(3-bromo-2-fluorophenyl)methanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon atmosphere, ethynyl(trimethyl)silane (9.0 ml) was mixed with triethylamine (50 ml), and (3-bromo-2-fluorophenyl)methanol, bis(triphenylphosphine)palladium chloride (II) (1.54 g), and copper iodide (420 mg) were added thereto, followed by stirring at 90° C. overnight. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol (4.88 g). were added The reaction mixture was cooled to room temperature by filtering The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (hexane/EtOAc)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a flask charged with (3-bromo-2-fluorophenyl)methanol (840 mg, 4.1 mmol) and a stir bar was added added thallium trifluoroacetate (2.3 g, 4.3 mmol) and TFA (4.0 mL) at 0° C. The mixture was allowed to stir for 16 hours. LC showed no SM left at that point. The volatiles were removed under reduced pressure, and the residue was dissolved in DCM and concentrated twice to affect azeotropic removal of all TFA. After pumping the residue under high vacuum for 20 minutes, palladium chloride (73 mg, 0.41 mmol), lithium chloride (350 mg, 8.2 mmol), magnesium oxide (330 mg, 8.2 mmol), and MeOH (15 mL) were added to the flask. The mixture was treated under an atmosphere of CO for 2 hours. To this mixtue was added EtOAc to precipitate all the inorganic solids. The crude solution was filtered through a Celite® pad, and the filtrate was collected, adsorbed onto silica gel, and purified by silica gel chromatography. Removal of solvents gave rise to 5-bromo-4-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 231 [M+1]+; was added left at that point The volatiles were removed under reduced pressure the residue was dissolved in DCM concentrated twice removal of all TFA for 20 minutes The mixture was treated under an atmosphere of CO for 2 hours to precipitate all the inorganic solids The crude solution was filtered through a Celite® pad the filtrate was collected purified by silica gel chromatography Removal of solvents

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and (3-bromo-2-fluorophenyl)methanol (Intermediate 11), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.

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

Procedure: Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and (3-bromo-2-fluorophenyl)methanol (Intermediate 11), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.

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

Procedure: A cooled (0° C.) solution of 3-bromo-2-fluorobenzoic acid (Fluorochem; 500 mg; 2.28 mmol) in anhydrous THF (4 mL) was slowly treated with borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) and the resulting solution was stirred at RT for 2 days. Borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) was added and the reaction mixture was stirred at RT for a further 3 hours. The reaction was carefully quenched with water and the mixture was concentrated. The residue was dissolved in Et2O, and the aqueous phase was saturated with K2CO3. The organic layer was separated and the aqueous phase was extracted with Et2O. The combined organic phases were washed with water and brine, dried over MgSO4 and concentrated to dryness affording the title compound as a colorless oil. was slowly treated with borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) Borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) was added the reaction mixture was stirred at RT for a further 3 hours The reaction was carefully quenched with water the mixture was concentrated The residue was dissolved in Et2O The organic layer was separated the aqueous phase was extracted with Et2O The combined organic phases were washed with water and brine dried over MgSO4 concentrated to dryness

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

Procedure: A cooled (0° C.) solution of 3-bromo-2-fluorobenzoic acid (Fluorochem; 500 mg; 2.28 mmol) in anhydrous THF (4 mL) was slowly treated with borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) and the resulting solution was stirred at RT for 2 days. Borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) was added and the reaction mixture was stirred at RT for a further 3 hours. The reaction was carefully quenched with water and the mixture was concentrated. The residue was dissolved in Et2O, and the aqueous phase was saturated with K2CO3. The organic layer was separated and the aqueous phase was extracted with Et2O. The combined organic phases were washed with water and brine, dried over MgSO4 and concentrated to dryness affording the title compound as a colorless oil. was slowly treated with borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) Borane-tetrahydrofuran complex (3.42 mL; 1.00 M; 3.42 mmol) was added the reaction mixture was stirred at RT for a further 3 hours The reaction was carefully quenched with water the mixture was concentrated The residue was dissolved in Et2O The organic layer was separated the aqueous phase was extracted with Et2O The combined organic phases were washed with water and brine dried over MgSO4 concentrated to dryness