Reaction Steps
A mixture of (rac)-tert-butyl ((1R,3S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate and (rac)-tert-butyl ((1R,3S)-3-((8-iodo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509a, 1.49 g, 3.30 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 1.331 g, 3.96 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (0.117 g, 0.165 mmol), and potassium phosphate (2.102 g, 9.90 mmol) in 1,4-dioxane (26.4 mL)/water (6.60 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 1 h. More (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.33 g) was added, and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the aqueous layer was extracted with EtOAc (4×100); the organic layers were separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-8% 2 M ammonia in MeOH/DCM to give (rac)-tert-butyl ((cis)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509, 0.59 g, 0.582 mmol, 17% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.34 (m, 3H) 1.37 (s, 9H) 1.40 (d, J=6.65 Hz, 3H) 1.42-1.54 (m, 2H) 1.73-1.89 (m, 2H) 1.99-2.20 (m, 2H) 3.44 (s, 3H) 3.92-4.11 (m, 1H) 4.48-4.59 (m, 0.5; H) 4.60-4.74 (m, 0.5; H) 6.79-6.99 (m, 3H) 7.15 (t, J=7.73 Hz, 1H) 7.63 (d, J=4.30 Hz, 1H) 7.82 (d, J=7.04 Hz, 1H) 7.97 (dd, J=11.54, 7.82 Hz, 1H) 11.99 (br. s., 0.4; H) 12.09 (br. s., 0.6; H). MS (ESI, pos. ion) m/z: 507.2 (M+1).
