9 °C

1H-NMR (CDCl₃), δ(ppm): 2.56 (s, 3 H, CH₃), 2.84 (t, 2 H, J = 6.4 Hz, CH₂), 3.88 (t, 2 H, J = 5.8 Hz, CH₂), 7.29 (s, 1 H, H-6), 7.50-7.60 (m, 6 H, Ph-H), 8.06 (dd, 2 H, Ph-H), 8.18 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 13.72 CH₃, 24.53 CH₂, 61.29 CH₂, 73.10 C, 91.64 C, 93.37 C, 105.31 CH(C-6), 127.46 CH; 128.73 CH, 128.87 CH, 129.32 CH, 130.49 CH, 131.04 C, 131.16 CH, 137.13 C, 146.69 C, 150.46 C, 156.66 C, 157.34 C.

Anal. Calcd. for C₂₃H₁₉N₃O_{(353.42):C, 73.16; H, 5.42; N, 11.89.}

Found: C, 73.32; H, 5.50; N, 11.74.

Toluene-4-sulfonic acid 4-(5-methyl-2,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-but-3-ynyl ester (113k)

Brown solid, yield 18 %, mp 158-9 °C;

1H-NMR (CDCl₃), δ(ppm): 2.36 (s, 3 H, CH₃), 2.67 (s, 3 H, CH₃), 2.95 (t, 2 H, J = 7.1 Hz, CH₂), 4.26 (t, 2 H, J = 7.1 Hz, CH₂), 6.81(s, 1 H, H-6), 7.25 (d, 2 H, J = 8.3 Hz, Ph-H), 7.42-7.45 (m, 6 H, Ph-H), 7.79 (d, 2 H, J = 8.3 Hz, Ph-H), 8.09 (dd, 2 H, Ph-H), 8.24 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):14.18 CH₃, 21.17 CH2, 24.96 CH₃, 67.99 CH₂, 74.30 C, 89.33 C, 89.83 C, 109.44 CH(C-6), 127.56 CH, 127.97 CH, 128.49 CH, 128.55 CH, 129.17 CH, 129.45 CH, 129.85 CH, 130.44 C, 131.17 CH, 132.42 C, 132.78 C, 144.86 C, 146.02 C, 151.46 C, 155.49 C, 160.16 C.

Anal. Calcd. for C₃₀H₂₅N₃O₃S (507.60):C, 70.98; H, 4.96; N, 8.28, S, 6.32.

Found: C, 70.84; H, 5.17; N, 8.05, S, 6.17.

3-(But-3-en-1-ynyl)-5-methyl-2,7-diphenyl-pyrazolo[1,5-a]pyrimidine(114)

The crude product was purified by flash column chromatography on silica, eluting with cyclohexane:EtOAc (4:1→2:1) to provide a yellow solid 123 mg, yield 36 %, mp. 186-8 °C;

1H NMR(CDCl_3,300 MHz), δ(ppm): 2.71 (s, 3 H, CH₃), 5.53 (dd, 1 H, J ₁ = 11.3 Hz, J ₂ = 2.3 Hz, CH=CH ₂), 5.77 (dd, 1 H, J ₁ = 17.9 Hz, J ₂ = 2.3Hz, CH=CH ₂), 6.19 (dd, 1H, J ₁ = 17.9 Hz, J ₂ = 11.3 Hz, CH=CH₂), 6.85 (s, 1 H, H-6), 7.40-7.58 (m, 6 H, Ph-H), 8.11 (dd, 2 H, Ph-H), 8.29 (dd, 2 H, Ph-H).

13C NMR (CDCl₃), δ(ppm): 25.0 CH₃, 81.7 C, 90.3 C, 93.9 C, 109.6 CH(C-6), 117.9 CH(CH=), 125.6 CH₂(=CH₂), 127.8 CH, 128.4 CH, 128.6 CH, 129.2 CH, 129.5 CH, 130.5 C, 131.2 CH,132.5 C, 146.1 C, 151.3 C, 155.5 C, 160.3 C.

Anal. Calcd. for C₂₃H₁₇N₃(335.40):C, 82.32; H, 5.11; N, 12.53.

Found: C, 82.07; H, 5.30; N, 12.28.

Using the same procedure, 104h reacted with 3-amino-phenylacetylene, no desired coupling product was obtained, but a nearly quantitative homo-coupling product 115 was isolated.

2-[4-(2-Amino-phenyl)-1,3-butadiynyl]phenyl-amine (115)

The crude product was purified by flash column chromatography on silica gel, eluting with cyclohexane:EtOAc (3:1 → 1:1) to afford a grey-green solid, yield: 100 %, mp.124-5°C.

1H-NMR(CDCl₃, 300MHz), δ(ppm): 3.70 (s, br, 4 H, 2NH₂), 6.69 (m, 2 H, Ph-H), 6.81 (t, 2 H, J = 1.9 Hz, Ph-H), 6.93 (dt, 2 H, J ₁ = 7.5 Hz, J ₂ = 1.2 Hz, Ph-H), 7.11 (t, 2 H, J = 7.9 Hz, Ph-H).

13C NMR (CDCl₃, 75MHz), δ(ppm):73.4 C, 81.7 C, 116.3 CH, 118.4 CH, 122.4 C(C-3), 123.0 CH, 129.4 CH, 146.3 C(C-1).

Anal. Calcd. for C₁₆H₁₂N₂( 232.28): C, 82.73; H, 5.21; N, 12.06.

Found: C, 82.84; H, 5.40; N, 12.01.

(2) Catalytic hydrogenation of 113a and 113b

General Procedure:

A 25 ml Schlenk-flask was charged with 113aor113b 0.3 mmol, 10 % Pd/C (67 mg, 0.06 mmol, 0.2 equiv) and EtOH (15ml). The mixture was stirred under hydrogen at atmospheric pressure (balloon) and room temperature for 16h. It was filtered through a pad of Celite, washed with EtOAc. The solvent was evaporated and the residue was purified by flash column chromatography on standard neutral Al₂O₃, eluting with EtOAc:MeOH(1:0→10:1) to provide the product 116a or 116b.

[3-(5,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-propyl]-dimethylamine (116a):

Yellow solid, Yield 37 %, mp 72-74 °C;

1H-NMR(CDCl_3,300 MHz), δ(ppm,): 1.95-2.06 (m, 2 H, CH₂), 2.28 (s, 6 H, 2CH₃), 2.44 (t, 2 H, J = 7.5 Hz, CH₂), 2.95 (t, 2H, J = 7.9Hz, CH₂), 7.31 (s, 1 H, H-6), 7.50-8.05 (m, 10 H, Ph-H), 8.07 (s, 1 H, H-2).

13C NMR (CDCl₃, 75MHz), δ(ppm):21.0 CH₂, 28.3 CH_2,45.5 CH_3,59.4 CH_2,104.7 CH(C-6), 110.8 C, 127.2 CH, 128.7 CH, 128.9 CH, 129.2 CH, 130.1 CH, 130.8 CH, 131.7 C, 137.7 C, 144.5 CH, 146.5 C, 147.1 C, 154.5 C.

Anal. Calcd. for C₂₃H₂₄N₄(356.46): C, 77.50; H, 6.79; N, 15.72.

Found: C, 77.62; H, 6.95; N, 15.48.

N,N-Dimethyl-[3-(2-methyl-5,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-propyl]-amine(116b)

Yellow solid, Yield 40 %, mp 93-4 °C;

1H NMR(CDCl_3,300 MHz), (ppm): 1.82-1.91 (m, 2 H, CH₂), 2.18 (s, 6 H, CH₃), 2.32 (t, 2 H, J = 7.5 Hz, CH₂), 2.40 (s, 3 H, CH₃), 2.81 (t, 2 H, J = 7.5 Hz, CH₂), 7.13 (s, 1 H, H-6), 7.40-7.49 (m, 6 H, Ph-H), 7.99-8.02 (dd, 2 H, Ph-H), 8.06-8.09 (dd, 2 H, Ph-H).

13C NMR(CDCl₃, 75MHz), (ppm): 13.2 CH₃, 20.6 CH₂, 28.3 CH₂, 45.6 CH₃, 59.6 CH₂, , 103.8 CH (C-6), 108.3 C, 127.1 CH, 128.7 CH, 128.8 CH, 129.2 CH, 129.9 CH, 130.7 CH, 131.9 C, 137.9 C, 145.7 C, 147.9 C, 153.6 C, 154.2 C.

Anal. Calcd for C₂₄H₂₆N₄(370.49): C, 77.80; H, 7.07; N, 15.12.

Found: C, 77.92; H, 7.14; N, 15.07.

(3) Other Sonogashira reaction

Synthesis of dimethyl-[4-(5-methyl-2,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-ylethynyl)-phenyl]-amine (117)

A 25 ml flask was charged with 3-iodo-5-methyl-2, 7-diphenylpyrazolo[1, 5]pyrimidine104a (206 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol), (4-ethynyl-phenyl)dimethylamine (73 mg, 0.5 mmol), and piperdine 2 ml Argon was passed three times and the mixture was heated at 80 °C for 24 h, the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel, eluting with cyclohehane:ethyl acetate (6/1→1/1), and 94 mg brown solid was obtained, yield 44 %, mp 150-2 °C.

1H-NMR (CDCl₃), δ(ppm): 2.86 (s, 3 H, CH₃), 2.98 (s, 6 H, 2CH₃), 6.69 (d, 2 H, J = 9.0 Hz, Ph-H), 7.18 (s, 1 H, H-6), 7.48-8.21 (m, 10 H, Ph-H), 8.44 (d, 2 H, J = 9.0 Hz, Ph-H).

13C NMR (CDCl₃), δ(ppm): 26.90 CH₃, 40.28 CH₃, 78.96 C, 92.42 C, 95.98 C, 105.84 CH(C-6), 111.87 CH, 127.46 CH, 127.74 CH, 128.47 CH, 128.61 C, 128.79 C, 128.99 CH, 130.34 CH, 132.57 CH, 132.94 C, 137.13 C, 146.08 C, 149.86 C, 149.98 C, 155.41 C, 155.99 C.

Anal. Calcd. for C₃₀H₂₄N₄ (428.53): C, 81.28; H, 5.65; N, 13.07.

Found: C, 81.40; H, 6.71; N, 13.18.

Synthesis of 2-[3-(2-Methyl-5,7-diphenyl-pyrazolo[1,5-a]pyrimidin-3-yl)-prop-2-ynyl]-isoindole-1,3-dione (118)

A 25 ml flask was charged with 3-iodo-2-methyl-5, 7-diphenylpyrazolo[1, 5]pyrimidine 104c (206 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol),TEA 5 ml, DMF 5 ml and N-propargyl-phthalamide 111 mg (0.6 mmol), Argon was passed three times and the mixture was heated at 50 °C for 24 h, the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel, eluting with cyclohehane:ethyl acetate (5/1→1/1), and 89 mg light brown solid was obtained, yield 38 %, mp 163-5 °C.

1H-NMR (CDCl₃), δ(ppm): 2.47 (s, 3 H, CH₃), 4.77 (s, 2 H, CH₂), 7.24 (s, 1 H, H-6), 7.42-8.14 (m, 14 H, Ph-H).

13C NMR (CDCl₃), δ(ppm): 13.74 CH₃, 28.61 CH₂, 74.24 C, 88.07 C, 92.46 C, 105.37 CH(C-6), 123.49 CH, 127.52 CH, 128.73 CH, 128.80 C, 128.88 CH, 129.32 CH, 130.54 CH, 131. 16 CH, 132.22 C, 134.07 CH, 134.32 C, 137.01 C, 146.72 C, 156.89 C, 158.23 C, 167.22 C(C=O).

Anal. Calcd. for C₃₀H₂₀N₄O₂(468.50): C, 76.91; H, 4.30; N, 11.96.

Found: C, 76.78; H, 4.51; N, 11.78.

Synthesis of substituted pyrazolo[1,5-a]pyrimidines via Suzuki cross-coupling reaction
Synthesis of 5-chloro-3,7-diphenylpyrazolo[1,5-a]pyrimidine(120)

A 50 ml Schlenk flask was charged with 5,7-dichloro-3-phenylpyrazolo[1,5-a]pyrimidine 101 (528 mg, 2 mmol), phenylboronic acid (244 mg, 2 mmol), anhydrous K₂CO₃ (331 mg, 2.4 mmol), Pd(PPh₃)₄ (70 mg, 0.06 mmol), and toluene 30 ml. Argon was passed inside the flask and the mixture was heated at 100 °C for 20 h, after cooled, the solid was filtered out, the filtrate was evaporated and the residue was separated by column chromatography on silica gel, eluting with hexane and then hexane:ethyl acetatate (10/1), the coupling product 5-chloro-3,7-diphenylpyrazolo[1,5-a]pyrimidine 120 347 mg (54 %) was first isolated, eluting with hexane:ethyl acetatate (5/1) and isolated 7-chloro-3,5-diphenylpyrazolo[1,5-a]pyrimidine 98 (138 mg yield 23 %).

Orange solid, yield 54 %, mp 121-3 °C;

1H-NMR (CDCl₃), δ(ppm): 6.80 (s, 1 H, H-6), 7.18-7.96 (m, 10 H, Ph-H), 8.38 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm): 108.20 CH(C-6), 110.82 C, 126.42 CH, 126.68 CH, 128.84 CH, 129.31 CH, 129.98 C, 131.23 C, 131.66 CH, 143.48 CH(C-2), 144.70 C, 148.35 C, 150.47 C.

Anal. Calcd for C₁₈H₁₂ClN₃ (305.76): C, 70.71; H, 3.96; Cl, 11.60; N, 13.74

Found: C, 70.77; H, 4.06; Cl, 11.62; N, 13.53.

Using the same conditions, 101 was coupled with 3 equiv. of phenylboronic acid, 3,5,7-triphenylpyrazolo[1,5-a]pyrimidine(89c) was obtained in 86 % yield. 100 or 104h was coupled with 1.5 equiv. of phenylboronic acid, 89c was obtained in 99 % and 62 % respectively.

Attempt to undergo regioselective Suzuki coupling, and chose Pd(PPh₃)₄ (0.05 equiv.) as catalyst, DME as solvent, 2 M aqueous (2 equiv.) Na₂CO₃ as base, and at 80 °C 16 h, 101 was treated with equal equivalent of phenylboronic acid, 5-chloro-3,7-diphenylpyrazolo-[1,5a]pyrimidine 120 was obtained in 72 % yield
Synthesis of substituted pyrazolo[1,5-a]pyrimidines by Nucleophilic substitution
3,7-Diphenylpyrazolo[1,5-a]pyrimidin-5-ylamine(127)

A 500 ml autoclave was charged5-Chloro-3,7-diphenylpyrazolo[1,5-a]pyrimidine 120 (162 mg, 0.53 mmol) and liquid ammonia 20ml, the mixture was heated at 100 °C for 24 h, after cooled the autoclave was opened, the residue was dissolve in 60 ml CH₂Cl₂, washed with water (2 × 30 ml), and dried with anhydrous MgSO₄, the solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate (1/1), and provided a yellow solid 126 mg, yield 83 %, mp 214-5 °C.

1H-NMR(CDCl₃), δ(ppm): 4.88 (s, 2 H, NH₂), 6.09 (s, 1 H, H-6), 7.11-7.93 (m, 10 H, Ph-H), 8.16 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ (ppm): 98.10 CH(H-6), 106.56 C, 125.38 CH, 125.87 CH, 128.59 CH, 128.63 CH, 129.15 CH,130.72 CH, 131.42 C, 142.61 CH(H-2), 145.74 C, 148.00 C, 156.17 C.

Anal. Calcd. for C₁₈H₁₄N₄: C,75.50; H, 4.93; N, 19.57.

Found: C, 75.43; H, 5.04; N, 19.55.

N'-(3,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-N,N-dimethyl-propane-1,3-diamine(128)

A solution of 5-chloro-3,7-diphenylpyrazolo[1,5-a]pyrimidine 47 (58 mg, 0.19 mmol) in N,N-dimethyl-propane-1,3-diamine 3 ml was heated at 100 °C for 24 h, the mixture was evaporated in vacuum, 30 ml water was added, the solution was extracted with chloroform (3 × 30 ml), the extract was washed with 10 % NaOH 30 ml and water 30 ml, then dried with anhydrous MgSO4, the solvent was evaporated and the residue was purified by flash column chromatography on standard neutral Al₂O₃ gel, eluting with EtOAc:MeOH(10:1), yellow solid 61 mg was obtained, yield 87 %, mp 195-7 °C.

1H-NMR (CDCl₃), δ(ppm): 1.76 (m, 2 H, CH₂), 2.18 (s, 6 H, CH₃), 2.38 (t, 2 H, J = 6.8Hz, CH₂), 3.54(m, 2 H, CH₂), 5.94 (s, 1 H, H-6), 6.31 (br, 1H, NH), 7.09-8.02 (m, 10 H, Ph-H), 8.14 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm):24.27 CH₂, 38.26 CH₂, 43.30 CH₃, 56.13 CH₂, 99.35 CH(C-6), 105.81 C, 125.22 CH, 125.38 CH, 128.48 CH, 128.59 CH, 129.12 CH, 130.44 CH, 131.47 C, 133.54 C, 141.81 CH(C-2), 145.93 C, 146.85 C, 155.95 C.

HRMS (EI) calcd for C₂₃H₂₅N₅(M⁺) 371.21100, found 371.21108.

Anal. Calcd. for C₂₃H₂₅N₅(371.48): C, 74.36; H, 6.78 N, 18.85.

Found: C, 74.46; H, 6.90; N, 18.61.

N'-(3,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-ylmethyl)-N,N-dimethyl-propane-1,3-diamine(129)

A solution of 5-bromomethyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine 105 (146 mg, 0.4 mmol) in N,N-dimethyl-propane-1,3-diamine 2 ml was stirred at RT for 12 h, then the solution was treated with saturated aq. NaHCO₃ 30 ml, the mixture was extracted with ethyl acetate (3 × 30 ml), the extract was dried with anhydrous MgSO₄, the solvent was evaporated and the residue was purified by flash column chromatography on standard neutral Al₂O₃ gel, eluting with EtOAc:MeOH(10:1)and provided a brown glass material 50 mg, yield 33 %.

