3-BROMO-OXETANE

Synthetic Scheme 35: (+/-)-4-[3-[2-chloro-4-(oxetan-3-yl)phenyl]-1, 4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (275) I-255 A Pyrex tube was charged with Formation of (+/-)-tert-butyl 3-(2-chloro-4-(oxetan-3-yl)phenyl)-1, 4-oxazepane-4-carboxylate (286) To a reaction vial was added NiCl2 glyme (0.003 g, 0.014 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.004 g, 0.015 mmol) and DME (1 mL). The mixture was bubbled with nitrogen for 5 minutes until the solid dissolved in DME (1 mL). In another vial was added tert-butyl 3-(4-bromo-2-chloro-phenyl)-1, 4-oxazepane-4-carboxylate, 258, (0.200 g, 0.510 mmol), To a 5 mL vial equipped with a stirring bar was added (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.42 mg, 1.27 pmol, CAS RN 870987-63-6 ), General procedure: To a stirred suspension of compound la (1 eq) in DMF (8.5 mL/mmol) was added K2CO3 (3 eq) followed by the appropriate halide (5 eq). The rxn mixture was stirred at a given temperature under microwave irradiation for a given time (see Table ). It was partitioned between EtOAc and H2O and the org. phase was washed with water and brine, dried over MgSC>4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAcMethod B /K'CC /DMF) To a stirred soln. of phenol E-2 (1 eq) in anh. DMF (8 mL/mmol) was added K2CO3 (2 eq) and the corresponding halide (2 eq). The rxn mixture was stirred for a given time and a given temperature (see Table 64). Additional amount of halide (3 x 2 eq) were added to bring the rxn to completion. It was partitioned between EtOAc and H2O and the org. phase was washed with brine, dried over MgS04 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.General procedure: To a stirred soln. of Ij (1 eq) in DMSO (10 mL/mmol) was added K2CO3 (2 eq) followed by the corresponding halide (1.1 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 34). It was partitioned between EtOAc and H2O. The org. phase was washed with water (3x) and brine, dried over MgSC>4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 3.General procedure: To a stirred soln. of compounds of formula la (1 eq) in DMF (6 mL/mmol) was added K2CO3 (2 eq) followed by the appropriate halide (1.5 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 26). It was partitioned between EtOAc and H2O. The org. phase was washed with water (2x) and brine (1x), dried over MgS04 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH.