methyl 5-bromo-2-fluoro-4-hydroxybenzoate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask containing 83.2B (13.15 g, 52.8 mmol) in dry DCM (90 mL) was added 3,4-dihydro-2H-pyran (10 mL, 110 mmol) followed by PPTS (0.13 g, 0.53 mmol). The reaction mixture was heated to a gentle reflux (50° C.) and monitored with TLC and LC-MS. After 24 hours, the reaction was concentrated under reduced pressure and then diluted with MeOH. After concentration, the residue was heated in a round bottom flask containing MeOH on the rotary evaporator (without vacuum.) to 40° C. After about 30 minutes, the solution was concentrated to a volume of about 5 mL. After cooling to room temperature, the white solid was filtered and rinsed once with MeOH to yield 83.2C (13.35 g, 76%). 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, m), 6.96 (1H, d, J=12.5 Hz), 5.56 (1H, m), 3.91 (3H, s), 3.79 (1H, td, J=11.1, 2.5 Hz), 3.65 (1H, d, J=10.6 Hz), 2.23 (2H, m), 1.96 (3H, m), 1.68 (1H, m). The reaction mixture was heated to the reaction was concentrated under reduced pressure diluted with MeOH After concentration the residue was heated in a round bottom flask containing MeOH on the rotary evaporator (without vacuum.) to 40° C After about 30 minutes the solution was concentrated to a volume of about 5 mL After cooling to room temperature the white solid was filtered rinsed once with MeOH

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom containing 66.43B (13.15 g, 52.8 mmol) in dry DCM (90 mL) was added 3,4-dihydro-2H-pyran (10 mL, 110 mmol) followed by PPTS (0.13 g, 0.53 mmol). The reaction mixture was heated to a gentle reflux (50° C.) and monitored with TLC and LC-MS. After 24 hours, the reaction was concentrated under reduced pressure and then diluted with MeOH. After concentration, the residue was heated in a round bottom flask containing MeOH on the rotary evaporator (without vacuum.) at 40° C. After about 30 minutes, the solution was concentrated to a volume of about 5 mL. After cooling to room temperature, the white solid was filtered and rinsed once with MeOH to yield 66.43C (13.35 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, m), 6.96 (1H, d, J=12.5 Hz), 5.56 (1H, m), 3.91 (3H, s), 3.79 (1H, td, J=11.1, 2.5 Hz), 3.65 (1H, d, J=10.6 Hz), 2.23 (2H, m), 1.96 (3H, m), 1.68 (1H, m). The reaction mixture was heated to the reaction was concentrated under reduced pressure diluted with MeOH After concentration the residue was heated in a round bottom flask containing MeOH on the rotary evaporator (without vacuum.) at 40° C After about 30 minutes the solution was concentrated to a volume of about 5 mL After cooling to room temperature the white solid was filtered rinsed once with MeOH

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 66.43A (2.03 g, 11.9 mmol) in acetic acid (65 mL) was added a pre-mixed solution of bromine (0.67 mL, 13.1 mmol) in acetic acid (10 mL). The mixture was stirred at 45° C. and monitored with TLC and LC-MS. After 18 hours, the reaction mixture was concentrated under reduced pressure. Brine was added to the residue, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to provide 66.43B as a white solid (2.12 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, d, J=7.4 Hz), 6.82 (1H, d, J=11.3 Hz), 6.04 (1H, s), 3.92 (3H, s). the reaction mixture was concentrated under reduced pressure Brine was added to the residue the mixture was extracted three times with EtOAc The combined organic layers were dried over anhydrous magnesium sulfate filtered concentrated