1H-NMR(CDCl₃), δ(ppm): 1.76 (m, 2 H, CH₂), 2.22 (s 6 H, 2CH₃), 2.38 (t, 2 H, J = 7.5Hz, CH₂), 2.49 (br, 1 H, NH), 2.80 (t, 2 H, J = 6.9Hz, CH₂), 4.05 (s, 2 H, CH₂), 6.99 (s, 1 H, H-6), 7.26-8.12 (m, 10 H, Ph-H), 8.43 (s, 1 H, H-2).

13C-NMR(CDCl₃), δ(ppm): 28.13 CH₂, 45.53 CH₃, 48.13 CH₂,54.99 CH₂, 57.95 CH₂, 107.00 CH(C-6), 109.86 C, 126.10 CH, 126.31 CH, 128.67 CH, 129.23 CH, 130.94 CH, 131.20 CH, 132.31 C, 142.59 CH(C-2), 145.62 C, 146.66 C, 160.67 C.

HRMS(EI) calcd for C₂₄H₂₆N₅( M⁺ ) 385.22665, found 385.22662.
Synthesis of pyrazolo[1,5-a]pyrimidine derivatives by ring-chain-transformation
2-(Dihydro-furan-2-ylidene)-1-phenyl-ethanone(130)

A 250 ml flask was charged with 95 % NaH (1.01 g, 0.04 mol), and dry ether 120 ml, ethanol 0.1 ml was added dropwise(as catalyst), 4-butyrolactone (1.80 g, 0.02 mol) was added inside in one portion, and the mixture was cooled to 15 °C, then a solution of acetophenone (2.40 g, 0.02 mol) in 20 ml ether was added dropwise over 1 h, the resulting mixture was stirred at RT for 24 h, and cooled to 0°C, 2 ml ethanol was added to destroy the excess NaH, then cold 10 % aq. ammonium sulphate 40 ml was added, and separated, the ether solution was dried with anhydrous sodium sulphate, evaporated the solvent, the residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate (4/1→1/1), and provided a yellow solid 1.05 g, yield 28 %, mp 36-8 °C.

1H-NMR(CDCl₃), δ(ppm): 1.95 (m, 2 H, CH₂), 2.58 (t, 2 H, J = 6.1 Hz, CH₂), 3.73 (t, 2 H, J = 7.3 Hz, CH₂), 6.21 (s, 1 H, C=CH), 7.42-7.90 (m, 5 H, Ph-H).

13C-NMR (CDCl₃), δ (ppm): 28.34 CH₂, 36.13 CH₂, 62.08 CH₂, 96.31 CH, 126.98 CH, 128.64 CH, 132.34 CH, 134.60 C, 182.45 C, 197.59 C.

Anal. Calcd. for C₁₂H₁₆O₂: C, 76.57; H, 6.43;

Found: C, 76.34; H, 6.60;

3-(3,7-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-propan-1-ol(131)

A 50ml flask was charged with 2-(dihydro-furan-2-ylidene)-1-phenyl-ethanone 130 (395 mg, 2.1 mmol, 3-amino-4-phenylpyrazole (320 mg, 2 mmol),ethanol 15 ml and 37 % HCl 1 ml, the mixture was heated at reflux for 6 h, ethanol was evaporated and neutralized with aq. Na₂CO₃, the mixture was extracted with ethyl acetate (3 × 30 ml), and dried with anhydrous MgSO₄, the solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with CH₂Cl₂:ethyl acetate (4/1), and provided a yellow solid 546 mg, yield 83 %, mp 147-8 °C.

1H-NMR(CDCl₃), δ(ppm): 2.13-2.21 (m, 2 H, CH₂), 2.24 (br, 1 H, OH), 3.07 (t, 2 H, J = 7.4 Hz, CH₂), 3.83 (t, 2 H, J = 6.0 Hz, CH₂), 6.82 (s, 1 H, H-6), 7.26-8.07 (m, 10 H, Ph-H), 8.42 (s, 1 H, H-2)

13C-NMR(CDCl₃), δ (ppm): 30.81 CH₂, 34.80 CH₂, 62.15 CH₂, 108.34 CH(C-6), 109.83 C, 126.19 CH, 126.42 CH, 128.72 CH, 128.75 CH, 129.22 CH, 131.00 CH, 131.13 C, 142.76 CH(C-2), 145.59 C, 146.65 C, 162.07 C, .

Anal. Calcd. for C₂₁H₁₉N₃O: C,76.57; H, 5.81; N, 12.76

Found: C, 76.27; H, 6.12; N, 12.59.

Synthesis of purine derivatives Synthesis of 2,6-dichloropurine
2,6-Dichloropurine was prepared fromcommercial available adenine. The synthetic route is as below (Scheme 7.7):

Scheme 7.7

Adenine 1-N-oxide(181)

Adenine (20.0 g, 0.15mol) was suspended in 120 ml of acetic acid and the mixture was heated at reflux for 1 h. After the solid was dissolved completely, the solution was cooled to room temperature. To this solution, 74 ml of 30 % H₂O₂ was added dropwise and then the solution was allowed to stand for 3 days at room temperature. The precipitate was collected and washed with water to give 51 as a white solid 13.60 g, yield 60 %, mp>300 °C.

Hypoxanthine 1-N-oxide(182)

Adenine 1-N-oxide (181) (7.19 g, 0.053 mol) was suspended in a solution containing NaNO₂ (33.07 g, 0.48 mol) in 500 ml water. The mixture was cooled to 10 °C in an ice bath, and 300 ml of 30 % aqueous was added dropwise with stirring over a period of 30 min. After the addition of acid was complete, the solution was heated at 70-80 °C for 2 h, then cooled to room temperature and allowed to stand for 4 days. The precipitate was collected and washed with water, alcohol, and ether to afford 52 as a yellow solid 4.0 g, yield 50 %, mp>300 °C.

2,6-dichloropurine(179)

Hypoxanthine 1-N-oxide (182) (3.6 g, 0.024 mol) was suspended in a mixture of 180 ml of phosphoryl chloride and 6 ml N,N-dimethylaniline and was was heated at reflux for 3 h under Argon. After the mixture was cooled to room temperature, excess phosphoryl chloride was distilled off under reduced pressure. The residue was dissolved in 100 ml water and extracted with CH₂Cl₂ (3 × 100 ml), the solvent was evaporated in vacuum to give a crude oil, which was chromatography on silica gel, eluting with ethyl acetate: hexane (1/1→1/0) to give a white solid 1.28 g, yield 28 %, mp 184-6 °C.

Anal. Calcd. for C₅H₂Cl₂N₄: C, 31.77; H, 1.07; Cl, 37.52; N, 29.64.

Found: C, 31.79; H, 1.13; Cl, 36.72; N, 29.35.

Benzylation of 2,6-dichloropurine and 6-chloropurine
(1) Benzylation of 2,6-dichloropurine

Scheme 7.8

A flask was charged with 2,6-dichloropurine (1.27 g, 6.6 mmol), anhydrous potassium carbonate (2.72 g, 20 mmol), and dry DMF 40 ml, Argon was passed, the mixture was stirred for 30 min, then benzylchloride (1.27 g, 16 mmol) was added, and stirred at room temperature for 2 days.The solid was filtered off, the filtratet was evaporated, and the residue was purified by column chromatography on silica gel.

9-Benzyl-2,6-dichloro-purine(137)

Eluting with hexane:ethyl acetate (2/1), and provide 0.81 g white solid, yield 44 %, mp 125-7 °C.

1H-NMR (CDCl₃), δ(ppm): 5.34 (s, 2 H, CH₂), 7.30-7.56 (m, 5 H, Ph-H), 7.98 (s, 1 H, H-8)

13C-NMR (CDCl₃), δ(ppm): 48.04 CH₂, 127.84 C, 128.09 CH, 129.03 C,129.09 CH, 129.39 CH, 133.99 C, 145.54 CH(H-8), 151.89 C, 153.02 C.

Anal. Calcd. for C₁₂H₈Cl₂N₄ (279.13): C, 51.64; H, 2.89; Cl, 25.40; N, 20.07.

Found: C, 51.58; H, 2.94; Cl, 25.27; N, 19.96.

7-Benzyl-2,6-chloro-purine(183)

Eluting with hexane:ethyl acetate (1/1), and obtain 0.36 g white solid, yield 21 %, mp 144-6 °C.

¹H-NMR(CDCl₃), δ(ppm): 5.74 (s, 2 H, CH₂), 7.23-7.45 (m, 5 H, Ph-H), 9.06 (s, 1 H, H-8).

13C-NMR(CDCl₃), δ(ppm): 49.8 CH2, 121.9 C(C-5), 126.8 CH, 128.0 CH, 128.9 CH, 136.3 C, 143.4 C, 151.2 C, 152.8 CH(C-8), 163.4 C.

Anal. Calcd. for C₁₂H₈Cl₂N₄ (279.13): C, 51.64; H, 2.89; Cl, 25.40; N, 20.07.

Found: C, 51.50; H, 2.98; Cl, 25.21; N, 19.99.

(2) Benzylation of 6-chloropurine

Scheme 7.9

A mixture of 6-chloropurine (2.47 g, 16 mmol), anhydrous potassium carbonate (2.76 g, 20 mmol), DMSO 40 ml and benzylbromide (2.74 g, 16 mmol) was stirred at room temperature for 2 days.

The reaction solution was decanted from the solid, ice water 50 ml was poured inside, the solution was acidified to PH = 5 with formic acid, the mixture was extracted with ethyl acetate (4 × 80ml), the combined extract was washed with water 100 ml, dried with anhydrous MgSO4, evaporated the solvent, the residue was separated by column chromatography on silica gel.

9-Benzyl-6-chloro-purine(132)

Eluting with hexane:ethyl acetate (2/1), 1.98 g white solid was obtained, yield 50 %, mp 80-2 °C.

1H-NMR (CDCl₃), δ(ppm): 5.46 (s, 2 H, CH₂), 7.30-7.39 (m, 5 H, Ph-H), 8.10 (s, 1 H, H-8), 8.19 (m, 1 H, H-2)

13C-NMR (CDCl₃), δ(ppm): 47.91 CH₂, 127.96 CH, 128.90 CH, 129.30 CH, 131.55 C, 134.52 C, 144.96 CH(C-8), 151.19 C, 151.88 C, 152.21 CH(C-2).

Anal. Calcd. for C₁₂H₉ClN₄ (244.69): C, 58.91; H, 3.71; Cl, 14.49; N, 22.90.

Found: C, 58.74; H, 3.86; Cl, 14.35; N, 22.71.

7-Benzyl-6-chloro-purine(155)

Eluting with hexane:ethyl acetate (1/1), and get 0.91 g white solid, yield 23 %, mp 144-6°C.

1H-NMR (CDCl₃), δ(ppm): 5.71 (s, 2 H, CH₂), 7.17-7.38 (m, 5 H, Ph-H), 8.25 (s, 1 H, H-8), 8.89 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm): 50.74 CH₂, 122.56 C, 127.08 CH, 128.94 CH, 129.39 CH, 134.64 C, 143.24 C, 149.16 CH(C-8), 152.62 CH(C-2), 162.05 C.

Anal. Calcd. for C₁₂H₉ClN₄ (244.69): C, 58.91; H, 3.71; Cl, 14.49; N, 22.90.

Found: C, 58.74; H, 3.86; Cl, 14.35; N, 22.71.

Suzuki cross-coupling of halopurines
General procedure:

A flask was charged with halopurine (137, 183, or 132) 0.6 mmol, phenboronic acid (79 mg, 0.6 mmol), K₂CO₃ (100 mg, 0.72 mmol), Pd(PPh₃)₄ (35 mg, 0.03 mmol), and dry toluene 10 ml. Argon was passed three times and heated at 100 °C for 20 h, the solvent was evaporated, and the residue was purified by column chromatography on silica gel.

9-Benzyl-2-chloro-6-phenylpurine(140)

Eluting with hexane:ethyl acetate (1:1), and a white solid 112 mg was obtained, yield 70 %, mp 141-3 °C.

1H-NMR (CDCl₃), δ(ppm): 5.36 (s, 2 H, CH₂), 7.30-7.49 (m, 8 H, Ph-H), 7.96 (s, 1 H, H-8), 8.72-8.78 (dd, 2H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 47.41 CH₂, 128.01 CH, 128.72 CH, 128,80 CH, 129.25 CH, 130.06 CH, 131.74 CH, 134.49 C, 134.76 C, 144.67 CH(C-8), 154.39 C, 154.43 C, 156.77 C, 160.11 C.

Anal. Calcd for C₁₈H₁₃ClN₄ (320.78): C, 67.40; H, 4.08; Cl, 11.05; N, 17.47

Found: C, 67.67; H, 4.36; Cl, 10.92; N, 17.23.

7-Benzyl-2-chloro-6-phenylpurine(184)

Eluting with hexane:ethyl acetate (1:3), and a white solid was obtained, yield 66 %, mp 154-5 °C.

1H-NMR (CDCl₃), δ(ppm): 5.12 (s, 2 H CH₂), 6.45-7.45 (m, 10 H, Ph-H), 8.22 (s, 1 H, H-8).

13C-NMR (CDCl₃), δ(ppm): 51.31 CH₂, 122.02 C, 126.46 CH, 128.53 CH, 128.63 CH, 128.98 CH, 130.43 CH, 133.98 C, 134.47 C, 150.70 CH(C-8), 154.41 C, 154.66 C, 164.04 C.

Anal. Calcd for C₁₈H₁₃ClN₄ (320.78): C, 67.40; H, 4.08; Cl, 11.05; N, 17.47

Found: C, 67.34; H, 4.33; Cl, 10.87; N, 17.52.

9-Benzyl-6-phenylpurine(134a)

Eluting with hexane:ethyl acetate (1:1), and a white solid was obtained, yield 75 %, mp 124-5 °C.

1H-NMR (CDCl₃), δ(ppm): 5.43 (s, 2 H, CH₂), 7.26-7.50 (m, 8 H, Ph-H), 8.04 (s, 1 H, H-8), 8.71 (dd, 2 H, Ph-H), 8.99 (s, 1 H, H-2)

13C-NMR (CDCl₃), δ(ppm): 47.32 CH₂, 127.83 CH, 128.61 CH, 128.70 CH, 129.17 CH, 129.80 CH, 130.93 C, 131.06 CH, 135.16 C, 135.48 C, 144.21CH(C-8), 149.45 C, 151.34 C, 152.55 CH(C-2).

Anal. Calcd for C₁₈H₁₄N₄ (286.33): C, 75.50; H, 4.93; N, 19.57

Found: C, 75.44; H, 5.14; N, 19.64.

9-Benzyl-8-iodo-6-chlorol-purine(152)

A 50 ml flask was charged with 9-Benzyl-6-chloro-purine(132)(367 mg, 1.5 mmol), NIS (1.01 g, 4.5 mmol), and THF 20 ml. The flask was draped with aluminium-foil, and the mixture was heated at reflux under Ar for 3 days. The solvent was evaporated, 60 ml CH₂Cl₂ was added inside, the solution was washed with sat. aq. Na₂S₂O₃ (2 × 30 ml), and water 30 ml, then dried with anhydrous MgSO₄, evaporated the solvent, the residue was separated by flash column chromatography on silica gel, eluting with hexane:ethyl acetate (2/1), to provide a white solid 254 mg, yield 46 %, mp 135-6 °C.

1H-NMR (CDCl₃), δ(ppm): 5.47 (s, 2 H, CH₂), 7.32-7.34 (m, 5 H, Ph-H), 8.71 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm): 49.69 CH₂, 108.17 C, 127.89 CH, 128.62 CH, 128.99 CH, 133.81 C, 134.27 C, 149.36 C, 152.09 CH(H-2), 153.06 C.

Anal. Calcd for C₁₂H₈ClIN₄ (370.58): C, 38.89; H, 2.18; N, 15.12

Found: C, 39.00; H, 2.20; N, 15.01

Sonogashira cross-coupling of halo-purines
(1)9-Benzyl-8-bromo-6-phenylpurine (185)

A 50 ml flask was charged with 9-benzyl-6-phenylpurine 134a (358 mg, 1.25 mmol), NBS (1.35 g, 7.5 mmol), and THF 20 ml. The mixture was heated at reflux for 2 days. The solvent was evaporated, the residue was separated by flash column chromatography on silica gel, eluting with hexane:ethyl acetate (3/1) to provide a white solid 255 mg, yield 56 %, mp 112-4 °C.

1H-NMR (CDCl₃), δ(ppm): 5.43 (s, 2 H, CH₂), 7.23-8.69 (m, 10 H, Ph-H), 8.91 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm): 47.64 CH₂, 127.84 CH, 128.43 CH, 128.74 CH, 128.94 CH, 129.72 CH, 131.20 CH, 131.31 C, 133.07 C, 134.77 C, 135.13 C, 152.09 CH(H-2), 153.59 C, 153.73 C.

Anal. Calcd for C₁₈H₁₃BrN₄ (365.23): C, 59.19; H, 3.59; Br, 21.88; N, 15.12

Found: C, 59.02; H, 3.75; Br, 22.03; N, 15.00

(2)[3-(9-Benzyl-6-phenyl-purin-8-yl)-prop-2-ynyl]-dimethylamine (186)

A 25 ml schlenk flask was charged 9-Benzyl-8-bromo-6-phenylpurine 185 (182 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol), triethylamine 10 ml, and N, N-dimethylpropargylamine (83 mg, 1.0 mmol), Argon was passed three times and the mixture was heated at 80 °C for 24 h. The mixture was concentrated, the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol (1/0→8/1), and provided a brown solid 158 mg, yield 86 %, mp 134-6 °C.

