2,4-dichloro-6-phenylpyrimidine

white powder

Under nitrogen atmosphere, 2, 4, 6-trichloropyrimidine (40.0g, 0.218mol) and phenylboronic acid (26.6g, 0.218mol) completely dissolved in 250mL of tetrahydrofuran, was added 2M aqueous potassium carbonate solution (125mL) and tetrakis(triphenylphosphine)palladium (7.6g, 6.5mmol) then heated and stirred for 5 hours. The temperature was lowered to room temperature, the aqueous layer is removed, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and treated with a column with 1:3 ratio of tetrahydrofuran and hexane to prepare the compound 6-A (40g, yield: 82percent).Under an Ar gas atmosphere, 2, 4, 6-trichloropyrimidine (25.0g, 136.3 mmol), phenylboronic acid (16.6g, 136.3 mmol), palladium acetate (1.53g, 6.82 mmol), triphenylphosphine (3.58g, 13.6 mmol), DME (1250 ml) and an aqueous solution of 2M sodium carbonate (211 ml) were stirred for 16 hours at a reflux temperature. The solvent was distilled away under reduced pressure. The obtained residue was extracted by dichloromethane. The residue obtained by concentrating the organic phase was refined by silica-gel column chromatography (a developing solvent: hexane-ethyl acetate) to provide an intermediate body XA suspension of 2, 4, 6—trichloropyrimidine (1000 mg, 5.29mmol), phenyl boronic acid (665 mg, 5.29 mmol), PdC12(dppf) dichloromethane complex (204 mg, 0.26 mmcl) and K2C03 2 M solution (5.3 ml, 10.58 mmol) in 1, 4—dioxane (26.4 ml) was stirred in a CEM® microwave apparatus at 60 °C for 1 hour.Resulting crude was portioned between dichloromethane (150 ml), NaHCO3 saturated solution (100 ml), the organic layer dried over Na2SO4 and concentrated to dryness at low pressure. Final normal phase purification (cyclohexane/DCM from 100/0 to 85/15) afforded pure title compound (857 mg, yield 72 percent) . Rt = 1.38 mm (analysis method 2); MS (ESI)m/z: 225.1 [M—H], [M—H] calculated: 225.0. ‘H NMR (400MHz, CDC13) 6 8.13 — 8.03 (m, 2H), 7.68 (s, 1H), 7.62 — 7.48(m, 3H)75.0 g (409 mmol) of 2, 4, 6-trichloropyrimidine, 54.8 g (450 mmol) of phenylboronic acid, and 11.8 g (10 mmol) of tetrakis- (triphenylphosphine)palladium were suspended in a mixed solvent of 450 ml of tetrahydrofuran and 300 ml of toluene to provide a suspension. The suspension was added to a solution in which 113.0 g (818 mmol) of potassium carbonate was dissolved in 300 ml of water, and the obtained mixture was heated and refluxed for 9 hours. After separating the reaction fluid into two layers, an organic layer was washed with a saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate.2, 4, 6-Trichloropyrimidine (1.00 g, 5.45 mmol) was dissolved in tetrahydrofuran (15 mL).Then tetrakis(triphenylphosphine)palladium (430 mg, 0.50 mmol) was added.Phenylboronic acid (0.66 g, 5.45 mol), aqueous sodium carbonate (1 M, 15 mL, 15 mmol), The resulting mixture was heated to 80 ° C under a nitrogen atmosphere to stir the reaction overnight.Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50mL×3).The combined organic layers were washed with brine (100 mL)Filter and filter the solution under reduced pressure.The residue obtained was purified by silica gel column chromatography (purified petroleum ether)The title compound was obtained as a green solid(0.76g, 62percent).To a solution of 2, 4, 6-trichloropyrimidine (1.00 g, 5.45 mmol) in THF (15 mL) were added tetrakis(triphenylphosphine)palladium (430 mg, 0.50 mmol), benzeneboronic acid (0.66 g, 5.45 mol) and aqueous sodium carbonate solution (1 M, 15 mL, 15 mmol). The mixture was stirred at 80 °C overnight under nitrogen protection. