Reaction Steps
Step 2—Synthesis of compounds xy1 and xy2: Tert-butyl 2-chloro-8-(cyanomethyl)-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.803 g, 0.00204 mol), [4-Ethylureido)phenyl]boronic acid, pinacol ester (0.778 g, 0.00268 mol), Tetrakis(triphenylphosphine)palladium(0) (0.148 g, 0.000128 mol) Sodium carbonate (0.334 g, 0.00315 mol) and Potassium acetate (0.330 g, 0.00336 mol) were combined, nitrogen purged three times, added dry Acetonitrile (17.0 mL, 0.325 mol) followed by deoxygenated Water (10.0 mL, 0.555 mol), heated at 90° C. and stirred overnight. The reaction mixture was diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, chromatographed through silica gel (40 g, 0-100% EtOAc in heptane), purified by HPLC, and the enantiomers were separated by SFC. Enantiomer 1 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.24 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.19 (t, J=5.5, 1H), 5.16 (t, J=5.9, 1H), 4.22 (s, 1H), 3.84-3.73 (m, 2H), 3.73-3.55 (m, 4H), 3.34 (m, 3H), 3.17-2.90 (m, 4H), 2.82 (s, 1H), 1.48 (s, 9H), 1.13 (t, J=7.2, 1H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+522.2 (M+H)+; Enantiomer 2 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.24 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.19 (t, J=5.6, 1H), 5.16 (t, J=5.9, 1H), 4.18 (s, 1H), 3.78 (dd, J=8.7, 6.2, 2H), 3.72-3.55 (m, 4H), 3.41-3.25 (m, 3H), 3.17-2.90 (m, 4H), 2.84 (d, J=11.0, 1H), 1.47 (d, J=9.3, 9H), 1.14 (t, J=7.2, 1H), 1.09-1.01 (m, 3H). LC/MS-m/z+522.3 (M+H)+