1H-NMR (CDCl₃), δ(ppm): 2.34 (s, 6 H, 2CH₃), 3.63 (s, 2 H, CH₂), 5.58 (s, 2 H, CH₂), 7.29-8.80 (m, 10 H, Ph-H), 9.03 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm): 44.21 CH₃, 46.90 CH₂, 47.64 CH₂, 75.13 C, 94.23 C, 127.60 CH, 128.22 CH, 128.69 CH, 128.80 C, 128.86 CH, 129.87 CH, 130.88 C, 131.08 CH, 135.46 C, 138.42 C, 152.32 C, 152.09 CH(H-2), 154.61 C.

Anal. Calcd for C₂₃H₂₁N₅ (367.45): C, 75.18; H, 5.76; N, 19.06.

Found: C, 75.05; H, 5.98; N, 19.01

(3)[3-(9-Benzyl-6-phenyl-purin-8-yl)-propyl]-dimethylamine (187)

A mixture of [3-(9-benzyl-6-phenyl-purin-8-yl)-prop-2-ynyl]-dimethylamine 186 (100 mg, 0.27 mmol), 10 % palladium on charcoal (65mg, 0.054 mmol on Pd, 0.2 equiv) in ethanol (15 mL) were stirred under hydrogen at room temperature and atmosphere 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with cyclohexane:ethyl acetate (1:1) to provide a white solid 71 mg, yield 70 %, mp 81-3 °C.

1H-NMR (CDCl₃), δ(ppm): 1.94-2.02 (m, 2 H, CH₂), 2.13 (s, 6 H, 2CH₃), 2.27 (t, 2 H, J = 7.2Hz, CH₂), 2.82 (t, 2 H, J = 7.4 Hz, CH₂), 5.45 (s, 2 H, CH₂), 7.07-8.78 (m, 10 H, Ph-H), 8.91 (s, 1 H, H-2).

13C-NMR (CDCl₃), δ(ppm): 25.01 CH₂, 25.54 CH₂, 45.42 CH₃, 45.51 CH₂, 58.68 CH₂, 126.85 CH, 128.08 CH, 128.60 CH, 129.00 C, 129.73 CH, 130.64 CH, 130.88 C, 132.16 C, 135.80 C, 151.76 CH(H-2), 152.86 C, 154.09 C, 157.42 C.

Anal. Calcd for C₂₃H₂₅N₅ (371.48): C, 74.36; H, 6.78; N, 18.85.

Found: C, 74.56; H, 6.91; N, 18.77.

Nucleophilic substitution of halopurines
(a) Introducing Me₂N(CH₂)₃NH to 2-position of purines

General procedure:

A solution of 2-Cl-substituted purine 0.3 mmol in 3 ml N,N-dimerhyl-1,3-propan-diamine was heated at 150 °C for 18 h, then evaporated in vacuum, the residue was dissolved in 50 ml chloroform, washed with aq. 10 % NaOH 30 ml and water 30 ml, dried with anhydrous MgSO₄, evaporated the solvent, and purified by column chromatograph on standard neutral Al₂O₃ gel.

N'-(9-Benzyl-6-phenyl--purin-2-yl)-N,N-dimethyl-propane-1,3-diamine(190)

Eluting with chloroform:methol (50/1) to provide a light brown solid, yield 98 %, mp 81-2 °C.

1H-NMR (CDCl₃), δ(ppm): 1.73 (m, 2 H, CH₂), 2.14 (s, 6 H, 2CH₃), 2.31 (t, 2 H, J = 7.6 Hz, CH₂), 3.48 (m, 2 H, CH₂), 5.17 (s, 2 H, CH₂), 5.60 (t, 1 H, J = 5.3 Hz, NH), 7.19-7.60 (m, 8 H, Ph-H), 7.62 (s, 1 H, H-8), 8.59-8.62 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 27.46 CH_2,40.68, 45.54 CH₃, 46.54 CH_2, 57.81 CH₂, 124.70 C, 127.77 CH, 128.26 CH, 128.39 CH, 128.90 CH, 129.48 CH, 130.43 CH, 136.08 CH, 140.72 CH(C-8), 154.56, 155.44 C, 159.72 C.

Anal. Calcd. for C₂₃H₂₆N₆: C, 71.48; H, 6.78; N, 21.74.

Found: C, 71.36; H, 6.87; N, 21.51.

N'-(7-Benzyl-6-phenyl-7H-purin-2-yl)-N,N-dimethyl-propane-1,3-diamine(189)

Eluting with ethyl acetate:methol (5/1) to give a light brown oil, yield 98 %.

1H-NMR (CDCl₃), δ(ppm): 2.17 (m, 2 H, CH₂), 2.71 (s, 6 H, 2CH₃), 3.07 (t, 2 H, J = 7.5 Hz, CH₂), 3.59 (m, 2 H, CH₂), 5.04 (s, 2 H, CH₂), 6.07 (br, 1 H, NH), 6.52 (dd, 2 H, J = 6.7 Hz, Ph-H), 7.12-7.40 (m, 8 H, Ph-H), 8.05 (s, 1 H, H-8)

13C-NMR (CDCl₃), δ(ppm): ): 24.90 CH_2,40.68 CH₂, 43.03 CH₃, 50.96 CH_2, 555.78 CH₂, 116.86 C, 126.42 CH, 128.11 CH, 128.44 CH, 128.58 CH, 128.75 CH, 129.74 CH, 134.82 C, 136.37 C, 148.44 CH(C-8), 154.01 C, 159.70 C, 163.88 C, 175.94 C.

HRMS (EI) calcd for C₂₃H₂₆N₆(M⁺) 386.22189; found 386.22182.

(b) Introducing Me₂N(CH₂)₃O- to 2 position of purine

[2-(9-Benzyl-6-phenyl-purin-2-yloxy)-ethyl]-dimethylamine(191)

A 10 ml flask was charged with 9-benzyl-2-chloro-6-phenylpurine 141 (51 mg, 0.16 mmol), t-BuOK (23 mg, 0.2 mmol) and 2-dimethylamino-ethanol 3 ml. Argon was passed and the mixture was heated at 150 °C for 16 h, evaporated in vacuum, the residue was dissolved in 60 ml chloroform, washed with sat. aq. NaHCO₃ 30 ml, then water 30 ml, dried with anhydrous MgSO₄, evaporated the solvent, and purified by column chromatograph on standard neutral Al₂O₃ gel, eluting with ethyl acetate:methol (10/1) to give a light brown oil 41 mg, yield 68 %.

1H-NMR (CDCl₃), δ(ppm): 2.48 (s, 6 H, 2CH₃), 3.00 (t, 2 H, J = 6.0 Hz, CH₂), 4.73 (t, 2 H, J = 6.0 Hz, CH₂), 5.38 (s, 2 H, CH₂), 7.32-7.52 (m, 8 H, Ph-H), 7.93 (s, 1 H, H-8), 8.78 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 45.13 CH₃, 47.01 CH₂, 57.29 CH₂, 64.84 CH₂, 127.85 CH, 128.47 CH, 128.54 CH, 129.08 CH, 129.79 CH, 131.17 CH, 135.35 C, 135.45 C, 143.12 CH(C-8), 154.78 C, 155.97 C, 161.18 C, 175.72 C.

HRMS (EI) calcd for C₂₂H₂₃N₅O (M⁺) 373.19026, found 373.19029.

Synthesis of pyrido[2,3-b]pyridazine derivatives Synthesis of 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (193)
A 100ml flask was charged with 2,3-diamino-5-bromopyridine (965mg, 5.0 mmol), benzil (1.26g, 6.0 mmol), ethanol 30 ml and 3 drops of hydrochloric acid, the mixture was heated at reflux for 12 h, the alcohol was evaporated, the solid was dissolve in 60 ml dichloromethane, and washed with water (2 × 30 ml), dried with anhydrous MgSO₄, evaporated the solvent, the residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate (4/1) and afforded a yellow solid 1.33 g, yield 73 %, mp 149-50 °C.

1H-NMR (CDCl₃), δ(ppm): 7.27-7.63 (m, 10 H, Ph-H), 8.67 (d, 1 H, J _6,8 _{= 2.6 Hz, H-8), 9.15 (d, 1 H, J

_6,8
= 2.6 Hz, H-6).}

13C-NMR (CDCl₃), δ(ppm): 120.92 C(C-7), 128.24 CH, 128.45 CH, 129.60 CH, 129.68 CH, 129.83 CH, 130.19 CH, 136.40 C, 137.78 C, 138.09 C, 139.37 CH(C-8), 148.25 C, 155.11 CH(C-6), 155.47 C, 156.48.

Anal. Calcd. for C₁₉H₁₂ BrN₃ (362.22): C, 63.00; H, 3.34; Br, 22.06; N, 11.60.

Found: C, 62.83; H, 3.45; Br, 22.29; N, 11.63.

Synthesis of 7-alkynyl-2,3-diphenylpyrido[2,3-b]pyrazine
General procedure of Sonogashira reaction:

A 25 ml Schlenk flask was charged with 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (181 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol),dryTEA 5 ml, dryDMF 5 ml and alkyne (1.0 mmol), Argon was passed three times and the mixture was heated at 100 °C for 24 h, the solvent was evaporated in vacuum, and the residue was purified by column chromatography on silica gel.

4-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-but-3-yn-1-ol(194a)

The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: and provided a yellow solid 172 mg, yield 98 %, mp 165-7 °C.

1H-NMR (CDCl₃), δ(ppm): 2.06 (br, 1 H, OH), 2.79 (t, 2 H, J = 6.4 Hz, CH₂), 3.90 (t, 2 H, J = 6.4 Hz, CH₂), 7.29-7.61 (m, 10 H, Ph-H), 8.44 (d, 1 H, J = 3.0 Hz, H-8), 9.09 (d, 1 H, J = 3.0 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm): 24.00 CH₂, 60.81 CH₂, 78.59 C, 93.42 C, 128.20 CH, 128.43 CH, 129.44 CH, 129.59 CH, 129.81CH, 130.23 CH, 135.33 C, 137.84 C, 138.27 C, 139.53 CH (C-8), 148.46 C, 155.32 C, 156.09 C, 156.24 CH(C-6).

Anal. Calcd. For C₂₃H₁₇N₃O: C, 78.61; H, 4.88; N, 11.96.

Found: C, 78.90; H, 5.12; N, 11.65.

[3-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-prop-2-ynyl]-dimethylamine (194b)

The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: methanol (4/1), and get light yellow solid 133 mg, yield 76 %, mp 101-3 °C.

1H-NMR(CDCl₃), δ(ppm): 2.32 (s, 6 H, 2CH₃), 3.47 (s, 2 H, CH₂), 7.20-7.7.53 (m, 10 H, Ph-H), 8.40 (d, 1 H, J = 2.3 Hz, H-8), 8.40 (d, 1 H, J = 2.3 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm): 44.34 CH₃, 48.64 CH₂, 81.67 C, 91.01 C, 121.71 C, 128.13 CH, 128.37 CH, 129.37 CH, 129.52 CH, 129.77 CH, 129.77 CH, 130.21 CH, 135.25 C, 137.86 C, 138.27 C, 139.61 CH(C-8), 148.60 C, 155.22 C, 156.07 CH(C-6).

Anal. Calcd. for C₂₄H₂₀N₄(364.44): C, 79.10; H, 5.53; N, 15.73.

Found: C, 78.94; H, 5.69; N, 15.46.

N'-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-N,N-dimethyl-propane-1,3-diamine (195)

A solution of [3-(2,3-diphenyl-imidazo[1,2-a]pyridin-6-yl)-prop-2-ynyl]-dimethylamine (81 mg, 0.22 mmol), ethanol (15 ml) and 10 % palladium on charcoal (46 mg, 0.044 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere for 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of celite, washed with ethyl acetate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate:methanol (10:1) to provide 44 mg brown liquid, yield, 54 %.

1H-NMR (CDCl₃), δ(ppm): 1.85-1.92 (m, 2 H, CH₂), 2.18 (s, 6 H; 2CH₃), 2.30 (t, 2 H, J = 7.2 Hz, CH₂), 2.88 (t, 2 H, J = 7.2 Hz, CH₂), 7.26-7.30 (m, 6 H, Ph-H), 7.46 (dd, 2 H, Ph-H), 7.51 (dd, 2 H, Ph-H), 8.21 (d, 1 H, J _6,8= 2.3 Hz, H-8), 8.96 (d, 1 H, J _6,8= 2.3 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm): 28.71 CH2, 30.70 CH2, 45.43 CH3, 58.67 CH2, 128.11 CH, 128.39 CH, 129.17, CH, 129.24 CH, 129.79 CH, 130.23 CH, 135.84 CH(C-8), 136.04 C, 138.23 C, 138.72 C, 140.24 C, 148.44 C, 154.52 C, 155.31 C, 155.84 CH(C-6).

HRMS (EI) calcd for C₂₄H₂₄N₃ (M⁺) 368.2001, found 368.2001.

Anal. Calcd. for C₂₄H₂₄N₄(368.47): C, 78.23; H, 6.57; N, 15.21.

Found: C, 78.32; H, 6.75; N, 15.09.

Buchwald-Hartwig amination of 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine
General procedure:

A 25 ml schlenk flask was charged with 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (181 mg, 0.5 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol), BINAP (19 mg, 0.03mmol), t-BuONa (68 mg, 0.7mmol), appropriate substituted amine1.0 mmol, dry toluene 5 ml, Argon was passed three times and the mixture was heated at 110 °C for 20 h, after cooled, 50 ml water was added, the mixture was extracted with ethyl acetate (3 × 40ml), the extract was washed with water (2 × 40 ml), dried with anhydrous MgSO₄, evaporated the solvent, the residue was purified by column chromatography

7-(4-Methyl-piperazin-1-yl)-2,3-diphenylpyrido[2,3-b]pyrazine (198)

The crude product was purified by flash column chromatography on silica gel, eluting with CH₂Cl₂:MeOH(10:1)and provided abrown sold 122 mg, yield 68 %, mp.164-6 °C;

1H-NMR (CDCl₃), δ(ppm): 2.28 (s, 3 H, CH₃), 2.55 (t, 4 H, J = 4.9 Hz, 2CH₂), 3.38 (t, 4 H, J = 4.9 Hz, 2CH₂), 7.20-7.51 (m, 11 H, 10Ph-H and H-8), 8.94 (d, 1H, J _6,8= 3.0 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm): 46.05 CH3, 48.05 CH2, 54.45 CH2, 116.13 CH(C-8),128.00 CH, 128.29 CH, 128.73 CH, 128.92 CH, 129.73 CH, 130.11 CH, 137.25 C, 138.98 C, 138.98 C, 144.27 C, 147.29 CH(H-6), 147.80 C, 152.22 C, 154.54 C.

Anal. Calcd. for C₂₄H₂₃N₅(381.47) C, 75.56; H, 6.08; N, 18.36.

Found: C, 75.44; H, 6.32; N, 18.07.

N'-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-N,N-dimethyl-propane-1,3-diamine (199)

The crude product was purified by flash column chromatography on standard neutral Al₂O₃ gel, eluting with ethyl acetate:methanol (10/1) and provided a brown solid 140 mg, yield:73 %, mp 150-2°C.

1H-NMR (CDCl₃), δ(ppm):1.83 (m, 2 H, CH₂), 2.25(s, 6H, 2CH₃), 2.43 (t, 2 H, J = 5.7 Hz, CH₂), 3.30 (m, 2 H, CH₂), 6.42 (s, 1 H, NH), 7.20 (d, 1 H, J = 3.0 Hz, H-8), 7.27-7.57 (m, 10 H, Ph-H), 8.68 (d, 1 H, J = 3.0 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm): 25.37 CH₂, 43.26 CH₂, 45.47 CH₃, 58.49 CH₂, 108.36 CH(C-8), 127.92 CH, 128.21 CH, 128.34 CH, 128.68 CH, 129.76 CH, 130.07 CH, 138.54 C, 138.76 C, 139.29 C, 143.64 C, 145.91 C, 147.86 CH(C-6), 150.02 C, 154.03 C.

Anal. Calcd. for C₂₄H₂₅N₅(383.49) C, 75.17; H, 6.57; N, 18.26.

Found: C, 75.21; H, 6.72; N, 17.99.

Synthesis of 7-alkenyl-2,3-diphenylpyrido[2,3-b]pyrazine (Heck reaction)
General procedure:

A 25 ml schlenk flask was checked with 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (181 mg, 0.5 mmol), Pd(OAc)₂ (11 mg, 0.05 mol), P(o-tolyl)₃ (15 mg, 0.05 mmol), TEA (200 mg, 2 mmol), and MeCN 10 ml, Argon was passed inside, appropriate alkene 1.5 mmol was added inside with a syringe, the mixture was heated at 100 °C for 20 h, the solvent was evaporated and the residue was purified by column chromatography on silica gel.

3-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-acrylic acid methyl ester (200)

The crude product was purified by flash column chromatography on silica gel, eluting with cyclohexane:ethyl acetate (5/1→1/1), and provided a yellow solid 176 mg, yield 96 %, mp 197-8°C;

1H-NMR (CDCl₃), δ(ppm): 3.88 (s, 3 H, CH₃), 6.77 (d, 1 H, J = 16.2 Hz, =C-H), 7.34-7.65 (m, 10 H, Ph-H), 7.91 (d, 1 H, J = 16.2 Hz, =C-H), 8.58 (d, 1 H, J = 2.6 Hz, H-8), 9.32 (d, 1 H, J = 2.6 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm): 52.14 CH₃, 121.99 CH(=C-H), 128.23 CH, 128.49, 129.54, 129.74 CH, 129.79 CH, 130.30 CH, 131.64 C, 135.65 C, 136.37 CH(=C-H), 137.80 C, 138.26 C, 140.00 CH(C-8), 150.32 C, 153.06 CH(C-6), 155.58 C, 156.79 C, 166.47 C(C=O).

Anal. Calcd. for C₂₃H₁₇N₃ O₂ (367.40): C, 75.19; H, 4.66; N, 11.44.