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a green solid (0.76 g, 62percent).[00299] To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 2.5 mmol) in tetrahydrofuran (5 mL) were added palladium acetate (8 mg, 0.035 mmol), triphenylphosphine (18 mg, 0.065 mmol), phenylboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carboante solution (1 M, 3.3 mL, 3.3 mmol). The mixture was stirred at 60 °C for 6 h, then cooled to rt and concentrated to remove the organic solvent. To the residue was added H20 (10 mL), and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dry and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.225 g, 6 1percent).To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 2.5 mmol) in tetrahydrofuran (5mL) were added palladium acetate (8 mg, 0.035 mmol), triphenylphosphine (18 mg, 0.065mmol), phenylboronic acid (0.20 g, 1.6 mmol) and an aqueous sodium carbonate solution (1 M, 3.3 mL, 3.3 mmol). The mixture was heated to 60 °C and stirred for 6 h. The mixture was cooled to rt, and concentrated in vacuo to remove organic solvent. To the residue was added H20 (10 mL), and the mixture was extracted with EtOAc (lOmL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuoto dryness, and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.225 g, 6 1percent).MS: (ESI, pos. ion) m/z: 224.95 [M+H]‘H NMR (400 IVIFIz, CDC13) (ppm): 8.15—8.04 (m, 2H), 7.70 (s, 1H), 7.63—7.50 (m, 3H).To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 2.5 mmol) in THF (5 mL) wereadded palladium acetate (8 mg, 0.035 mmol), triphenylphosphine (18 mg, 0.065 mmol), benzeneboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carbonate solution (1 M, 3.3 mL, 3.3 mmol). The mixture was stirred at 60 oc for 6 h under nitrogen protection. After the reactionwas completed, the mixture was cooled to rt, and concentrated in vacuo. To the residue wasadded H20 (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). Thecombined organic layers were washed with saturated brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified by silica gel columnchromatography (PE) to give the title compound as a white solid (0.225 g, 61 percent ).MS (ESI, pos. ion) m/z: 225.0 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 8.15-8.04 (m, 2H), 7.70 (s, 1H), 7.63-7.50 (m, 3H).To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 48.0 mmol) in THF (5 mL) were added palladium acetate (8 mg, 0.035 mmol) , triphenylphosphine (18 mg, 0.065 mmol) , benzeneboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carbonate solution (1 M, 3.3 mL, 3.3 mmol) . The mixture was stirred at 60 for 5 h under nitrogen protection. The mixture was cooled to rt, and concentrated in vacuo. To the residue was added HExample 84 {4-[4-(4, 5-Dihydro-lH-pyrrol-2-ylammo)-phenyl]-6-phenyl-pyrimidin-2-yl}- hexyl-methyl-amineStep a 2, 4-Dichloro-6-phenyl-pyrirnidine 2, 4, 6-Trichloropyrimidine (1.Og, 5.5mmol) and phenylboronic acid (0.67g, 5.5mmol) were dissolved in DME (5OmL) under an Argon atmosphere. A solution OfNa100.0 g (545.2 mmol) of 1, 3, 5-trichloro pyrimidine, 59.83 g (490.68 mmol) of phenylboronic acid, 188.38 g (1.36 mol) of potassium carbonate, and 18.90 g (16.36 mmol) of tetrakis(triphenylphosphine) palladium (0) were added to 800 mL of 1, 4-dioxane and 400 mL of water in a 2 L flask, and the mixture was heated at 60° C. under a nitrogen flow for 12 hours. The obtained mixture was added to 2000 mL of methanol to crystallize a solid, and the solid was filtered, dissolved in monochlorobenzene, filtered with silica gel/Celite, and then, recrystallized with methanol after