In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (100 mg, 0.194 mmol) in dioxane (3 mL). Pyridine 3-boronic acid (23.822 mg, 0.194 mmol), and a 1N solution of potassium carbonate [(80.349 mg, 0.581 mmol) dissolved in 1.25 mL water] were added at room temperature, and the reaction mixture was purged with argon for 30 min. Then, Pd(triphenyl phosphine)4 (22.395 mg, 0.019 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.911 mg, 0.039 mmol) were added and the reaction mixture was further degassed for another 10 min. The reaction mixture was heated at 80° C. for 4 h (monitored by LC-MS). The reaction mixture was filtered through a pad of cellite and the filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column (using amine bound silica gel) to get 9-benzyloxy-6-(4-chloro-2-pyridin-3-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (389) (50 mg, 50.1%) as an off-white solid.