Found: C, 75.19; H, 4.85; N, 11.28.

3-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-acrylonitrile (201)

The crude product was purified by flash column chromatography on silica with cyclo-hexane:ethyl acetate (3/1-1/1) as eluting solvent and provided a yellow solid 109 mg, yield: 65 %, mp.188-9 °C;

1H-NMR (CDCl₃), δ(ppm): 6.23 (d, 1 H, J = 17.0 Hz, =C-H), 7.60 (d, 1 H, J = 17.0 Hz, =C-H), 7.32-7.66 (m, 10 H, Ph-H), 8.53 (d, 1 H, J = 2.3 Hz, H-8), 9.32 (d, 1 H, J = 2.3 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm):100.84 CH(=C-H), 117.07 C, 128.29 CH, 128.52 CH, 129.72 CH, 129.95 CH, 130.28 CH, 130.52 C, 135.34 C, 136.00 CH(=C-H), 137.62 C, 138.04 C,145.84 CH(C-8), 150.64 C, 151.93 CH(C-6), 155.94 C, 157.36 C.

Anal. Calcd. for C₂₂H₁₄N₄ (334.37): C, 79.02; H, 4.22; N, 16.76.

Found: C, 79.14; H, 4.35; N, 16.67

2-[3-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-allyl]-isoindole-1,3-dione (202)

The crude product was purified by flash column chromatography on silica, eluting with cyclohexane:ethyl acetate (3/1→1/1) and provided a light yellow solid 78 mg, yield:33 %, mp 89-91 °C;

1H-NMR (CDCl₃), δ(ppm): 4.57 (dd, 2 H, J ₁ = 6.3 Hz, J ₂ = 1.1 Hz, CH₂), 6.63 (dt, 1 H, J ₁ = 16.0 Hz, J ₂ = 6.3 Hz, =C-H), 6.87 (d, 1 H, J = 16.0 Hz, 7.31-7.63 (m, 10 H, Ph-H), 7.75 (dd, 2 H, J ₁ = 5.7 Hz, J ₂ = 3.0 Hz, Ph-H), 7.90 (dd, 2 H, J ₁ = 5.7 Hz, J ₂ = 3.0 Hz, Ph-H), 8.37 (d, 1H, J = 2.3 Hz, H-8), 9.19 (d, 1 H, J = 2.3 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm):39.54 CH₂, 123.52 CH(=C-H), 127.95 CH, 128.13 CH, 128.39 CH, 129.10 CH, 129.29 CH, 129.41 CH, 129.81 CH, 130.26 CH, 132.04 C, 133.57 C, 133.93CH(=C-H), 134.21(C-8), 135.94 C, 138.01 C, 138.50 C, 149.25 C, 152.92 (C-6), 155.04 C, 155.70 C, 167.89 C.

Anal Calcd for C₃₀H₂₀N₄O (468.50): C, 76.91; H, 4.30; N, 11.96.

Found: C, 76.70; H, 4.48; N, 11.83.

Synthesis of 7-aryl-2,3-diphenylpyrido[2,3-b]pyrazine (Suzuki reaction)
General procedure of Suzuki reaction:

A 25ml schlenk flask was charged with 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (181 mg, 0.5 mmol), K₂CO₃ (97 mg, 0.7 mmol), arylbronic acid (0.7 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol), and dry toluene 10 ml, Argon was passed three times and the mixture was heated at 100 °C for 16 h, the solvent was evaporated in vacuum, the residue was dissolved in 50 ml CH₂Cl₂, washed with water (2 × 30 ml), the solution was dried with anhydrous MgSO₄. The solvent was evaporated, and the residue was purified by column chromatography.

2,3,7-Triphenylpyrido[2,3-b]pyrazine (203)

The crude product was purified by flash column chromatography on silica gel, eluting with cyclohexane:ethyl acetate (6/1→2/1),and provide yellow solid 172 mg, yield 96 %, mp: 172-3 °C. (lit. ^[9], 282-4 °C)

1H-NMR (CDCl₃), δ(ppm): 7.31-7.82 (m, 15 H, Ph-H), 8.67 (d, 1 H, J = 2.6 Hz, H-8), 9.45 (d, 1 H, J= 2.6 Hz, H-6).

13C-NMR (CDCl3), δ(ppm): 127.56 CH, 128.16 2CH, 128.45 CH, 128.95 CH, 129.32 CH, 129.44 CH, 129.81 CH, 130.29 CH, 134.50 CH, 136.01 C, 136.50 C, 138.11 C, 138.60 C, 149.06 C, 153.61 CH, 155.12 C, 155.90 C.

HRMS (EI) calcd for C₂₅H₁₇N₃ (M⁺) 359.14225, found 359.14226.

Anal. Calcd. for C₂₅H₁₇N₃: C, 83.54; H, 4.77; N, 11.69.

Found: C, 83.69; H, 4.83; N, 11.48.

1-[4-(2,3-Diphenyl-pyrido[2,3-b]pyrazin-7-yl)-phenyl]-ethanone(204)

The crude product was purified by flash column chromatography on silica gel, eluting with cyclohexane:ethyl acetate (4/1→1/1), and provided a yellow solid 101 mg, yield 50 %, mp 273-4 °C;

1H-NMR (CDCl₃), δ(ppm): 2.66 (3, 3 H, CH₃), 7.32-7.65 (m, 10 H, Ph-H), 7.88 (d, 2 H, J = 10.3 Hz, Ph-H), 8.13 (d, 2 H, J = 10.3 Hz, Ph-H), 8.69 (d, 1 H, J _6,8= 2.6 Hz, H-8), 9.43 (d, 1 H, J _6,8= 2.6 Hz, H-6).

13C-NMR (CDCl₃), δ(ppm): 26.79 CH₃, 127.71 CH, 128.21 CH, 128.48 CH, 129.39 CH, 129.46 CH, 129.61 CH, 129.80 CH, 130.28 CH, 135.16 CH(C-8), 135.78 C, 136.75 C, 137.04 C, 137.94 C, 138.41 C, 140.88 C, 149.40 C, 153.09 CH(C-6), 155.41 C, 156.42 C, 197.45 C(C=O).

HRMS (EI) calcd for C₂₇H₁₉N₃O(M⁺) 401.15285, found 401.15281.

Anal. Calcd. for C₂₇H₁₉N₃O: C, 80.78; H, 4.77; N, 10.47.

Found: C, 81.01; H, 4.92; N, 10.24.

Synthesis of imidazo[1,2-a]pyridine derivatives Synthesis of 6-bromo-2,3-diphenyl-imidazo[1,2-a]pyridine (218)
A 50 ml flask was charged 2-amino-5-bromopyridine (892 mg, 5 mmol), 2-bromo-2-phenyl-acetophenone (desyl bromide) (1.70 g, 6 mmol), NaHCO₃ (491 mg (6 mmol), and iso-propanol 15 ml, the mixture was heated at reflux for 12 h, the alcohol was evaporated, then 30 ml water and 60 ml dichloromethane were added, the mixture was separated and the organic phase was washed with water (2 × 30 ml), dried with anhydrous MgSO₄, evaporated the solvent, the residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate(3/1) and provided white solid 1.17 g, yield 67 %, mp 198-9 °C.

6-Bromo-2,3-diphenylimidazo[1,2-a]pyridine (218)

1H-NMR (CDCl₃), δ(ppm): 7.23-7.66 (m, 12 H, Ph-H H-7 and H-8), 8.05 (dd, 1 H, J ₁ = 1.8 Hz, J ₂ = 0.8 Hz, H-5)

13C-NMR (CDCl₃), δ(ppm): 107.11 C, 118.20 CH(C-8), 121.44 C(C-7), 123.32 CH(C-5), 127.77 CH, 128.03 CH, 128.06 CH, 128.34 CH, 129.20 C, 129.30 CH, 129.75 CH, 130.64 CH(C-5), 133.62 C, 143.17 C.

Anal. Calcd. for C₁₉H₁₃BrN₂ (349.22): C, 65.35; H, 3.75; Br, 22.88 N, 8.02.

Found: C, 65.09; H, 3.97; Br, 23.17; N, 7.91.

Synthesis of [3-(2,3-diphenyl-imidazo[1,2-a]pyridin-6-yl)-prop-2-ynyl]-dimethylamine and related compounds (Sonogashira reaction)
[3-(2,3-Diphenyl-imidazo[1,2-a]pyridin-6-yl)-prop-2-ynyl]-dimethylamine (220)

A 25 ml flask was charged with 6-bromo-2,3-diphenylimidazo[1,2-a]pyridine 218 (153 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.5 mmol),TEA 5 ml, DMF 5 ml and N,N-dimethylpropargylamine 83 mg (1.0 mmol), Argon was passed and the mixture was heated at 100 °C for 24 h, the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel, eluting with ethyl acetate: methanol (4/1), and afforded a light yellow solid 130 mg, yield 74 %, mp 136-7 °C.

1H-NMR (CDCl₃), δ(ppm): 2.27 (s, 6 H, CH₃), 3.34 (s, 2 H, CH₂), 7.15-7.59 (m, 12 H, Ph-H, H-7 and H-8), 7.98 (s, 1 H, H-5).

13C-NMR (CDCl₃), δ(ppm): 44.43 CH₃, 48.57 CH₂, 81.43 C, 86.28 C, 108. 91 C, 117.2 CH(C-8), 126.22 CH(C-7), 127.66 CH, 127.83 CH, 128.02 CH, 128.30 CH, 129.15 CH, 129.67 CH, 130.73 CH(C-5)132.02 C, 132.15 C, 133.76 C, 143.09 C, 143.62.

Anal. Calcd. for C₂₄H₂₁N₃ (351.44): C, 82.02; H, 6.02; N, 11.96.

Found: C, 82.06; H, 6.26; N, 11.78.

[3-(2,3-Diphenyl-imidazo[1,2-a]pyridin-6-yl)-propyl]-dimethylamine (221)

A solution [3-(2,3-diphenyl-imidazo[1,2-a]pyridin-6-yl)-prop-2-ynyl]-dimethylamine 220(84 mg, 0.24 mmol), ethanol (15 ml) and 10 % palladium on charcoal (52 mg, 0.048 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate:methanol (10:1) to give 40 mg light brown solid, yield, 47 %, mp 70-1 °C.

1H-NMR (CDCl₃), δ(ppm): 1.67 (m, 2 H, CH₂), 2.12 (s, 3 H, CH₃), 2.19 (t, 2 H, J = 7.2 Hz, CH₂), 2.49(t, 2 H, J = 7.7 Hz, CH₂), 7.01 (dd, 1 H, J ₁ = 9.0 Hz, J ₂ = 1.5 Hz , H-7), 7.16-7.58 (m, 11 H, Ph-H and H-8), 7.67 (s, 1 H, H-5)

13C-NMR (CDCl₃), δ(ppm):28.74 CH2, 30.39 CH2, 45.44 CH3, 58.70 CH₂, 117.9 CH, 120.81 CH, 126.26 C, 126.85 CH, 127.31 CH, 128.01 CH, 128.21 CH, 128.77 Ch, 129.52 CH, 130.08 C,130.74 CH,132.15 C, 134.34 C, 142.38 C, 142.38 C, 144.06 C.

HRMS (EI) calcd for C₂₄H₂₅N₃(M⁺) 355.2048, found 355.2045.
Buchwald-Hartwig amination of 6-bromo-2,3-diphenylimidazo[1,2-a]pyridine
General procedure:

A schlenk 25ml flask was charged with 6-bromo-2,3-diphenyl-imidazo[1,2-a]pyridine 218 (175 mg, 0.5 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol), BINAP (19 mg, 0.03 mmol), t-BuONa 68 mg (0.7 mmol), appropriate substituted amine 1.0 mmol, dry toluene 5 ml, Argon was passed three times and the mixture was heated at 110 °C for 20 h, after cooled, 50 ml water was added, the mixture was extracted with ethyl acetate (3 × 40 ml), the extract was washed with water (2 × 40 ml), dried with anhydrous MgSO₄, evaporated the solvent, the residue was purified by column chromatography.

6-Morpholin-4-yl-2,3-diphenylimidazo[1,2-a]pyridine (225)

The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate, and provided a grey needle crystal 142 mg, yield 80 %, mp 201-2 °C.

1H-NMR (CDCl₃), δ(ppm): 2.90 t, 4 H, J = 4.6 Hz, 2CH₂), 3.76 (t, 4 H, J = 4.6 Hz, 2CH₂), 7.01 (dd, 1 H, J ₁ = 9.8 Hz, J ₂ = 2.2 Hz, Ar-H), 7.14-7.22 m, 3 H, Ph-H), 7.29 (d, 1 H, J = 1.9 Hz, Ar-H), 7.37-7.53 (m, 7 H, Ph-H), 7.56 (d, 1 H, J = 1.9 Hz, Ar-H).

13C-NMR (CDCl₃), δ(ppm): 50.66 CH₂, 66.68 CH₂, 108.74 CH(C-8), 117.55 CH(C-7),121.07 CH(C-5), 121.71 C, 127.24 CH, 127.88CH, 128.22 CH, 128.82 CH, 129.60 CH, 130.16 C, 130.60 CH, 134.34 C, 139.90 C, 142.01 C, 142.45 C.

Anal. Calcd. for C₂₃H₃₁N₃O (355.439): C, 77.72; H, 5.96; N, 11.82.

Found: C, 77.62; H, 6.22; N, 11.50.

6-(4-Methyl-piperazin-1-yl)-2,3-diphenylimidazo[1,2-a]pyridine (226)

The product was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol:TEA (10/1/0.2), and get grey needle crystal 112 mg, yield 61 %, mp 229-230 °C.

1H-NMR (CDCl₃), δ(ppm): 2.33 (s, 3 H, CH₃), 2.56 (t, 4 H, J = 4.5 Hz, 2CH₂), 3.01 (t, 4 H, J = 4.5 Hz, 2CH₂), 7.10 (dd, 1 H, J ₁ = 9.4 Hz, J ₂ = 2.2 Hz, Ar-H), 7.21-7.29 (m, 3 H, Ph-H), 7.38 (d, 1 H, J = 1.9 Hz, Ar-H), 7.44-7.60 (m, 7 H, Ph-H), 7.62 (d, 1 H, J = 1.9Hz, Ar-H).

13C-NMR (CDCl₃), δ(ppm): 46.07 CH3, 50.38 CH2, 54.86 CH2,108.83CH(C-8),117.38 CH(C-7), 121.48 CH(C-5), 121.66 C, 127.17 CH, 127.89 CH, 128.19 CH, 128.73 CH, 129.55 CH, 130.22 C, 130.60 C, 134.45 C, 139.88 C, 141.98 C, 142.37 C.

Anal. Calcd. for C₂₄H₂₄N₄ (368.47): C, 78.23; H, 6.57; N, 15.21.

Found: C, 78.22; H, 6.58; N, 15.22.

N'-(2,3-Diphenyl-imidazo[1,2-a]pyridin-6-yl)-N,N-dimethyl-propane-1,3-diamine (227)

The productwas purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate:methanol 20:1 to give 40 mg brown solid, yield 22 %, mp 125-6 °C

1H-NMR (CDCl₃), δ(ppm): 1.70-1.79 (m, 2 H, CH₂), 2.21 (s, 6H, 2CH₃), 2.37 (t, 2H, J = 6.4 Hz, CH₂), 2.97 (t, 2 H, J = 6.4 Hz, CH₂), 6.75 (dd, 1 H, Ar-H), 7.11 (s, 1 H, N-H), 7.19-7.62 (m, 12 H, Ph-H and Ar-H).

13C-NMR (CDCl₃), δ(ppm): 26.22 CH₂, 43.99 CH₂, 45.54 CH₃, 58.48 CH₂, 102.21 CH(C-8),117.41 CH(C-7), 120.24 CH(C-5), 121.31 C, 126.93 CH, 127.79 CH, 128.13 CH, 128.52 CH, 129.43 C, 129.44 CH, 130.65 CH, 134.69 C, 136.98 C. 141.47 C, 141.61.

Anal. Calcd. for C₂₄H₂₆N₄ (370.49): C, 77.80; H, 7.07; N, 15.12.

Found: C, 77.81; H, 6.98; N, 15.03.

Synthesis of imidazo[1,2-b]pyridazine derivatives Synthesis of 6-chloro-2,3-diphenylimidazo[1,2-b]pyridazine (219)
A 50 ml flask was charged with 3-amino-6-chloropyridazine (1.30 g, 10 mmol), 2-bromo-2-phenyl-acetophenone (desyl bromide) (3.40 g, 12 mmol), NaHCO₃ (982 mg, 12 mmol), and iso-propanol 30 ml, the mixture was heated at reflux for 12 h, the alcohol was evaporated, then 50 ml water and 100 ml dichlomethane was added inside, separated and the organic phase was washed with water (2 × 30 ml), dried with anhydrous MgSO₄, evaporated the solvent, the residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate(2/1) and provided a yellow needle crystal 2.35 g, yield 77 %, mp 207-8 °C.

6-Chloro-2,3-diphenylimidazo[1,2-b]pyridazine (219)

1H-NMR (CDCl₃), δ (ppm):7.07 (d, 1 H, J = 9.0 Hz, H-7), 7.31-7.67 (m,10 H, Ph-H), 7.94 (d, 1 H, J = 9.0 Hz, H-8)

13C-NMR (CDCl₃), δ (ppm): 118.83 CH, 126.56 CH, 128.03 C, 128.24 CH, 128.39 CH, 128.47 CH, 128.78 CH, 128.95 CH, 130.41 CH, 133.63 C, 137.29 C, 144.09 C, 146.49.

Anal. Calcd. for C₁₈H₁₂ClN₃ (305.76): C, 70.71; H, 3.96; Cl, 11.60; N, 13.74.

Found: C, 70.64; H, 3.93; Cl, 11.80; N, 13.63.