removing an appropriate of the organic solvent to obtain Intermediate 8-1 (65.0 g, yield of 53percent). (0202) calcd. C10H6Cl2N2: C, 53.36; H, 2.69; Cl, 31.50; N, 12.45; found: C, 53.36; H, 2.69; Cl, 31.50; N, 12.44.Phenylboronic acid (5.00 mmol, 610 mg) and 2, 4, 6-trichloropyrimidine (6.00 mmol, 0.70 mL) are dissolved in a sodium carbonate solution (1 M in water, 10.0 mmol, 10.0 mL), and palladium(II) acetate (0.10 mmol, 22.5 mg) and triphenylphosphine (0.20 mmol, 52.5 mg) are added. The reaction mixture is heated to 60 °C and stirred for 3 hours. After cooling, the solution is extracted with diethyl ether (3 × 30 mL). The combined organic phases are washed with brine and dried over sodium sulphate. Subsequently, the solvent is removed under reduced pressure and the crude product is purified via column chromatography (SiO2, NEt3 (1 percent), hexane / dichloromethane = 2:1) to yield 9 (478 mg, 42percent) as white solid; Rf 0.3 (hexane / dichloromethane = 2:1) [UV]; 1H NMR (360 MHz, CDCl3): δ 7.50-7.60 (m, 3 H), 7.67 (s, 1 H), 8.07 (dd, J = 1.5 Hz, J = 8.3 Hz, 2 H); 13C NMR (151 MHz, CDCl3): δ 115.3 (CH), 127.6 (2 × CH), 129.2 (2 × CH), 132.4 (CH), 134.1 (Cq), 161.0 (Cq), 162.9 (Cq), 168.2(Cq)Step 2: 2, 4-dichloro-6-phenylpyrimidine; A 50.0 ml. round bottom flask equipped with a magnetic stir bar and a reflux condenser was charged with argon prior to the addition of 6-phenyl-2, 4(1 H, 3H)- pyrimidinedione (2.22 g, 11.8 mmol) and phosphorus oxychloride (11.0 ml, 1 18 mmol) at room temperature. The flask was placed in a 1 16°C pre-heated oil bath and rapidly warmed to reflux. The mixture was stirred at 1 16°C under argon for 4 hours and allowed to cool to room temperature, after which time product was observed by LC-MS (m/e 225 [M+1]Under nitrogen atmosphere, 2, 4, 6-trichloropyrimidine (40.0g, 0.218mol) and phenylboronic acid (26.6g, 0.218mol) completely dissolved in 250mL of tetrahydrofuran, was added 2M aqueous potassium carbonate solution (125mL) and tetrakis(triphenylphosphine)palladium (7.6g, 6.5mmol) then heated and stirred for 5 hours. The temperature was lowered to room temperature, the aqueous layer is removed, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and treated with a column with 1:3 ratio of tetrahydrofuran and hexane to prepare the compound 6-A (40g, yield: 82%).Under an Ar gas atmosphere, 2, 4, 6-trichloropyrimidine (25.0g, 136.3 mmol), phenylboronic acid (16.6g, 136.3 mmol), palladium acetate (1.53g, 6.82 mmol), triphenylphosphine (3.58g, 13.6 mmol), DME (1250 ml) and an aqueous solution of 2M sodium carbonate (211 ml) were stirred for 16 hours at a reflux temperature. The solvent was distilled away under reduced pressure. The obtained residue was extracted by dichloromethane. The residue obtained by concentrating the organic phase was refined by silica-gel column chromatography (a developing solvent: hexane-ethyl acetate) to provide an intermediate body X4 as a white solid. A yield of the intermediate body X4 was 22.1 g and a yield rate thereof was 72%. (reference document : J.Org.Chem. 66 7125-7128 (2001))A suspension of 2, 4, 6-trichloropyrimidine (1000 mg, 5.29mmol), phenyl boronic acid (665 mg, 5.29 mmol), PdC12(dppf) dichloromethane complex (204 mg, 0.26 mmcl) and K2C03 2 M solution (5.3 ml, 10.58 mmol) in 1, 4-dioxane (26.4 ml) was stirred in a CEM microwave apparatus at 60 C for 1 hour.Resulting crude was portioned between dichloromethane (150 ml), NaHCO3 saturated solution (100 ml), the organic layer dried over Na2SO4 and concentrated to dryness at low pressure. Final normal phase purification (cyclohexane/DCM from 100/0 to 85/15) afforded pure title compound (857 mg, yield 72 %) . Rt = 1.38 mm (analysis method 2); MS (ESI)m/z: 225.1 [M-H], [M-H] calculated: 225.0. 