5,6,7,8-Tetrahydro-7-(phenylmethyl)pyrido[3,4-d]pyrimidin-4(3H)-one

To a solution of sodium methoxide (25 wt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 °C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 °C for 20 h. The mixture was cooled to 0 °C. Water (90mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 °C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and thendried under vacuum to afford 7-benzyl-5, 6, 7, 8-tetrahydropyrido[3, 4-d]pyrimidin-4(3H)-one (16.10 g, 79 percent) as an off-white solid; LC/MS:m/z 242.06 (M + H)Preparation of 1 -(4-methoxy-7-(3 -methyl- IH-1 , 2, 4-triazol- 1 -yl)- 1 H-pyrrolo[2, 3 - c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5, 6-dihydropyrido[3, 4-d]pyrimidin-7(8H)- yl)ethane-l, 2-dione, compound 18; [00126] Part A: To a solution of sodium methoxide (25 wgt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 To a solution of sodium methoxide (1.67 g, 30.9 mmol) in anhydrous MeOH (10 mL) at room temperature was added formamidine acetate (1.15 g, 11 mmol) in one portion as solid followed by ethyl-1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (2.63 g, 8.83 mmol) in one portion. The reaction mixture was stirred at rt for 20 h. The reaction was cooled at 0° C., and water (6 mL) was added followed by acetic acid (0.63 mL, 11 mmol) and the mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum to remove the methanol and then stirred at rt overnight. The resulting solid was collected by filtration and washed with water (5 mL.x.3) and dried on filter to afford the title compound a (1.50 g, 70percent) as an orange solid. LCMS [M+H]To a slurry of sodium methoxide (10.0 g, 185 mmol) in anhydrous MeOH (60 mL) at room temperature was added formamidine acetate (6.60 g, 63.4 mmole) followed by ethyl-l-benzyl-3-oxo-4-piperidine-carboxylate (15.8 g, 52.9 mmol) in one portion. After stirring at rt for 20h, the mixture was cooled to 10°C whereupon 36 mL of water was added followed by 3.8 mL of acetic acid, and the mixture was stirred for an additional hour. The resulting mixture was concentrated and 150 mL of water was added. The solid was collected by filtration and washed with water and air dried. The crude product (9.60 g) was purified by recrystallization from MeOH (~100 mL) to provide 69A as near white needles (7.86 g, 61. 8percent yield). HPLC Ret. Time: 0.46 min. MH+ (m/z) 253. 1H NMR (400 MHz, CDC13, ppm) : 8 2.65 (t, 3H), 2.75 (t, 3H), 3.50 (s, 2H), 3.70 (s, 2H), 7.35 (m, 5H), 7.98 (s, 1H).The Preparation of Compound 12E: Sodium methoxide (MeONa, 11 g, 161.65 mmol) was dissolved in methanol (280 mL), cooled to 5° C., and then formamidine acetate (3.0 g, 29.15 mmol) was added. The reaction mixture was stirred for 0.5 hour, and then compound 12D (17 g, 65.1 mmol) was added. The reaction mixture was stirred at 40° C. overnight. The reaction was monitored via TLC (DCM/Methanol=10:1). After the reaction was completed, the reaction mixture was cooled to room temperature, evaporated to remove most of the solvent. The residue was extracted with EA. The organic phase was washed with brine, dried with Na7- (3-Chloropyridin-2-yl)-N- (4- (trifluoromethyl) phenyl)-5, 6, 7, 8-tetrahydropyrido [3, 4- d] pyrimidin-4-amine A. 7-Benzyl-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4 (3H) -one [00227] 1-Benzyl-3-ethoxycarbonyl-4-piperidone hydrochloride (12.89g, 43.3mmol) was suspended in a sodium methoxide solution in methanol (25percent wt/wt, 50mL, 216. 2mmol) and formamidine acetate (5.4g, 51.9 mmol) was added to the mixture. The reaction mixture was refluxed until all of the starting material was consumed (2 h). The methanol was removed under vacuum, and the resulting white solid was dissolved in a 3: 1 mixture of chloroform: isopropanol. The mixture was washed with water and brine, dried over Na2SO4, filtered and evaporated to give the desired product as a white solid (9.4g, 90percent).