Synthesis of [3-(2,3-diphenyl-imidazo[1,2-b]pyridazin-6-yl)-prop-2-ynyl]-dimethylamine (223)
A 25ml flask was charged with 6-Chloro-2,3-diphenylimidazo[1,2-b]pyridazine 219 (153mg, 0.5mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10mg, 0.5mmol),TEA 5 ml, DMF 5 ml and N,N-dimethylpropargylamine (83 mg, 1.0 mmol), Argon was passed three times and the mixture was heated at 100 °C for 24 h, the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol (6/1), and provided a light yellow solid 160 mg, yield 86 %, mp 144-5 °C.

1H-NMR (CDCl₃), δ (ppm):2.38 (s, 6 H, CH₃), 3.50 (s, 2 H, CH₂), 7.15 (d, 1 H, J = 9.3 Hz, H-7), 7.28-7.66 (m, 10 H, Ph-H), 7.98 (d, 1 H, J = 9.1 Hz, H-8)

13C-NMR (CDCl₃), δ (ppm): 44.47 CH3, 48.53 CH2, 81.66 C, 88.59 C, 120.99 CH, 124.70 CH, 125.32 C, 128.06, 128.34 CH, 128.45 CH, 128.67 CH, 128.71 CH, 130.55 CH, 133.71 C, 137.59 C, 138.01, 143.88 C, 146.57 C.

Anal. Calcd. for C₂₃H₂₀N₄ (352.43): C, 78.38; H, 5.72; N, 15.90.

Found: C, 78.22; H, 5.91; N, 15.86.

Synthesis of [3-(2,3-diphenyl-imidazo[1,2-b]pyridazin-6-yl)-propyl]-dimethylamine (224)
A solution [3-(2,3-Diphenyl-imidazo[1,2-b]pyridazin-6-yl)-prop-2-ynyl]-dimethylamine 223(130 mg, 0.37 mmol), ethanol (15 ml) and 10 % palladium on charcoal (82 mg, 0.074 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate:methanol (10:1) to give 96 mg of light brown solid, yield, 73 %, mp 112-3 °C

1H-NMR (CDCl₃), δ (ppm): 1.80 (m, 2 H, CH₂), 2.11 (s, 3 H, CH₃), 2.23 (t, 2 H, J = 7.3 Hz, CH₂), 2,73 (t, 2 H, J = 7.7 Hz, CH₂), 6.85 (d, 1 H, J = 9.1 Hz, H-7), 7.19-7.60 (m, 10 H, Ph-H), 7.79 (d, 1 H, J = 9.0 Hz, H-8).

13C-NMR (CDCl₃), δ ( ppm): 26.64 CH₂, 33.30 CH₂, 45.46 CH₃, 58.86 CH₂, 118.50 CH, 124.89 CH, 127.74 CH, 128.29 CH, 128.34 CH, 128.40 CH, 128.44 CH, 129.05 C, 130.53 CH,134.38 C, 137.92 C, 142.85 C, 154.92 C.

Anal. Calcd. for C₂₃H₂₄N₄ (356.46): C, 77.50; H, 6.79; N, 15.72.

Found: C, 77.52; H, 6.82; N, 15.62.

Synthesis of pyrimidine derivatives Synthesis of aryl substituted chloro- or iodopyrimidine Using general methods and starting with benzamidine
2,6-Diphenyl-3H-pyrimidin-4-one(249)

Benzamidine hydrochloride hydrate (10.48 g, 0.067mol) and ethyl benzolacetate (14.82 g, 0.074 mol) were added to a solution of sodium (1.8 g, 0.077 mol ) in 80 ml dry ethanol, the mixture was heated at reflux for 16 hours. Ethanol was evaporated in vacuum to dryness and the residue was dissolve in 100 ml water, the mixture was acidified with concentrated hydrochloric acid (pH = 3), the precipitate was collected, washed with water, the crude product was recrystallized with ethanol and provided a white solid 12.70 g, yield 76 %, mp 296-7 °C.

4-Chloro-2,6-diphenylpyrimidine (250)

A 100 ml flask was charged with 2,6-diphenyl-3H-pyrimidin-4-one 249 (12.70 g, 0.051 mol), phosphoryl chloride (36.0 ml, 59.20 g, 0.38 mol), phosphorpentachloride (10.20 g, 0.049 mol). The mixture was heated at reflux for 3 h, the excess of phosphoryl chloride was evaporated in vacuum, then 100 g ice was added slowly and carefully, the solid was collected and washed with water completely. The crude product was recrystallized with petroether (40-60 °C), and provided a white solid 10.20 g, yield 75 %, mp 103-4 °C.

1H-NMR (CDCl₃), δ(ppm): 7.43-7.49 (m, 6 H, Ph-H), 7.55 (s, 1 H, H-5), 8.11-8.14 (dd, 2 H, Ph-H), 8.48-8.52 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 114.47 CH(C-5), 127.40 CH, 128.58 CH, 128.65 CH, 129.01 CH, 131.42 CH, 131.51 CH,135.90 C, 136.48 C, 162.22 C, 165.21 C, 165.67 C.

Anal. Calcd for C₁₆H₁₁ClN₂ (266.72): C, 72.05; H, 4.16; Cl, 13.29; N, 10.50

Found: C, 72.15; H, 4.29; Cl, 13.14; N, 10.36

4-Iodo-2,6-diphenylpyrimidine (251)

A mixture of 4-Chloro-2,6-diphenylpyrimidine 250 (3.0 g, 8.3 mmol) and 57 % HI (30 ml, 0.23 mol) was stirred at room temperature for 20 h, then 100 ml cold 10 % NaOH was added, the precipitate was collected and washed with cold water, the crude product was recrystallized with petroether (40-60 °C), and provided a light brown solid 1.70 g, yield 42 %, mp 98 °C.

1H-NMR (CDCl₃), δ(ppm): 7.41-7.48 (m, 6 H, Ph-H), 7.95 (s, 1 H, H-5), 8.06-8.10 (dd, 2 H, Ph-H), 8.44-8.48 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 125.57 CH(C-5), 127.33 CH, 128.52 CH, 128.57 CH, 128.99 CH, 130.80 (C-4) 131.32 CH, 131.40 CH,135.46 C, 136.34 C, 163.44 C, 164.60 C.

Anal. Calcd for C₁₆H₁₁IN₂ (358.18): C, 53.65; H, 3.10; I, 35.43; N, 7.82.

Found: C, 53.79; H, 3.24; I, 35.27; N, 7.58.

2-Phenyl-1H-pyrimidine-4,6-dione (252)

Benzamidine hydrochloride hydrate (10.90 g, 0.070mol) and diethyl malonate (11.20 g, 0.070mol) were added to a solution of sodium (4.30 g, 0.19mol) in 70 ml dry ethanol, the mixture was heated at reflux for 3 hours. Ethanol was evaporated in vacuum to dryness and the residue was dissolve in 80 ml warm water, the mixture was acidified with concentrated hydrochloric acid (pH = 3), the precipitate was collected, washed with water, the crude product was recrystallized with DMF/water and afforded a white solid 6.90 g, yield 52 %, mp 324-5 °C.

4,6-Dichloro-2-phenylpyrimidine (253)

A mixture of 2-Phenyl-pyrimidine-4,6-dione(2-phenyl-4,6-dihydroxypyrimidine) 252 (6.90 g, 0.037 mol), phosphoryl chloride (18 ml, 0.19 mol), N,N-dimethylaniline (4.4 g, 0.036 mol), was heated at reflux for 2 h, the excess POCl₃ was evaporated in vacuum, then 50 g ice was added inside slowly and carefully, the solid was collected and washed with water completely. The crude product was recrystallized with ethanol, and provided a light yellow solid 7.5 g, yield 89 %, mp 93-4°C.

1H-NMR (CDCl₃), δ(ppm): 7.20 (s, 1 H, H-5), 7.42-7.46 (m, 3 H, Ph-H), 8.35-8.38 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 118.8 CH(C-5), 128.73 CH, 128.87 CH, 132.26 CH, 134.87 C, 162.03 C, 165.76. C.

Anal. Calcd for C₁₀H₆Cl₂N₂ (225.07): C, 53.36; H, 2.69; Cl, 31.50; N, 12.45.

Found:C, 53.24; H, 2.86; Cl, 31.75; N, 12.32.

4,6-Diiodo-2-phenylpyrimidine (254)

A mixture of 2-phenyl-4,6-dichloropyrimidine 254 (2.0 g, 9.0 mmol), NaI (2.7 g, 18 mmol) and 57 % HI 40 ml was stirred at 40 °C under Argon for 24 h, 50 g ice was added, the mixture was neutralizd with 40 % NaOH, and extracted with CH₂Cl₂ (3 × 40 ml), the extract was washed with water, dried with anhydrous MgSO₄, the solvent was evaporated, and the crude product was recrystallized with with petroether (40-60 °C), and provided a yellow solid 3.30 g, yield 91 %, mp 103-5 °C.

1H-NMR (CDCl₃), δ(ppm): 7.38-7.46 (m, 3 H, Ph-H), 8.05 (s, 1 H, H-5), 8.28-8.33 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 128.67 CH, 128.84 CH, 132.07 CH, 134.73 C, 139.67 CH(C-5), 164.94. C.

Anal. Calcd for C₁₀H₆I₂N₂ (407.98): C, 29.44; H, 1.48; I, 62.21; N, 6.87.

Found: C, 29.60; H, 1.63; I, 62.01; N, 6.72.

Using Suzuki cross-coupling and starting with 2,4,6-trichloropyrimidine
(a)2-Chloro-4,6-diarylpyrimidine

General procedure:

To a solution of 2,4,6-trichloropyrimidine (1.0 g, 5.5 mmol) in 50 ml DME, appropriate arylboronic acid (11.0 mmol, 2.0 equiv), sodium carbonate (3.61 g, 34.1 mmol, 6.2 equiv, dissolve in a minimium amount of water) was added. The active catalyst was generated by the addition of palladium acetate (31 mg, 0.14 mmol, 2.5 % equiv), and triphenylphosphine (72 mg, 0.28 mmol, 5 % equiv) to the mixture. Argon was passed, and the mixture was heated at 70 °C for 24 h. The solvent was removed by rotary evaporation and the product was extracted with methylene chloride (3 × 50 ml), the organics washed with water (2 × 50 ml), and dried over anhydrous magnesium sulphate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate(15/1→6/1).

2-Chloro-4,6-diphenylpyrimidine (240a)

White solid, yield 67 %, mp 106-8 °C;

1H-NMR(CDCl₃), δ(ppm): 7.53-7.55 (m, 6 H, Ph-H), 8.01 (s, 1 H, H-5), 8.12-8.16 (m, 4 H, Ph-H).

13C-NMR(CDCl₃), δ(ppm):110.93 CH(H-5), 127.46 CH, 129.09 CH, 131.66 CH, 135.65 C, 162.07 C, 167.64 C.

Anal. Calcd. for C₁₆H₁₁ClN₂(266.73): C, 72.05; H, 4.16; Cl, 13.29; N, 10.50.

Found: C, 72.21; H, 4.30; Cl, 13.47; N, 10.50.

2-Chloro-4,6-bis-(4-chloro-phenyl)-pyrimidine

White solid, yield: 82%; mp.151-3°C;

1H-NMR(CDCl₃), δ(ppm): 7.42 (dd, 4 H, J = 8.7 Hz. Ph-H), 7.85 (s, 1 H, H-5), 8.01 (dd, 4 H, J = 8.7 Hz, Ph-H).

13C-NMR(CDCl₃), δ(ppm):110.31CH(H-5), 128.73 CH, 129.41 CH, 133.83 C, 138.19 C, 162.17 C, 166.52 C.

Anal. Calcd. for C₁₆H₉Cl₃N₂(335.62): C, 57.26; H, 2.70; Cl, 31.69; N, 8.35.

Found: C, 57.23; H, 2.61; Cl, 31.80; N, 8.44.

(b)2,4-dichloro-6-arylpyrimidine

General procedure:

To a solution of 2,4,6-trichloropyrimidine (1.0 g, 5.5 mmol) in 50 ml DME, appropriate arylboronic acid (5.5 mmol, 1.0 equiv), sodium carbonate (1.80 g, 17.0 mmol, 3.1 equiv, dissolve in a minimium amount of water) was added. The active catalyst was generated by the addition of palladium acetate (31 mg, 0.14 mmol, 2.5 % equiv), and triphenylphosphine (72 mg, 0.28 mmol, 5 % equiv) to the mixture. Argon was passed, and the mixture was heated at 70 °C for 24 h. The solvent was removed by rotary evaporation and the product was extracted with methylene chloride (3 × 50 ml), the organic layer was washed with water (2 × 50 ml), and dried over anhydrous magnesium sulphate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel, eluting with cyclohexane:CH₂Cl₂ (5/1→1/1).

2,4-dichloro-6-phenylpyrimidine (239a)

White solid, yield: 81 %; mp 83-4 °C;

1H-NMR(CDCl₃), δ(ppm): 7.44-7.48 (m, 3 H, Ph-H), 7.59 (s, 1 H, H-5), 7.96-8.01 (dd, 2 H, J = 8.7 Hz, Ph-H).

13C-NMR(CDCl₃), δ(ppm):115.33 CH(H-5), 127.61 CH, 129.24 CH, 132.48 CH, 134.09 C, 160.97 C, 162.93 C, 168.20 C.

Anal. Calcd. for C₁₀H₆Cl₂N₂(225.08): C, 53.36; H, 2.69; Cl, 31.50; N, 12.45.

Found: C, 53.41; H, 2.51; Cl, 31.20; N, 12.68.

2,4-Dichloro-6-(4-chloro-phenyl)-pyrimidine (239b)

White solid, yield: 78 %; mp.123-5 C;

1H-NMR(CDCl₃), δ(ppm): 7.41-7.45 (dd, 2 H, Ph-H), 7.57 (s, 1 H, H-5), 7.93-7.96 (dd, 2 H, Ph-H).

13C-NMR(CDCl₃), δ(ppm):115.12CH(H-5), 128.87 CH, 129.56 CH, 132.49 C, 138.97 C, 161.07 C, 163.17 C, 166.88 C.

Anal. Calcd. for C₁₀H₅Cl₃N₂(259.52): C, 46.28; H, 1.94; Cl, 40.98; N, 10.79.

Found: C, 46.32; H, 2.04; Cl, 40.70; N, 10.48.

(c)2-Chloro-4-(4-chloro-phenyl)-6-phenylpyrimidine (255)

To a solution of 2,4-dichloro-6-(4-chloro-phenyl)-pyrimidine 239b (290 mg, 1.1 mmol) in 15 ml DME, phenyllboronic acid (134 mg, 1.1 mmol, 1.0 equiv), sodium carbonate (360 mg, 3.4 mmol, 3.1 equiv, dissolve in a minimium amount of water) was added. The active catalyst was generated by the addition of palladium acetate (12 mg, 0.055 mmol, 5 % equiv), and triphenylphosphine (29 mg, 0.11 mmol, 10 % equiv) to the mixture. Argon was passed, and the mixture was heated at 70 °C for 24 h. The solvent was removed by rotary evaporation and the product was extracted with methylene chloride (3 × 20 ml), the organic layer was washed with water (2 × 20 ml), and dried over anhydrous MgSO₄. The solvent was evaporated, the residue was purified by flash column chromatography on silica gel, eluting with cyclohexane:CH₂Cl₂(5/1→1/1), and provided a white solid 274 mg, yield 82 %, mp 97-9 °C;

1H-NMR (CDCl₃), δ(ppm): 7.39-7.46 (m, 5 H, Ph-H), 7.87 (s, 1 H, H-5), 7.98-8.05 (m, 4 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):110.63 CH(C-5), 127.46 CH, 128.73 CH, 129.12 CH, 129.35 CH, 131.80 CH, 134.05 C, 135.84 C, 138.02 C, 162.13 C, 166.31 C, 167.86 C.

Anal. Calcd. for C₁₆H₁₀Cl₂N₂: C, 63.81; H, 3.35; Cl, 23.54; N, 9.30.

Found: C, 63.71; H, 3.46; Cl, 23.66; N, 9.13.

Sonogashira cross-coupling of halopyrimidines From 4-iodo-2,6-diphenylpyrimidine 251
General procedure:

A 25 ml flask was charged with 4-iodo-2,6-diphenylpyrimidine 251 (358 mg, 1.0 mmol), Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol), cuprous iodide (19 mg, 0.10 mmol), dry triethylamine 10 ml, and appropriate alkyne 1.5 mmol. Argon was passed inside and the mixture was stirred at room temperature for 24 h, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel.

[3-(2,6-Diphenyl-pyrimidin-4-yl)-prop-2-ynyl]-dimethylamine (256)

The product was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol (8:1) and provided 237 mg brown solid, yield 76 %, mp 62-3 °C.

1H-NMR (CDCl₃), δ (ppm):2.29 (s, 6 H, CH₃), 3.44 (s, 2 H, CH₂), 7.35-7.37 (m, 6 H, Ph-H), 7.51 (s, 1 H, H-5), 8.05 (dd, 2 H, Ph-H), 8.48 (dd, 2 H, Ph-H).

13C-NMR (CDCl₃), δ (ppm): 44.47 CH₃, 48.59 CH₂, 84.19 C, 89.11 C, 116.91 CH(H-5), 127.20 CH, 128.46 CH, 128.52 CH, 128.92 CH, 130.89 CH, 132.15 CH, 136.44 C, 137.44 C, 151.39 C, 164.01 C, 164.70 C.

Anal. Calcd. for C₂₁H₁₉N₃ (313.4): C, 80.48; H, 6.11; N, 13.41.

Found: C, 80.30; H, 6.35; N, 13.24.

2-[3-(2,6-Diphenyl-pyrimidin-4-yl)-prop-2-ynyl]-isoindole-1,3-dione (258)

The product was purified by column chromatography on silica gel, ethyl acetate:cyclohexane (1:1) was as eluting solvent and provided a brown solid, yield 84 %, mp 221-2 °C.