'H NMR (400MHz, CDC13) 6 8.13 - 8.03 (m, 2H), 7.68 (s, 1H), 7.62 - 7.48(m, 3H)75.0 g (409 mmol) of 2, 4, 6-trichloropyrimidine, 54.8 g (450 mmol) of phenylboronic acid, and 11.8 g (10 mmol) of tetrakis- (triphenylphosphine)palladium were suspended in a mixed solvent of 450 ml of tetrahydrofuran and 300 ml of toluene to provide a suspension. The suspension was added to a solution in which 113.0 g (818 mmol) of potassium carbonate was dissolved in 300 ml of water, and the obtained mixture was heated and refluxed for 9 hours. After separating the reaction fluid into two layers, an organic layer was washed with a saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate.<1-f> was synthesized according to Scheme 6 below. In a 10 L round bottom flask, 500.82 g (2.753 mol) of 2, 4, 6-trichloropyrimidine, 280.00 g (2.294 mol) of phenylboronic acid, 53.07 g of tetrakistriphenylphosphinepalladium (Pd (PPh3) 4) 0.046 mol), 951.22 g (6.882 mol) of potassium carbonate (K2CO3), 2100 mL of water and 4200 mL of tetrahydrofuran are added and refluxed for 12 hours.After the reaction was completed, the reaction solution was cooled to room temperature, and then separated using ethyl acetate and water. The organic layer was anhydrous and concentrated under reduced pressure. After removing all solvents, the precipitates were precipitated at below 70 degrees with methanol and filtered. 330.0g (yield 64.2%) <1-f> was obtained.2, 4, 6-Trichloropyrimidine (1.00 g, 5.45 mmol) was dissolved in tetrahydrofuran (15 mL).Then tetrakis(triphenylphosphine)palladium (430 mg, 0.50 mmol) was added.Phenylboronic acid (0.66 g, 5.45 mol), aqueous sodium carbonate (1 M, 15 mL, 15 mmol), The resulting mixture was heated to 80 C under a nitrogen atmosphere to stir the reaction overnight.Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50mL×3).The combined organic layers were washed with brine (100 mL)Filter and filter the solution under reduced pressure.The residue obtained was purified by silica gel column chromatography (purified petroleum ether)The title compound was obtained as a green solid(0.76g, 62%).To a solution of 2, 4, 6-trichloropyrimidine (1.00 g, 5.45 mmol) in THF (15 mL) were added tetrakis(triphenylphosphine)palladium (430 mg, 0.50 mmol), benzeneboronic acid (0.66 g, 5.45 mol) and aqueous sodium carbonate solution (1 M, 15 mL, 15 mmol). The mixture was stirred at 80 C overnight under nitrogen protection. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a green solid (0.76 g, 62%).[00299] To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 2.5 mmol) in tetrahydrofuran (5 mL) were added palladium acetate (8 mg, 0.035 mmol), triphenylphosphine (18 mg, 0.065 mmol), phenylboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carboante solution (1 M, 3.3 mL, 3.3 mmol). The mixture was stirred at 60 C for 6 h, then cooled to rt and concentrated to remove the organic solvent. To the residue was added H20 (10 mL), and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dry and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.225 g, 6 1%).To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 2.5 mmol) in tetrahydrofuran (5mL) were added palladium acetate (8 mg, 0.035 mmol), triphenylphosphine (18 mg, 0.065mmol), phenylboronic acid (0.20 g, 1.6 mmol) and an aqueous sodium carbonate solution (1 M, 3.3 mL, 3.3 mmol). The mixture was heated to 60 C and stirred for 6 h. The mixture was cooled to rt, and