4-bromo-N-tert-butyl-3-fluorobenzamide

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (11.7 mL, 82.0 mmol) in THF (200 mL) was treated with n-butyllithium (33 mL, 82 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (9.0 g, 33 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, (R)-(+)-propylene oxide (6.9 mL, 98 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude material was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound. LC-MS: m/z 332.08 (M+H)+. The solution was then warmed to −40° C. maintained there for 1 h the solution warmed to 0° C After 1 h the ice bath was removed to warm to rt The solution was quenched with MeOH diluted with brine (200 mL) extracted with EtOAc (300 mL) The organic layer was removed dried over MgSO4 filtered concentrated The crude material was purified

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-bromo-3-fluorobenzoic acid (19 g, 87 mmol) in DCM (200 mL) was added oxalyl chloride (9.10 mL, 104 mmol), followed by 1 drop of DMF. The mixture was allowed to stir at rt for 2 h. Upon clarification of the suspension, the solution was concentrated to dryness. The residue was redissolved in DCM (200 mL) and cooled to 0° C. Next the solution was treated with TEA (30.2 mL, 217 mmol) followed by tert-butyl amine (12.0 mL, 113 mmol). The solution was allowed to stir for 12 h. The reaction was diluted with 1N HCl (200 mL). The organic layer was then removed and washed with 1N NaOH. The organic layer was dried over MgSO4, filtered and concentrated to afford the title compound. Upon clarification of the suspension, the solution was concentrated to dryness The residue was redissolved in DCM (200 mL) cooled to 0° C to stir for 12 h The organic layer was then removed washed with 1N NaOH The organic layer was dried over MgSO4 filtered concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisopropylamine (6.2 mL, 44 mmol) in THF (200 mL) was treated with n-butyllithium (17.4 mL, 44.0 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (4.8 g, 17 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, ethylene oxide (10 mL, 200 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude product was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound: LC-MS: m/z 319.98 (M+H)+. The solution was then warmed to −40° C. maintained there for 1 h the solution warmed to 0° C After 1 h the ice bath was removed to warm to rt The solution was quenched with MeOH diluted with brine (200 mL) extracted with EtOAc (300 mL) The organic layer was removed dried over MgSO4 filtered concentrated The crude product was purified