1H-NMR (CDCl₃), δ (ppm):4.71 (s, 2 H, CH₂), 7.40-7.46 (m, 6 H, Ph-H), 7.60 (s, 1 H, H-5), 7.67-7.70 (dd, 2 H, Ph-H), 7.83-7.86 (dd, 2 H, Ph-H), 8.10-8.13 (dd, 2 H, Ph-H), 8.46-8.49 (dd, 2 H, Ph-H)

13C-NMR (CDCl₃), δ (ppm): 27.73 CH₂, 81.42 C, 86.28 C, 117.12 CH(C-5), 123.70 CH, 127.24 CH, 128.49 CH, 128.95 CH, 130.92 CH, 131.24 CH, 131.99 C, 134.35 CH, 136.34 C, 137.27 C, 150.74 C, 164.17 C, 164.78 C, 166.94 C.

Anal. Calcd. for C₂₇H₁₇N₃ O (415.44): C, 78.06; H, 4.12; N, 10.11.

Found: C, 78.16; H, 4.28; N, 10.05

[3-(2,6-Diphenyl-pyrimidin-4-yl)-propyl]-dimethylamine (257)

A solution [3-(2,6-diphenyl-pyrimidin-4-yl)-prop-2-ynyl]-dimethylamine 256 (126 mg, 0.4 mmol), ethanol (15 ml) and 10 % palladium on charcoal (89 mg, 0.08 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, using ethyl acetate:Methanol (10:1) as eluting solvent to provide 96 mg light brown oil, yield 76 %.

1H-NMR (CDCl₃), δ(ppm): 1.91-2.01 (m, 2 H, CH₂), 2.17(s, 3 H, CH₃), 2.31 (t, 2 H, J = 7.3 Hz, CH2), 2.79 (t, 2 H, J = 7.5 Hz, CH2), 7.35 (s, 1 H, H-5), 7.38-7.41 (m, 6 H, Ph-H), 8.11 dd, 2 H, Ph-H), 8.51 (dd, 2 H, Ph-H)

13C-NMR (CDCl₃), δ(ppm):26.46 CH₂, 35.77 CH₂, 45.35 CH₃, 58.99 CH₂, 113.54 CH(C-5), 127.10 CH, 128.38 CH, 128.42 CH, 128.85 CH, 130.46 CH, 130.65 CH, 137.34 C, 138.21 C, 163.71 C, 164.22 C, 171.00 C.

HRMS (EI) calcd for C₂₁H₂₃N₃(M⁺) 317.18920, found 317.18920.
From 2-chloro-4,6-diarylsubstituted pyrimidine
General procedure:

A 25 ml flask was charged with appropriate 2-chloro-4,6-diarylpyrimidine (0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol),TEA 5 ml, DMF 5 ml and N,N-dimethylpropargylamine 83 mg (1.0 mmol), Argon was passed three times and the mixture was heated at 100 °C for 24 h, the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel, eluting with ethyl acetate: methanol (5/1),

[3-(4,6-Diphenyl-pyrimidin-2-yl)-prop-2-ynyl]-dimethylamine (259a)

Brown solid 60 mg was obtained, yield 38 %, mp 101-3 °C. When using KOAc as base, 112 mg brown solid was obtained, yield 70 %.

1H-NMR(CDCl₃), δ(ppm):2.39 (s, 6 H, CH₃), 3.54(s, 2 H, CH₂), 7.43-7.46 (m, 6 H, Ph-H), 7.93 (s, 1 H, H-5), 8.06-8.10 (dd, 4 H, Ph-H).

13C-NMR(CDCl₃), δ(ppm): 44.35 CH₃, 48.44 CH₂, 83.07 C, 85.40 C, 111.55CH(H-5), 127.37 CH, 128.96 CH, 131.08 CH, 136.56C, 153.09C, 165.16 C

HRMS ( EI ) calcd for C₂₁H₁₉N₃(M⁺) 313.15790, found , 313.15785

Anal. Calcd. for C₂₁H₁₉N₃(313.40) C, 80.48; H, 6.11; N, 13.41.

Found: C, 80.14; H, 6.12; N, 13.37.

{3-[4,6-Bis-(4-chloro-phenyl)-pyrimidin-2-yl]-prop-2-ynyl}-dimethylamine (259b)

Brown solid 98 mg was obtained, yield: 51 %, mp 112-4 °C.

1H-NMR (CDCl₃), δ(ppm): 2.35 (s, 6 H, CH₃), 3.50 (s, 2 H, CH₂), 7.37 (d, 4 H, J = 8.7 Hz), 7.80 (s, 1 H, H-5), 7.98 (d, 4 H, J = 8.7 Hz)

13C-NMR (CDCl₃), δ(ppm):44.38 CH₃, 48.40 CH₂, 83.72 C, 85.06 C, 111.77 CH(H-5), 128.63 CH, 129.18 CH, 134.67 CH, 137.47 C, 153.09 C, 163.97 C

Anal. Calcd. for C₂₁H₁₇Cl₂N₃ (382.28): C, 65.98; H, 4.48; Cl, 18.55; N, 10.99.

Found: C, 65.84; H, 4.61; Cl, 18.73; N, 10.81.

{3-[4-(4-Chloro-phenyl)-6-phenyl-pyrimidin-2-yl]-prop-2-ynyl}-dimethylamine (259c)

Brown solid 88 mg was obtained, yield 51 %, mp 86-8 °C.

1H-NMR(CDCl₃), δ(ppm):2.35 (s, 6 H, CH₃), 3.50 (s, 2 H, CH₂), 7.36-7.42(m, 5 H, Ph-H), 7.84 (s, 1 H, H-5), 7.97-8.05 (m, 4 H, Ph-H).

13C-NMR(CDCl₃), δ (ppm): 44.39 CH₃, 48.44 CH₂, 83.45 C, 85.22 C, 111.13CH(H-5), 127.34 CH, 128.64 CH, 128.96 CH, 129.16 CH, 131.20 CH, 134.89 C, 136.32 C, 137.33 C, 153.10C, 163.80 C, 165.30 C

Anal. Calcd. for C₂₁H₁₈ ClN₃(347.84): C, 72.51; H, 5.22; Cl, 10.19; N, 12.08.

Found: C, 72.66; H, 5.41; Cl, 10.26; N, 11.94.

[3-(4,6-Diphenyl-pyrimidin-2-yl)-propyl]-dimethylamine (260)

A solution [3-(4,6-diphenyl-pyrimidin-2-yl)-prop-2-ynyl]-dimethylamine 259a (76mg, 0.24 mmol) in ethanol (15 ml) and 10 % palladium on charcoal (51 mg, 0.048 mmol on Pd, 0.2equiv) was stirred under hydrogen at room temperature and atmosphere 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvents were removed under reduced pressure, the residue was purified by column chromatography on neutral Al₂O₃ gel, using ethyl acetate:cyclohexane (1:1) as eluting solvent to provide 55 mg light brown oil, yield 72 %.

1H-NMR (CDCl₃), δ(ppm): 2.04-2.14 (m, 2 H, CH₂), 2.20 (s, 2 × 3 H, CH₃), 2.37 (t, 2 H, J = 7.5 Hz, CH₂), 3.03 (t, 2 H, J = 7.7 Hz, CH₂), 7.41-7.44 (m, 6 H, Ph-H), 7.81 (s, 1 H, H-5), 8.05-8.08 (m, 4 H, Ph-H),

13C-NMR (CDCl₃), δ(ppm):26.53 CH₂, 37.52 CH₂, 45.61 CH₃, 59.56CH₂, 110.03 CH(C-5), 127.25 CH, 128.91 CH, 130.62 CH, 137.56 C, 164.66 C, 171.27 C.

HRMS (EI) calcd for C₂₁H₂₃N₃ (M⁺) 317.18920, found 317.18920.

259b and 259c were hydrogenated with hydrogen, using the same conditions, only 260 was obtained, and the yields were 37 % and 44 %, respectively.
Nucleophilic substitution of 2-chloropyrimidine To introduce 3-dimethylamino-propylamino group
N'-(4,6-Diphenyl-pyrimidin-2-yl)-N,N-dimethyl-propane-1,3-diamine (262)

A mixture of 2-chloro-4,6-diphenylpyrimidine (107 mg, 0.4 mmol) in N,N-dimethyl-propanediamine 3 ml was heated at 110 °C for 16 h, then evaporated the solvent to dryness in high vacuum, the residue was dissolved in 20 ml 2 N HCl, and washed with dichloromethane (2 × 20 ml), the aqueous layer was basified with solid potassium carbonate (ph > 10), then extracted with dichloromethane (4 × 20 ml), the organic phase was dried with anhydrous MgSO₄, evaporated the solvent, and provide yellow solid 105 mg, yield 79 %, mp 62-4 °C;

1H-NMR (CDCl₃), δ(ppm): 1.73 (m, 2 H, CH₂), 2.14 (s, 3 H, CH₃), 2.31 (t, 2 H, J = 7.2 Hz, CH₂), 3.51 (dt, 2 H, J ₁ = 6.0 Hz, J ₂ = 6.7 Hz, CH₂), 5.73 (t, 1 H, J = 6.0 Hz, NH), 7.29 (s, 1 H, H-5), 7.35-7.38 (m, 6 H, Ph-H), 7.99 (dd, 4 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm): 27.50 CH₂, 40.32 CH₂, 45.57 CH₃, 57.82 CH₂, 102.67 CH(C-5), 127.10 CH, 128.66 CH, 130.28 CH, 138.12 C, 163.11 C, 165.57 C.

HRMS (EI) calcd for C₂₁H₂₄N₄(M⁺) 332.20010, found 332.20014.
To introduce 2-dimethylamino-ethoxy group
[2-(4,6-Diphenyl-pyrimidin-2-yloxy)-ethyl]-dimethylamine (263)

A mixture of 2-chloro-4,6-diphenylpyrimidine 240a (107 mg, 0.4 mmol) and t-BuOK (56 mg, 0.5 mmol) in 2-(dimethylamino)-ethanol 3 ml was heated at 110 °C for 16 h, then evaporated to dryness in high vacuum, the residue was dissolved in 20 ml 2 N HCl, and washed with dichloromethane (2 × 20 ml), the aqueous layer was basified with solid potassium carbonate (pH > 10), then extracted with dichloromethane (4× 20 ml), the organic phase was dried with anhydrous MgSO₄, evaporated the solvent, and provided a yellow glass 38 mg, yield 30 %.

1H-NMR (CDCl₃), δ(ppm): 2.35 (s, 6 H, CH₃), 2.84 (t, 2 H, J = 6.0 Hz, CH₂), 4.62 (t, 2 H, J = 6.0 Hz, CH₂), 7.41-7.44 (m, 6 H, Ph-H), 7.70 (s, 1 H, H-5), 8.08 (dd, 4 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):45.81 CH₃, 57.83 CH₂, 65.01 CH₂, 106.65 CH(C-5), 127.30 CH, 128.83 CH, 130.98 CH, 136.87 C, 165.64 C, 167.05 C.

HRMS (EI) calcd for C₂₀H₂₁N₃O (M⁺) 319.16846, found 319.16852.
To introduce 2-dimethylamino-ethylsulfanyl group
General procedure:

A 50 ml flask was charged with appropriate 2-chloro-4,6-diarylpyrimidine (0.4 mmol), 2-(dimethylamino)-ethanethiol hydrochloride (N, N-dimethylamino-2-mercaptoethyl ammonium chloride) (63 mg, 0.42 mmol), sodium hydroxide (40 mg, 1.0 mmol) and ethanol 20 ml. The mixture was refluxed overnight (16 h), evaporated the solvent, 30 ml water was added, and neutralized the mixture with 2 N HCl. The mixture was extracted dichloromethane (3 × 30 ml), washed with water 30 ml, the organic phase was dried with anhydrous magnesium sulphate, evaporated the solvent, the residue was column chromatography on silica gel.

[2-(4,6-Diphenyl-pyrimidin-2-ylsulfanyl)-ethyl]-dimethylamine (261a)

Eluting with ethyl acetate: methanol (9:1) to provide light yellow solid 47 mg, yield: 35 %, mp. 86-8 °C;

1H-NMR (CDCl₃), δ(ppm): 2.30 (s, 6 H, CH₃), 2.71 (t, 2 H, J = 7.5 Hz, CH₂), 3.35 (t, 2 H, J = 7.5 Hz, CH₂), 7.42-7.43 (m, 6 H, Ph-H), 7.68 (s, 1 H, H-5), 8.05 (dd, 4 H, Ph-H).

13C-NMR (CDCl₃), δ(ppm):28.52 CH₂, 45.33 CH₃, 58.80 CH₂, 107.98 CH(C-5), 127.20 CH, 128.84 CH, 130.95 CH, 136.78 C, 164.75 C, 172.06 C.

HRMS (EI) calcd for C₂₀H₂₁N₃S (M⁺) 335.14562, found 335.14558.

{2-[4,6-Bis-(4-chloro-phenyl)-pyrimidin-2-ylsulfanyl]-ethyl}-dimethylamine (261b)

Eluting with ethyl acetate: methanol (10:1) to provide light yellow solid 54 mg, yield 33 %, mp 131-2 °C;

1H-NMR(CDCl₃), δ(ppm):2.29 (s, 6 H, CH₃),2.69 (t, 2 H, J = 7.5 Hz,CH₂),3.34 (t, 2 H, J = 7.5 Hz,CH₂), 7.40 (dd, 4 H, Ph-H), 7.60 (s, 1 H, H-5), 8.00 (dd, 4 H, Ph-H).

13C-NMR (CDCl₃), δ (ppm): 28.68 CH₂, 45.37 CH₃, 58.71 CH₂, 107.38 CH(H-5), 128.52 CH, 129.18 CH,135.04 C, 137.34 C, 163.70 C, 172.49.

HRMS (EI) calcd for C₂₀H₁₉Cl₂N₃S_{(M⁺): 403.06767, found 403.06746.}
To introduce 3-hydroxypropylamino group
A solution of 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) in THF (10ml) was added dropwise to a stirred solution of propanlamine (1.50 g, 20 mmol) in THF 20ml at room temperature. The

turbid mixture was allowed to stir at room temperature overnight (about 16 h). The solvent was removed by evaporation under vacuum to give a white solid. The crude product was separated by flash chromatograph on silica gel.

3-(2,6-Dichloro-pyrimidin-4-ylamino)-propan-1-ol (264b)

264b was eluted with hexane:ethyl acetate (1/2), a white solid 0.882 g was obtained, yield 40 %, mp 91-2 °C.

1H-NMR(CDCl₃), d(ppm): 1.81-1.90 (m, 2 H, CH₂), 3.49-3.56(m, 2 H, CH₂), 3.63-3.68 (m, 2H, CH₂), 4.85 (t, 1 H, J = 4.7 Hz, NH), 6.69(s, 1 H, H-6), 8.39 (br, 1 H, OH).

13C-NMR(CDCl₃), d(ppm): 31.52 CH₂, 37.76 CH₂, 58.26 CH₂, 102.70 CH(C-6), 156.74 C, 159.17 C, 164.12 C.

Anal. Calcd. for C₇H₉Cl2N2O (222.08): C, 37.86; H, 4.08; Cl, 31.93; N, 18.92.

Found: C, 38.02; H, 4.03; Cl, 31.69; N, 18.95.

3-(4,6-Dichloro-pyrimidin-2-ylamino)-propan-1-ol (264a)

264a was eluted with ethyl acetate, a white solid 1.089 g was obtained, yield 49 %, mp 118-9 °C.

1H-NMR(CDCl₃), d(ppm): 1.36-1.45 (m, 2 H, CH₂), 3.00-3.06(m, 2 H, CH₂), 3.17-3.23 (m, 2 H, CH₂), 4.36 (t, 1 H, J = 4.9 Hz, NH), 6.57(s, 1 H, H-6), 7.81 (br, 1 H, OH).

13C-NMR(CDCl₃), d(ppm): 31.63 CH₂, 38.30 CH₂, 58.49 CH₂, 107.23 CH(C-6), 160.80 C, 161.50 C.

Anal. Calcd. for C₇H₉Cl2N2O (222.08): C, 37.86; H, 4.08; Cl, 31.93; N, 18.92.

Found: C, 38.10; H, 4.08; Cl, 31.99; N, 19.04.

Synthesis of pyridine derivatives Synthesis of 2-amino-3,5-diphenylpyridine (283):
2-Amino-3,5-dibromopyridine (2.52 g, 10.0 mmol) and phenylboronic acid (2.53 g, 21.0 mmol) were dissolved in methanol (20 ml). Na₂CO₃ (25 g, 0.24 mol) in water (50 ml) and then toluene (100 ml) were added, and the suspension was degassed with evaporating for 10 min and then passing Argon. Pd (PPh₃)₂Cl₂ (177 mg, 0.25 mmol) was then added, and the mixture was heated under reflux under argon with vigorous stirring for 66 h. The organic solvents were removed under reduced pressure, followed by extraction with ethyl acetate (3 × 50 ml), washed with water (2 × 50 ml), and dried with anhydrous MgSO₄, evaporated the solvents, the residue

was separated with column chromatography on silica ( eluting with diethyl ether) and provide 1.37 g light brown solid, yield: 53 %, mp 106 °C.

1H-NMR(CDCl₃), d(ppm): 4.83 (s, 2 H, NH₂), 7.39-7.64 (m, 10 H, Ph-H), 7.69 (d, 1 H, J = 2.3 Hz, H-4), 7.81 (d, 1 H, J = 2.3 Hz, H-6).

13C-NMR(CDCl₃), d(ppm): 121.74 C, 126.29 CH, 126.94 CH, 127.86 CH, 127.94 CH, 128.76 CH, 128.93 CH, 129.18 CH, 136.60 CH(C-4), 137.98 C, 138.20 C, 145.48 CH(C-6), 155.21 C.

Anal. Calcd. for C₁₇H₁₄N₂ (246.30): C, 82.90; H, 5.73; N, 11.37.