concentrated in vacuo to remove organic solvent. To the residue was added H20 (10 mL), and the mixture was extracted with EtOAc (lOmL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuoto dryness, and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.225 g, 6 1%).MS: (ESI, pos. ion) m/z: 224.95 [M+H]?H NMR (400 IVIFIz, CDC13) (ppm): 8.15-8.04 (m, 2H), 7.70 (s, 1H), 7.63-7.50 (m, 3H).To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 2.5 mmol) in THF (5 mL) wereadded palladium acetate (8 mg, 0.035 mmol), triphenylphosphine (18 mg, 0.065 mmol), benzeneboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carbonate solution (1 M, 3.3 mL, 3.3 mmol). The mixture was stirred at 60 oc for 6 h under nitrogen protection. After the reactionwas completed, the mixture was cooled to rt, and concentrated in vacuo. To the residue wasadded H20 (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). Thecombined organic layers were washed with saturated brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified by silica gel columnchromatography (PE) to give the title compound as a white solid (0.225 g, 61 % ).MS (ESI, pos. ion) m/z: 225.0 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 8.15-8.04 (m, 2H), 7.70 (s, 1H), 7.63-7.50 (m, 3H).To a solution of 2, 4, 6-trichloropyrimidine (0.29 mL, 48.0 mmol) in THF (5 mL) were added palladium acetate (8 mg, 0.035 mmol) , triphenylphosphine (18 mg, 0.065 mmol) , benzeneboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carbonate solution (1 M, 3.3 mL, 3.3 mmol) . The mixture was stirred at 60 for 5 h under nitrogen protection. The mixture was cooled to rt, and concentrated in vacuo. To the residue was added H2O (10 mL) , and the mixture was extracted with ethyl acetate (10 mL × 3) . The combined organic layers were washed with saturated brine (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.225 g, 61%) .MS (ESI, pos. ion) m/z: 225.0 [M+H]+;1H NMR (400 MHz, CDCl3) delta (ppm) : 8.15 -8.04 (m, 2H) , 7.70 (s, 1H) , 7.63 -7.50 (m, 3H) .Example 84 {4-[4-(4, 5-Dihydro-lH-pyrrol-2-ylammo)-phenyl]-6-phenyl-pyrimidin-2-yl}- hexyl-methyl-amineStep a 2, 4-Dichloro-6-phenyl-pyrirnidine 2, 4, 6-Trichloropyrimidine (1.Og, 5.5mmol) and phenylboronic acid (0.67g, 5.5mmol) were dissolved in DME (5OmL) under an Argon atmosphere. A solution OfNa2CO3 (1.81g, 17.1mmol) in H2O (5mL) was added, followed by palladium acetate (61.2mg) and PPh3 (143mg). The reaction mixture was refluxed for 5-6 h. The solution was evaporated and the residue suspended in between H2O-DCM (3:5 / 8OmL). The separated organic layer was separated, washed with H2O (3OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chomatography (Hexane-EtOAc (4.5:0.5)) (0.725g, 59%). 1H NMR (CDCl3) 8.07 (2H, d), 7.68 (IH, s), 7.61-7.51 (3H, m).100.0 g (545.2 mmol) of 1, 3, 5-trichloro pyrimidine, 59.83 g (490.68 mmol) of phenylboronic acid, 188.38 g (1.36 mol) of potassium carbonate, and 18.90 g (16.36 mmol) of tetrakis(triphenylphosphine) palladium (0) were added to 800 mL of 1, 4-dioxane and 400 mL of water in a 2 L flask, and the mixture was heated at 60 C. under a nitrogen flow for 12 hours. The obtained mixture was added to 2000 mL of methanol to crystallize a solid, and the solid was filtered, dissolved in monochlorobenzene, filtered with silica gel/Celite, and then, recrystallized with methanol after removing an appropriate of the organic solvent to obtain Intermediate 8-1 (65.0 g, yield of 53%). (0202) calcd. C10H6Cl2N2: C, 53.36; H, 2.69; Cl, 31.50; N, 12.45; found: C, 53.36; H, 2.69; Cl, 31.50; N, 12.44.Phenylboronic acid (5.00 mmol, 