3-bromo-6-fluoro-2-methoxybenzonitrile

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

Procedure: A solution of 3-bromo-6-fluoro-2-methoxybenzamide (14 g, 61 mmol) in 100 mL of DMF was added 2,4,6-trichloro-[1,3,5]triazine (12.3 g, 67.0 mmol) portionwise at 0° C. and stirred for 2 hours before poured to ice/water. The white solid was collected by filtration and was washed with water, dissolved in DCM, dried over anhydrous Na2SO4 and concentrated to afford 3-bromo-6-fluoro-2-methoxybenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.71˜7.74 (m, 1H), 6.84˜6.88 (m, 1H), 4.09 (s, 3H); The white solid was collected by filtration was washed with water dissolved in DCM dried over anhydrous Na2SO4 concentrated

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

Procedure: 3-bromo-6-fluoro-2-methoxybenzonitrile (4.40 g, 19.1 mmol), potassium vinyl trifluoroborate (5.12 g, 38.3 mmol), PdCl2(dppf)-CH2Cl2 Adduct (0.7 g, 1 mmol) and TEA (5.33 mL, 38.3 mmol) were added to 80 mL ethanol in a 200 mL flask. The reaction mixture was degassed and heated to reflux for 4 h. The reaction mixture was cooled and then most of the EtOH was removed. The residue was diluted with ethyl acetate. The mixture was washed with brine twice. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified through a 330 g RediSep column and eluted with 10% EtOAc/hexane solvent system to yield the title compound. The reaction mixture was degassed heated to reflux for 4 h The reaction mixture was cooled most of the EtOH was removed The residue was diluted with ethyl acetate The mixture was washed with brine twice The organic layer was separated dried over Na2SO4 filtered evaporated to dryness The residue was purified through a 330 g RediSep column eluted with 10% EtOAc/hexane solvent system

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

Procedure: 2-Fluoro-6-methoxybenzonitrile (8.30 g, 54.9 mmol) was dissolved in triflic acid (75 mL) at 0° C. then NBS (10.3 g, 57.7 mmol) was added. The reaction mixture was stirred at RT for 1 h. LC-MS showed no starting material peak. The reaction mixture was poured into ice and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by chromatography through a 330 g Redi-Sep column and eluted with 10% to 50% EtOAc/hexane solvent system to yield the title compound. The reaction mixture was poured into ice extracted twice with DCM The combined organic layers were washed with brine dried over Na2SO4 filtered evaporated to dryness The residue was purified by chromatography through a 330 g Redi-Sep column eluted with 10% to 50% EtOAc/hexane solvent system

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

Procedure: A solution of 3-bromo-6-fluoro-2-methoxybenzamide (14 g, 61 mmol) in 100 mL of DMF was added 2,4,6-trichloro-[1,3,5]triazine (12.3 g, 67.0 mmol) portionwise at 0° C. and stirred for 2 hours before poured to ice/water. The white solid was collected by filtration and was washed with water, dissolved in DCM, dried over anhydrous Na2SO4 and concentrated to afford 3-bromo-6-fluoro-2-methoxybenzonitrile. The white solid was collected by filtration was washed with water dissolved in DCM dried over anhydrous Na2SO4 concentrated

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

Procedure: 3-bromo-6-fluoro-2-methoxybenzonitrile (4.40 g, 19.1 mmol), potassium vinyl trifluoroborate (5.12 g, 38.3 mmol), PdCl2(dppf)-CH2Cl2 Adduct (0.7 g, 1 mmol) and TEA (5.33 mL, 38.3 mmol) were added to 80 mL ethanol in a 200 mL flask. The reaction mixture was degassed and heated to reflux for 4 h. The reaction mixture was cooled and then most of the ETOH was removed. The residue was diluted with ethyl acetate. The mixture was washed with brine twice. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified thru a 330 g RediSep column and eluted with 10% ETOAc/hexane solvent system to yield the title compound. The reaction mixture was degassed heated to reflux for 4 h The reaction mixture was cooled most of the ETOH was removed The residue was diluted with ethyl acetate The mixture was washed with brine twice The organic layer was separated dried over Na2SO4 filtered evaporated to dryness The residue was purified thru a 330 g RediSep column eluted with 10% ETOAc/hexane solvent system

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

Procedure: 2-Fluoro-6-methoxybenzonitrile (8.30 g, 54.9 mmol) was dissolved in Triflic acid (75 mL) at 0° C. then NBS (10.3 g, 57.7 mmol) was added. The reaction mixture was stirred at RT for 1 h. LC-MS showed no starting material peak. The reaction mixture was poured into ice and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by chromatography through a 330 g Redi-Sep column and eluted with 10% to 50% EtOAc/hexane solvent system to yield the title compound. The reaction mixture was poured into ice extracted twice with DCM The combined organic layers were washed with brine dried over Na2SO4 filtered evaporated to dryness The residue was purified by chromatography through a 330 g Redi-Sep column eluted with 10% to 50% EtOAc/hexane solvent system