Found: C, 82.83; H, 5.93; N, 11.41.

Synthesis of 2-iodo-3,5-diphenylpyridine (284):
Aminopyridine 283 (1.00 g, 4.0 mmol) was dissolved in CH₂I₂ (13 ml), aided by ultrasound. tert-Butyl nitrite (0.65 g, 6.0 mmol) and I₂ (1.02 g, 4.0 mmol) were then added, and the reaction mixture was stirred at room temperature for 24 h under exclusion of light. To complete the reaction (TLC monitoring), additional of tert-butyl nitrite (0.32 g 3.0 mmol) was added and the mixture was stirred for further 12 h. The reaction was stopped by addition of 30 ml of satd. Na₂CO₃ solution and an excess of solid Na₂S₂O₃. The solvents were evaporated to dryness under reduced pressure, followed by addition of 40 ml water and extraction with ethyl acetate (3 × 40 ml). The combined organic layers were dried with MgSO₄ and concentrated. The residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate (10:1-3:1), to provide 660 mg light brown solid, yield 46 %, mp 86-7 °C.

1H-NMR(CDCl₃), d(ppm): 7.31-7.44 (m, 10 H, Ph-H), 7.54 (d, 1 H, J = 2.6 Hz, H-4), 8.43 (d, 1 H, J = 2.6 Hz, H-4).

13C-NMR (CDCl₃), d(ppm): 120.77 C, 127.08 CH, 128.40 CH, 128.53 CH, 128.67 CH, 129.31 CH, 129.38 CH, 135.39 CH(C-4), 136.05 C, 136.27 C, 141.36 C, 144.05 C, 147.46 CH(C-6).

Anal. Calcd. for C₁₇H₁₂IN (357.19): C, 57.16; H, 3.39; I, 35.53; N, 3.93.

Found: C, 57.48; H, 3.60; I, 35.30; N, 3.98.

3,5-Diphenyl-1H-pyridin-2-one (285):

Further elution of the crude product described above with ethyl acetate, 161 mg light yellow solid was obtained, yield: 16 %, mp 192-3 °C.

1H-NMR(CDCl₃), d(ppm): 7.30-7.46(m, 8H, Ph-H), 7.62(d, 1H, J=2.6Hz, H-4), 7.76-7.79(dd, 2H, J=5.4Hz, Ph-H), 7.90(d, 1H, J=2.6Hz, H-6), 13.63(s, 1H, N-H).

13C-NMR(CDCl₃), d(ppm): 121.32 C, 125.83 CH, 127.35 CH, 128.03 CH, 128.41 CH, 128.63 CH, 129.10 CH, 131.29 CH(C-4), 131.35 C, 136.49 C, 139.50 CH(C-6), 163.45 C.

Anal. Calcd. for C₁₇H₁₃NO (247.29): C, 82.57; H, 5.30; N, 5.66.

Found: C, 82.68; H, 5.42; N, 5.57.

Synthesis of 3-(3,5-diphenyl-pyridin-2-yl)-prop-2-ynyl]-dimethylamine(286):
2-Iodo-3,5-diphenylpyridine 284 (250 mg, 0.7 mmol)CuI (13 mg, 0.10 equiv.), Pd(PPh₃)₂Cl₂ (25 mg, 0.05 equiv), N,N-dimethyl-propargylamine (116 mg, 1.4 mmol 2 equiv) was suspended in triethylamine (10 ml) and pass the Argon, the suspension was stired at room temperature 24 hours, The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol 6:1) and provided 196 mg of 286 as a brown crystal yield, 89 %, mp 82-83 °C.

1H-NMR(CDCl₃), d(ppm): 2.08 (s, 6 H, CH₃), 3.35 (s, 2 H, CH₂), 7.28-7.51 (m, 10 H, Ph-H), 7.74 (d, 1H, J = 1.8 Hz, H-4), 8.70 (d, 1 H, J = 1.8 Hz, H-6).

13C-NMR (CDCl₃), d(ppm): 44.00 CH₃, 48.47 CH₂, 84.68 C, 88.34 C, 127.07 CH, 128.12 CH, 128.29 CH, 128.42 CH, 129.16 CH, 129.26 CH, 135.06 CH(C-4), 135.54 C, 136.95 C, 138.29 C, 139.60 C, 139.84 C, 146.97 CH(C-6).

HRMS (EI) calcd for C₂₂H₂₀N₂(M⁺) 312.16265, found 312.16260.

Anal . Calcd. for C₂₂H₂₀N₂ (312.41): C, 84.58; H, 6.45; N, 8.97.

Found: C, 84.52; H, 6.50; N, 8.94.

Synthesis of 3,5-diphenyl-2-(3-dimethylaminopropyl)-pyridine (287):
A solution [3-(3,5-diphenyl-pyridin-2-yl)-prop-2-ynyl]-dimethylamine 286 (125 mg, 0.4 mmol) in ethanol (15 ml) and 10 % palladium on charcoal (89 mg, 0.08 mmol on Pd, 0.2 equiv) wase stirred under hydrogen at room temperature and atmosphere 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel (ethyl acetate and ethyl acetate:Methanol 10:1) to provide 90 mg of 287 as a light brown oil, yield 71%.

1H-NMR(CDCl₃), d(ppm): 1.73-1.83 (m, 2 H, CH₂), 2.08 (s, 6 H, 2CH₃), 2,20 (t, 2 H, J = 7.5 Hz, CH₂), 2.73 (t, 2 H, J = 7.9 Hz, CH₂), 7.26-7.52 (m, 10 H, Ph-H), 7.61 (d, 1 H, J = 2.3 Hz, H-4), 8.70 (d, 1 H, J = 2.3 Hz, H-6).

13C-NMR (CDCl₃), d(ppm): 27.39 CH₂, 33.08 CH₂, 45.02 CH₃, 59.26 CH₂, 127.00 CH, 127.59 CH, 127.90 CH, 128.47 CH, 129.04 CH, 129.08 CH, 133.86 C, 135.89 C, CH(C-4), 136.83 C, 137.59 C, 139.72 C, 146.45 CH(C-6), 157.97 C.

HRMS (EI) calcd for C₂₂H₂₄N₂(M⁺) 316.1940, found 316.1937.

Anal. Calcd. for C₂₂H₂₄N₂ (316.44): C, 83.50; H, 7.64; N, 8.85.

Found: C, 83.40; H, 7.80; N, 8.85.

3,5-Diphenyl-2-propylpyridine (288):

The crude product described above was purified by column chromatography on neutral Al₂O₃ gel, 17 mg of 288 was at first isolate (eluting with cyclohexane:ethyl acetate 1:1) as a light yellow liquid, yield 16 %.

1H-NMR(CDCl₃), d(ppm): 0.80 (t, 3 H, J= 7.3 Hz, CH₃), 1.60-1.69 (m, 2 H, CH₂), 2.71 (t, 2H, J = 7.9 Hz, CH₂), 7.27-7.55 (m, 10 H, Ph-H), 7.63 (d, 1 H, J = 2.3 Hz, H-4), 8.72 (d, 1 H, J = 2.3 Hz, H-6).

13C-NMR (CDCl₃), d(ppm): 14.11 CH₃, 23.09 CH2, 37.16 CH₂, 127.02 CH, 127.50 CH, 127.87 CH, 128.39 CH, 129.04 CH, 129.12 CH, 133.69 C, 135.85 CH(C-4), 136.83 C, 137.70 C, 139.95 C, 146.43 CH(C-6). 158.42 C.

HRMS (EI) calcd for C₂₀H₁₉N_{(M⁺) 273.15175, found 273.15174.}

Synthesis of pyrazine derivatives Synthesis of 5-chloro-2,3-diphenylpyrazine
5-Chloro-2,3-diphenylpyrazine was chosen as the starting diphenyl-haloheterocycle, 2-hydroxy-5,6-diphenylpyrazine was prepared at first.

2-Hydroxy-5,6-diphenylpyrazine (296)

To a stirring and refluxing mixture of glycine amide hydrochloride 6.6 g (0.06 mol) and benzyl 12.6g (0.06 mol) in 150 ml methanol, a solution of 12 N aq. NaOH 9.6 ml (0.12 mol) was added dropwise over 20 min, the mixture was continue refluxing for 2 h and cooled, treated with 12 N hydrochloric acid 7.5 ml, follow by 6 g solid KHCO₃, the yellow solid was filtered off, washed well with water and methanol, dried in air, recrystallized from butanol, and provided a yellow solid 10.56 g, yield 71 %, mp 225-7°C.

1H-NMR(DMSO-d₆), d(ppm): 7.21-7.34 (m, 10 H, Ph-H), 8.13 (s, 1 H, H-3), 12.23 (s, 1 H, N-H)

13C-NMR(DMSO-d₆), d(ppm): 117.84 C, 127.04 CH, 127.68 CH, 128.05 CH, 128.78 CH, 129.03 CH, 129.43 CH, 137.75 C, 156.68 C.

Anal. Calcd. for C₁₆H₁₂N₂O (248.28): C, 77.40; H, 4.87; N, 11.28.

Found: C, 77.24; H, 4.94; N, 11.20.

5-Chloro-2,3-diphenylpyrazine (297)

A solution of 2-hydroxy-5,6-diphenylpyrazine 296 (5.0 g, 0.02 mol), phosphoryl chloride 20 ml, and one drop of sulphuric acid was refluxed for 16 h, after cooled, the mixture was poured slowly onto 200 g chopped ice, stirred to complete hydrolysis, then the mixture was neutralized with 28 % ammonia while keeping it below 10°C, the mixture was extracted with chloroform (3 × 50 ml), the extract was dried with anhydrous MgSO₄, evaporated the solvent, the crude product was recrystallized with methanol, and provided a light yellow solid 4.94 g, yield 93 %, mp 124-5 °C.

1H-NMR(CDCl₃), d(ppm): 7.30-7.47 (m, 10 H, Ph-H), 8.60 (s, 1 H, H-6).

13C-NMR (CDCl₃), d(ppm): 128.38 CH, 128.40 CH, 128.96 CH, 129.23 CH, 129.59 CH, 129.74 CH, 137.11 C, 137.47 C, 141.58 CH(C-6), 146.45 C, 150.78 C, 152.22 C.

Anal. Calcd. for C₁₆H₁₁Cl N₂ (266.72): C, 72.05; H, 4.16; Cl, 13.29; N, 10.50.

Found: C, 72.05; H, 4.24; Cl, 13.33; N, 10.56.

Synthesis of [3-(5,6-diphenyl-pyrazin-2-yl)-prop-2-ynyl]-dimethylamine (298):
A 25 ml schlenk flask was charged with 5-chloro-2,3-diphenylpyrazine 297 267 mg (1.0 mmol), Pd(PPh₃)₂Cl₂ 36 mg (0.05 mmol), CuI 20 mg (0.1mmol), KOAc 147 mg (1.5 mmol), DMF 5 ml and N,N-dimethylpropargylamine 125 mg (1.5 mmol), Argon was passed and the mixture was heated at 100 °C for 24 h, DMF was evaporated in vacuum, the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with cyclohexane:ethyl acetate (1/1) to give 165 mg light brown oil 163 mg, yield 52 %.

1H-NMR(CDCl₃), d(ppm): 2.31 (s, 6 H, 2CH₃), 3.48 (s, 2 H, CH₂), 7.18-7.37 (m, 10 H, Ph-H), 8.58 s, 1 H, H-3)

13C-NMR(CDCl₃), d(ppm): 44.42 CH₃, 48.61 CH₂, 82.49 C, 89.23 C, 128.27 CH, 128.82 CH, 128.86 CH, 129.64 CH, 129.74 CH, 136.95 C, 138.10 C, 138.13 C, 144.73 CH(C-3), 150.81 C, 152.30 C.

HRMS (EI) calcd for C₂₁H₁₉N₃ (M⁺) 313.1579, found 317.1576.

Anal. Calcd. for C₂₁H₁₉N₃(313.40): C, 80.48; H, 6.11; N, 13.41.

Found: C, 80.65; H, 6.30; N, 13.37.

Synthesis of [3-(5,6-diphenyl-pyrazin-2-yl)-propyl]-dimethylamine (299):
A solution 3-(5,6-diphenyl-pyrazin-2-yl)-prop-2-ynyl]-dimethylamine 298 (84 mg, 0.27 mmol) in ethanol (15 ml) and 10 % palladium on charcoal (67 mg, 0.06 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere 16 hours. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel eluting with ethyl acetate:methanol 10:1) to provide 58 mg of brown oil, yield, 58 %.

1H-NMR(CDCl₃), d(ppm): 1.89-1.99 (m, 2 H, CH₂), 2.18 (s, 6 H, 2CH₃), 2.32 (t, 2 H, J = 7.3 Hz, CH₂), 2.86 (t, 2 H, J = 7.7Hz, CH₂),7.20-7.36 (m, 10 H, Ph-H), 8.40 (s, 1 H, H-3).

13C-NMR(CDCl₃), d(ppm): 27.31 CH₂, 32.84 CH₂, 45.49 CH₃, 59.09 CH2, 128.21 CH, 128.31 CH, 128.47 CH, 129.60 CH, 129.74 CH, 138.75 C, 138.85 C, 141.60 CH(C-3), 149.96 151.62 C, 154.54 C.

HRMS (EI) calcd for C₂₁H₂₃N₃ (M⁺) 317.1892, found 317.1890.

Anal. Calcd. for C₂₁H₂₃N₃(317.43): C, 79.46; H, 7.30; N, 13.24.

Found: C, 79.66; H, 7.46; N, 13.12..

Synthesis of oxazole derivatives Synthesis of 4-bromo-2,5-diphenyloxazole (310):
To a solution of 2,5-diphenyloxazole (2.21 g, 10 mmol), NBS (2.14 g, 12 mmol), in CCl4 20 ml, a few (5~6) drops of hydrobromic acid was added as catalyst, the mixture was heated at reflux for 4 hours, cooled and filtered, the filtrate was evaporate, the crude product was purified by recrystallization from methanol, and provide white solid 1.30 g, yield 43 %, mp 64-5 °C.

4-Bromo-2,5-diphenyloxazole (310)

1H-NMR(CDCl₃), d(ppm): 7.29-7.43 (m, 6 H, Ph-H), 7.93 (dd, 2 H, Ph-H), 8.00-8.03 (m, 2 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 112.72 C, 124.27 C, 125.39 CH, 126.37 CH, 127.03 C, 128.79 CH, 128.83 CH, 128.90 CH, 130.89 CH, 146.14 C, 160.07 C.

Anal. Calcd. for C₁₅H₁₀BrNO(300.15): C, 60.02; H,3.36; Br, 26.62, N, 4.67.

Found: C, 60.13; H, 3.52; Br, 25.81; N, 4.77.

Synthesis of 4-alkyl-2,5-diphenyloxazole by Sonogashira reactions
[3-(2,5-Diphenyl-oxazol-4-yl)-prop-2-ynyl]-dimethylamine (311)

A 25ml flask was charged with 4-bromo-2,5-diphenyloxazole(150 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10mg, 0.05mmol),TEA 5 ml, DMF 5 ml and N,N-dimethylpropargylamine (83 mg, 1.0 mmol), Argon was passed and the mixture was heated at 100 °C for 24 h, the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel, eluting with ethyl acetate: methanol (6/1), and provided a brown glass material 63 mg, yield 42 %. When using TEA as base and solvent and reacted at 80 °C 24 h, 311 was isolated in 10 %, When using KOAc as base and DMF as solvent and reacted at 100 °C 24 h, 311 was isolated in 66 %.

1H-NMR(CDCl₃), d(ppm): 2.35 (s, 6 H, CH₃), 3.58 (s, 2 H, CH₂), 7.37-8.02 (m, 10 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 44.07 CH₃, 48.62 CH₂, 77.86 C, 91.06 C, 119.23 C, 124.99 CH, 126.55 CH, 128.79 CH, 128.97 CH, 130.79 CH, 132.01 CH, 133.08 C, 135.18 C, 151.78 C, 159.64 C.

HRMS (EI) calcd for C₂₀H₁₈N₂O (M⁺) 302.14191, found 302.14193.

[3-(2,5-Diphenyl-oxazol-4-yl)-propyl]-dimethylamine (312)

A solution [3-(2,5-diphenyl-oxazol-4-yl)-prop-2-ynyl]-dimethylamine(112 mg, 0.37 mmol) in ethanol (15 ml) and 10 % palladium on charcoal (83 mg, 0.074 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere 16 h. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with cyclohexane:ethyl acetate(1:1) to provide 66 mg of brown oil, yield, 58 %.

1H-NMR(CDCl₃), d(ppm): 1.78-1.88 (m, 2 H, CH₂), 2.09(s, 6 H, CH₃), 2.25 (t, 2 H, J = 7.4 Hz, CH₂), 2.70 (t, 2 H, J = 7.7 Hz, CH₂),7.17-7.95 (m, 10 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 25.06 CH₂, 26.81 CH₂, 45.49 CH₃, 59.16 CH₂, 125.59 CH, 126.28 CH, 127.57 C, 127.71 CH, 128.73 CH, 128.81 CH, 129.13 C, 130.11 CH, , 133.08 C, 137.54 C, 145.39 C, 159.53 C.

HRMS (EI) calcd for C₂₀H₂₂N₂O (M⁺) 306.17321, found 306.17321.

Synthesis of 3-(2,5-diphenyl-oxazol-4-ylethynyl)-phenylamine (313)

A 25 ml flask was charged with 4-bromo-2,5-diphenyloxazole(150 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.05mmol),TEA 5 ml, and 3-ethynyl-phenylamine (117 mg, 1.0 mmol), Argon was passed and the mixture was heated at 80 °C for 24 h, the solvent was evaporated in vacuum, the residue was purified by column chromatography on silica gel, eluting with cyclohexane:ethyl acetate(2/1), and gave a light yellow solid 125 mg, yield 74 %, mp 195-6 °C.