610 mg) and 2, 4, 6-trichloropyrimidine (6.00 mmol, 0.70 mL) are dissolved in a sodium carbonate solution (1 M in water, 10.0 mmol, 10.0 mL), and palladium(II) acetate (0.10 mmol, 22.5 mg) and triphenylphosphine (0.20 mmol, 52.5 mg) are added. The reaction mixture is heated to 60 C and stirred for 3 hours. After cooling, the solution is extracted with diethyl ether (3 × 30 mL). The combined organic phases are washed with brine and dried over sodium sulphate. Subsequently, the solvent is removed under reduced pressure and the crude product is purified via column chromatography (SiO2, NEt3 (1 %), hexane / dichloromethane = 2:1) to yield 9 (478 mg, 42%) as white solid; Rf 0.3 (hexane / dichloromethane = 2:1) [UV]; 1H NMR (360 MHz, CDCl3): delta 7.50-7.60 (m, 3 H), 7.67 (s, 1 H), 8.07 (dd, J = 1.5 Hz, J = 8.3 Hz, 2 H); 13C NMR (151 MHz, CDCl3): delta 115.3 (CH), 127.6 (2 × CH), 129.2 (2 × CH), 132.4 (CH), 134.1 (Cq), 161.0 (Cq), 162.9 (Cq), 168.2(Cq)Step (ii): Synthesis of 2, 4-dichloro-6-phenyl-pyrimidine The title compound was prepared by following procedures reported in (a) Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66, 7125-7128, and (b) Peng, Z-H.; Journet, M.; Humphrey, G. Org. Lett. 2006, 8, 395-398.To 2, 4, 6-trichloropyrimidine (25.01 g, 136 mmol) dissolved in THF was added phenylboronic acid (13.97 g, 114 mmol), palladium acetate (II) (516.2 g, 2.3 mmol), triphenylphosphine (1.193 g, 4.5 mmol) and sodium carbonate (114 mL, 228 mmol, 2 M) sequentially. The resulting mixture was stirred at reflux in a 60 C. oil bath under a nitrogen atmosphere for 3.5 h. The mixture was diluted with TBME, and was washed two times with water and one time with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The solid was triturated with ether and hexanes, filtered, and dried under vacuum to give title compound as a white solid (13.7 g, 45% yield).HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 11.7 min, 92% purity.1H NMR (300 MHz, CDCl3, TMS): delta 8.24-8.21 (m, 2H), 8.07-8.03 (m, 2H), 7.64 (s, 1H), 7.54-7.50 (m, 1H).LC-MSD (ES+): m/z [226 (M+H)+, 100].A mixture of 2, 4, 6-trichloropyrimidine 8 (1 g, 5.45 mmol), phenylboronic acid (665 mg, 5.45 mmol), Pd(PPh3)4 (100 mg) and 2N aqueous Na2CO3 (4.1 mL) in 1 :1 toluene:EtOH (15 mL) was heated in a microwave at 120 C for 20 min. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 2, 4-dichloro-6-phenylpyrimidine as a solid (1.35 g), which was used without further purification in the next step.As shown in Figure 3-step i, a mixture of phenylboronic acid (1.22 g), 2, 4, 6-trichloropyrimidine (compound 1011), tetrakis(triphenylphosphine) palladium(O) and 2N sodium carbonate (15 mL) in DME (25 mL) was heated at 80 0C overnight. After cooling to it, addition of water (30 mL), extraction with dichloromethane (3 x 20 mL), drying and evaporation, purification by column chromatography (SiO2, 10-20% ethyl acetate in hexane) afforded the desired product, 6-phenyl-2, 4-dichloropyrimidine (compound 1012) (0.544 g). As shown in Figure 3-step ii, compound 1012 (0.34 g) was mixed with (, S)-2-amino-N-(2, 2, 2- trifluoroethylpropanamide (0.3 g) and diisopropylethylamine (0.63 mL) in isopropanol (5 mL) and the reaction mixture heated at 80 0C overnight. Evaporation gave a residue, which after aqueous workup and purification (SiO2, 20% ethyl acetate/hexane) produced 2-(2- chloro-6-phenyl-pyrimidin-4-ylamino)-nu-(2, 2, 2-trifluoro-ethyl)propionamide (compound 1013) (0.165 g). As shown in Figure 3-step iii, compound 1013 (29 mg), 5-(4, 4, 5, 5- Tetramethyl-[l, 3, 2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2, 