1H-NMR(CDCl₃), d(ppm): 3.74 (s, 2 H, NH₂), 6.69-6.72 (dd, 1 H, J = 8.8 Hz, Ph-H), 6.93 (t, 1 H, J = 1.9 Hz, Ph-H), 7.17 (t, 1 H, J = 7.9 Hz, Ph-H), 7.39 (t, 1 H, Ph-H), 7.47-7.52 (m, 5 H, Ph-H), 8.13-8.16 (m, 4 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 80.88 C, 95.66 C, 115.89 CH, 117.74 CH, 119.68 C, 122.13 CH, 123.22 C, 125.06 CH, 126.61 CH,126.71 C, 127.75 C, 128.84 CH, 128.97 CH, 129.39 CH, 130.81 CH, 146.37 C, 151.87 C, 159.81 C.

Anal. Calcd. for C₂₃H₁₆N₂O (336.39): C, 82.12; H,4.79; N,8.33.

Found: C, 81.94; H, 4.90; N, 8.19.

Buchwald-hartwig amination of 4-bromo-2,5-diphenyloxazole
Synthesis of 1-(2,5-diphenyl-oxazol-4-yl)-4-methyl-piperazine (314):

A schlenk 25 ml flask was charge with 4-bromo-2,5-diphenyloxazole 310 (150 mg, 0.5 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol), BINAP (19 mg, 0.03 mmol), t-BuONa (68 mg, 0.7 mmol), 4-methyl-piperazine (100 mg, 1.0 mmol), dry toluene 5 ml, Argon was passed three times and the mixture was heated at 110 °C for 20 h, evaporated the solvent, the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate, and get light yellow solid 22 mg, yield 14 %, mp 110-2 °C;

1H-NMR(CDCl₃), d(ppm): 2.38 (s, 3 H, CH₃), 2.60 (t, 4 H, J = 4.8 Hz, CH₂), 3.20 (t, 4 H, J = 4.8 Hz, CH₂), 7.23-7.45 (m, 6 H, Ph-H), 7.84 (dd, 2 H, J ₁ _{= 8.2Hz, J

₂
= 1.0 Hz, Ph-H), 8.06 (dd, 2 H, J

₁
= 8.4 Hz, J

₂
= 1.5 Hz, Ph-H),}

13C-NMR (CDCl₃), d(ppm): 46.38 CH₃, 50.20 CH₂, 55.28 CH₂, 124.45 CH, 126.15 CH, 126.74 CH, 127.70 C, 128.56 CH, 128.67 CH, 129.35 C, 129.97 CH, 135.93 C, 146.61 C, 157.54.

HRMS (EI) calcd for C₂₀H₂₁N₃O_{( M⁺ ) 319.16846, found 319.16845.}

Synthesis of Pyrazole derivatives Synthesis of 4-iodo-3-methyl-1,5-diphenylpyrazole
4-Iodo-3-methyl-1,5-diphenylpyrazole was started from 3-methyl-1,5-diphenylpyrazole.

3-Methyl-1,5-diphenylpyrazole (320)

A 250ml flask was charged with phenylhydrazine (6.68 g, 0.06mol), sodium acetate (3.28 g, 0.04mol), benzoylacetone (9.74 g, 0.06mol), ethanol 80 ml and water 40 ml, the mixture was heated at reflux for 3 h and concentrated the solvent in vacuum, 40 ml ether and 40 ml water were added inside the flask, separated, the aqueous layer was extracted with ether (40 2 × 40 ml), the combined extracts were washed with 1 N NaOH 30 ml, brine 30 ml, and dried with anhydrous MgSO₄, the solvent was evaporated in vacuum and provided an orange oil 13.03 g, yield 93 %.

1H-NMR(CDCl₃), d(ppm):2.56 (s, 3 H, CH₃), 6.48 (s 1 H, H-4), 7.39-7.46 (m, 10 H, Ph-H).

13C-NMR(CDCl₃), d (ppm): 13.63 CH₃, 107.79 CH(C-4), 125.13 CH, 127.09 CH, 128.08 CH, 128.42 CH, 128.65 CH, 128.86 CH, 130.77 C, 140.19 C, 143.69 C, 149.45 C.

HRMS (EI) calcd for C₁₆H₁₄N₂(M⁺) 234.11570, found 234.11575.

4-Iodo-3-methyl-1,5-diphenylpyrazole (321)

A 100ml flask was charged with 4-methyl-1,2-diphenylpyrrole 320 (2.34 g,10 mmol), 50 ml DMF, the solution was cooled to 0 °C and passed Argon, NIS (2.70 g, 12 mmol) was added and stirred at room temperature overnight (16 h), then the solution cooled again to 0°C, NIS (0.13 g, 0.5 mmol) was added and continue to stir at RT for another 12 h, 250 ml water was added inside, the mixture was extracted with ether (2 × 120 ml), ethyl acetate 100 ml and hexane 100 ml, the combined extract was washed with water 50 ml, 10 % aq. Na₂S₂O₃ 50ml, water 50 ml, and dried with anhydrous MgSO₄, the solvent was concentrated and provided a brown solid 2.12 g, yield 59 %, mp 94-6 °C.

1H-NMR(CDCl₃), d(ppm):2.33 (s, 3 H, CH₃), 7.08-7.19 (m, 10 H, Ph-H).

13C-NMR(CDCl₃), d(ppm): 14.39 CH₃, 66.23 C, 124.64 CH, 127.27 CH, 128.27 C, 128.44 CH, 128.79 CH, 128.85 CH, 130.15 CH, 139.93 C, 144.02 C, 151.64 C.

HRMS (EI) calcd for C₁₆H₁₃IN₂ (M⁺) 360.01235, found 360.01241.
Dimethyl-[3-(3-methyl-1,5-diphenyl-pyrazol-4-yl)-prop-2-ynyl]-amine (322)
A 25ml Schlenk flask was charged with 4-Iodo-3-methyl-1,5-diphenylpyrazole (320 mg, 1.0 mmol), K₂CO₃ (332 mg, 2.4 mmol), CuI (20 mg, 0.1 mmol), 10 % Pd/C (44 mg, 0.04 mmol ), and PPh₃ (42 mg, 0.16 mmol) in DME (10 ml) and water (10 ml). Argon was passed through the flask 3 times and the mixture was stirred at 25 °C for 0.5 h, then N,N-dimethylpropargyl amine 100 mg(1.2 mmol) was added. After refluxing under argon for 24 h the mixture was cooled to 25 °C and filtered through a pad of Celite. After washing with EtOAc, the combined crude solution was washed with water (50 mL) twice. The organic layer was dried with anhydrous MgSO₄, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with EtOAc:MeOH(1:0→6:1) and provided a light brown solid 306 mg, yield 97 %, mp 66-7 °C.

1H-NMR(CDCl₃), d(ppm):2.23 (s, 6 H, CH₃), 2.36 (s, 3 H, CH₃), 3.40 (s, 2 H; CH₂), 7.14-7.61 (m, 10 H, Ph-H).

13C-NMR(CDCl₃), d (ppm): 12.65 CH₃, 44.01 CH₃, 48.73 CH₂, 88.05 C, 104.10 C, 125.04 CH, 127.32 CH, 128.26 CH, 128.50 CH, 128.89 CH, 129.39 CH,132.02 C, 133.24 C, 139.75 C, 144.21 C, 151.95 C.

Anal. Calcd. for C₂₁H₂₁N₃: C, 79.97; H, 6.71; N, 13.32.

Found: C, 80.12; H, 6.72; N, 13.15.

Dimethyl-[3-(3-methyl-1,5-diphenyl-pyrazol-4-yl)-propyl]-amine (323)
A solution dimethyl-[3-(3-methyl-1,5-diphenyl-pyrazol-4-yl)-prop-2-ynyl]-amine 322(158 mg, 0.5 mmol) in ethanol (15 ml) and 10 % palladium on charcoal (111 mg, 0.1 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere 16 h. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate:methanol (10:1) to give 122 mg of brown oil, yield, 76 %.

1H-NMR(CDCl₃), d(ppm): 1.48-1.58 (m, 2 H, CH₂), 2.06 (s, 3 H, CH₃), 2.12 (t, 2 H, J = 7.4 Hz, CH₂), 2.28 (s, 3 H, CH₃), 2.37 (t, 2 H, J = 7.9 Hz, CH₂), 7.07-7.62 (m,10 H, Ph-H).

13C-NMR(CDCl₃), d(ppm): 12.19 CH₃, 21.30 CH₂, 28.91 CH₂, 45.39 CH₃, 59.44 CH₂, 119.42 C, 124.39 CH, 126.30 CH, 128.05 CH, 128.40 CH, 128.58, 129.80 CH, 131.12 C, 140.10 C, 140.39 C, 148.31 C.

HRMS (EI) calcd for C₂₁H₂₅N₃ (M⁺) 319.2049, found 319.2046.

Anal. Calcd. for C₂₁H₂₅N₃ (319.44): C, 78.96; H, 7.89; N, 13.15.

Found: C, 78.83; H, 8.02; N, 13.07.

Synthesis imidazole derivatives Nucleophilic substitution of 4,5-diphenylimidazole
Synthesis of 3-(4,5-diphenyl-imidazol-1-yl)-propylamine 335

(1)2-[3-(4,5-Diphenyl-imidazol-1-yl)-propyl]-isoindole-1,3-dione 334

A mixture of4,5-diphenylimidazole (440 mg, 2.0 mmol), N-3-bromopropylphthalimide (1.07 g, 4.0 mmol), cesium carbonate (1.30 g, 4.0 mmol) and DMF 15 ml was heated at 60 °C for 4 h, then the mixture was cooled and diluted with 30 ml water, the mixture was extracted with ethyl acetate (3 × 40 ml), the combined extract was washed with water (3 × 30 ml) and then brine 30 ml, the solution was dried with anhydrous sodium sulphate. Evaporated the solvent and the residue was purified by column chromatography on SiO₂ gel, eluting with ethyl acetate and ethylacetate: methanol(10/1) and provided a white solid 767 mg, yield 94 %, mp 109-110 °C.

1H-NMR(CDCl₃), d(ppm): 1.79-1.89 (m, 2 H, CH₂), 3.53 (t, 2 H, J = 6.6 Hz, CH₂), 3.79 (t, 2 H, J = 7.5 Hz, CH₂), 7.01-7.37 (m, 10 H, Ph-H), 7.61 (s, 1 H, H-2), 7.64-7.76 (m, 4 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 30.07 CH₂, 35.02 CH₂, 42.80 CH₂, 123.33 CH, 126.28 CH, 126.47 CH, 128.08 CH, 128.63 CH, 129.00 CH, 130.61 C, 130.68 CH, 131.86 C, 134.09 CH, 134.48 C, 136.72 CH(C-2), 138.38 C, 168.09 C(C=O).

HRMS (EI) calcd for C₂₆H₂₁N₃O₂(M⁺) 407.16338, found 407.16330.

(2) 3-(4,5-Diphenyl-imidazol-1-yl)-propylamine (335)

A soution of 2-[3-(4,5-diphenyl-imidazol-1-yl)-propyl]-isoindole-1,3-dione 334 (408 mg, 1.0 mmol) 80 % hydrazine hydrate (75 mg, 1.2 mmol), and ethanol 15 ml was heated at reflux for 8 h, then the solution was cooled, 4 N HCl solution 20 ml was added, and the solution was heated at reflux for 6 h, after cooled, the white precipitate was filtered away, the solution was concentrated, the precipitate was removed again, then 30 ml water and excess Na₂CO₃ solid was added, the mixture was extracted with dichloromethane (4 × 30 ml), and dried the solution with anhydrous MgSO₄, evaporated the solvent and 235 mg white solid was obtained, yield 85 %, mp 42-4 °C.

1H-NMR(CDCl₃), d(ppm): 1.26 (m, 2 H, CH₂), 1.66 (t, 2 H, J = 6.8 Hz, CH₂), 2.58 (br, 2 H, NH₂), 3.89 (t, 2 H, J = 7.2 Hz, CH₂), 7.12-7.48 (m, 10 H, Ph-H), 7.63 (s, 1 H, H-2).

13C-NMR(CDCl₃), d(ppm): 34.23 CH₂, 38.72 CH₂, 42.59 CH₂, 126.22 CH, 126.50 CH, 128.09 CH, 128.70 CH, 129.01 C, 129.10 CH, 130.80 CH, 130.84 C, 134.60 C, 136.78 CH(C-2), 138.13 C.

HRMS (EI) calcd for C₁₈H₁₉N₃ (M⁺) 277.15790, found 277.15794.
Sonogashira cross-coupling of 1-benzyl-2-bromo-4,5-diphenylimidazole
1-Benzyl-4,5-diphenylimidazole(336)

A mixture of4,5-diphenylimidazole (6.61 g, 30 mmol), potassium carbonate (2.40 g, 17 mmol) and dry DMF 90 ml was passed with Argon, and heated to 80 °C, benzyl chloride (3.80 g, 30 mmol) was added inside slowly, then stirred over night (16 h), the solid was filtered away, and the solvent was evaporated, the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate: hexane (2/1), and a white solid 8.68 g was obtained, yield 93 %, mp 112-4 °C.

1H-NMR(CDCl₃), d(ppm): 4.96 (s, 2 H, CH₂), 6.94-7.50 (m, 15 H, Ph-H), 7.61(s, 1 H, H-2)

13C-NMR(CDCl₃), d(ppm): 48.79 CH₂, 126.25 CH, 126.56 CH, 126.94 CH, 127.68 CH, 127.99 CH, 128.15 CH, 128.79 CH, 128.93 CH, 130.94 CH, 133.23 C, 134.45 C, 134.90 C, 136.50 C, 137.09 CH(C-2), 138.27 C.

Anal. Calcd. for C₂₂H₁₈N₂(310.39): C, 85.13; H, 5.85; N, 9.03

Found: C, 85.33; H, 5.99; N, 8.91

1-Benzyl-2-bromo-4,5-diphenylimidazole(338)

A 50 ml flask was charged 1-benzyl-4,5-diphenylimidazole 336 (1244 mg, 4.0 mmol) NBS (890 mg, 5.0 mmol) and CH₃CN 30 ml, the mixture was stirred at room temperature 2 h. The solvent was concentrated and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate: hexane (1/6→1/2), and a yellow solid 929 mg was obtained, yield 60 %, mp 106-8 °C.

1H-NMR(CDCl₃), d(ppm): 5.09 (s, 2 H, CH₂), 6.98-7.55 (m, 15 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 48.99 CH₂, 120.58 C(C-2), 126.34 CH, 126.51 CH, 126.76 CH, 127.71 CH, 128.15 CH, 128.71 CH, 129.02 CH, 129.17 CH, 130.24 C, 130.92 CH, 131.39 C, 133.52 C, 136.05 C, 139.17 C.

Anal. Calcd. for C₂₂H₁₇BrN₂(389.29): C, 67.88; H, 4.40; Br, 20.53; N, 7.20.

Found: C, 67.65; H, 4.59; Br, 20.80; N, 7.02.

[3-(1-Benzyl-4,5-diphenyl-imidazol-2-yl)-prop-2-ynyl]-dimethylamine (339)

A 25 ml schlenk flask was charged 1-benzyl-2-bromo-4,5-diphenylimidazole 338 (195 mg, 0.5 mmol), Pd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol), triethylamine 10 ml, and N, N-dimethylpropargylamine (83 mg, 1.0 mmol), Argon was passed three times and heated at 80 °C for 24 h. The mixture was concentrated, the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate: hexane (1/3→1/1), and provided a brown oil 85 mg, yield 43 %. When using DMF as solvent and reacted at 100 °C 24 h, 339 was isolated in 27 % yield.

1H-NMR(CDCl₃), d(ppm): 2.20 (s, 6 H, 2CH₃), 3.49 (s, 2 H, CH₂), 5.09 (s, 2 H, CH₂), 6.88-7.48 (m, 15 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 43.98 CH₃, 48.34 CH₂, 48.42 CH₂, 75.58 C, 89.24 C, 126.57 CH, 126.65 CH, 126.75 CH, 126.92 C, 127.57 CH, 128.07 CH, 128.58 C, 128.77 CH, 128.92 CH, 130.28 C, 130.82 CH, 131.64 C, 133.86 C, 136.63 C, 138.49 C.

HRMS (EI) calcd for C₂₇H₂₅N₃ (M⁺) 391.20485, found 391.20462.

[3-(1-Benzyl-4,5-diphenyl-imidazol-2-yl)-propyl]-dimethylamine (340)

A solution [3-(1-benzyl-4,5-diphenyl-imidazol-2-yl)-prop-2-ynyl]-dimethylamine 339(70 mg, 0.18 mmol), ethanol (15 ml) and 10 % palladium on charcoal (40 mg, 0.036 mmol on Pd, 0.2 equiv) was stirred under hydrogen at room temperature and atmosphere 16 h. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of Celite, washed with ethyl acetate, the solvents were removed under reduced pressure, and the residue was purified by column chromatography on neutral Al₂O₃ gel, eluting with ethyl acetate to provide 45 mg of yellow oil, yield, 63 %.

1H-NMR(CDCl₃), d(ppm): 1.92-2.02 (m, 2 H, CH₂), 2.19 (s, 6 H, 2CH₃), 2,35 (t, 2 H, J = 7.8 Hz, CH₂), 2,70 (t, 2 H, J = 7.58 Hz, CH₂), 5.01 (s, 2 H, CH₂), 6.92-7.52 (m, 15 H, Ph-H).

13C-NMR (CDCl₃), d(ppm): 25.14 CH₂, 26.04 CH₂, 45.34 CH₃, 46.84 CH₂, 59.05 CH₂, 125.80 CH, 126.07 CH, 126.69 CH, 127.45 CH, 128.07 C, 128.47 CH, 128.78 CH, 128.87 CH, 130.98 CH, 132.43 C, 134.79 C, 136.70 C, 137.41 C, 148.28.

HRMS (EI) calcd for C₂₇H₂₉N₃(M⁺) 395.2362, found 395.2359.