3-d]pyrimidine (compound 1005), PdCl2dppf2 (7 mg), and potassium phosphate (32 mg) were heated in 1, 4- dioxane (2 mL) at 80 0C overnight. To the reaction was added aqueous lithium hydroxide solution (2 mL). After heating at 600C for Ih, water (20 mL) was added. Extraction with dichloromethane (3X), drying, evaporation and purification (SiO2, 50-100% ethyl acetate/hexane) gave 3.7 mg of 2-[6-phenyl-2-(7eta-pyrrolo[2, 3-d]pyrimidin-5-yl)-pyrimidin- 4-ylamino]-N-(2, 2, 2-trifluoro-ethyl)-propionamide (compound 18).In the synthesis of intermediate 2, Using 2, 4, 6-trichloropyrimidine instead of Intermediate 1, The synthesis was carried out in the same manner. Under an argon gas flow, Intermediate 1 (11.9 g, 50 mmol) was added successively to the reaction vessel, Phenylboronic acid (7.9 g, 65 mmol), Tetrakis (triphenylphosphine) palladium (1.73 g, 1.5 mmol), Toluene 170 mL, Ethanol 30 mL, 2M aqueous sodium carbonate solution (50 mL), And the mixture was heated under reflux for 8 hours.After the reaction solution was cooled to room temperature, The organic layer was separated, The organic solvent was removed by distillation under reduced pressure.The resulting residue was purified by silica gel chromatography, To give intermediate 2 (11.6 g, 49 mmol (yield 98%)).A mixture of compound, The following compounds presented in Examples 40-47 were prepared in accordance with Scheme 5, by a procedure analogous to that disclosed in Example 39, using starting materials with the appropriate substitution. (1.0 eq), pyridinylphenylboronic acid (1.05 eq, CAS No. 170230-28-1), Pd(PPh3)4 (0.012 eq), Na2CO3 (2.0 eq, 3 M) in THF (0.3 M) was heated at 60 C. for 16 h. After completion of the reaction, the volatiles were removed under vacuum, and the resulting solution was extracted with CH2Cl2. The combined organic extract was washed with brine solution, dried over Na2SO4. Then the resulting solution was concentrated under reduced pressure and purified by column chromatography to obtain Reactant B8 in a yield of 68%. The purified product was identified as Reactant B8 by FD-MS analysis. FD-MS analysis C21H14ClN3: theoretical value of 343.81 and observed value of 343.81.<1-i> was synthesized by the following Scheme 9. In a 5000 mL round bottom flask, 100.6 g (0.506 mol) <1-f> from Scheme 6, 125.15 g (0.556 mol) <1-h> from Scheme 8, 209.60 g (1.517 mol) of potassium carbonate (K2CO3), 11.69 g (0.010 mmol) of tetrakistriphenylphosphinepalladium (Pd (PPh3) 4), 500 mL of water, 1000 mL of toluene and 500 mL of ethanol were added and refluxed for 12 hours. After the reaction was completed, the resulting product was separated into layers to remove the aqueous layer, and the organic layer was separated and concentrated under reduced pressure. Then, the precipitate was precipitated using methanol and filtered. 100 g (yield 57.5%) <1-i> was obtained.Under nitrogen, Compound A was dissolved in tetrahydrofuran / toluene (5: 1) and 1.2 equivalents of Compound B was added. 4.4 equivalents of potassium carbonate was dissolved in distilled water (DI water) and 0.05 equivalent of Pd (0) was added. The reaction mixture was refluxed at 80 DEG C and stirred for 24 hours to terminate the reaction. After extraction with an organic solvent, the organic solvent was removed. Through column re-precipitation, Compound C was obtained.

Molecular Weight:225.07
XLogP3:3.8
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:223.9908036
Monoisotopic Mass:223.9908036
Topological Polar Surface Area:25.8
Heavy Atom Count:14
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes