4-bromo-5-fluoro-2-methoxyphenol

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

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

Procedure: To a reaction flask was added 4-bromo-5-fluoro-2-methoxyphenol (500 mg, 2.26 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (998 mg, 3.39 mmol), potassium phosphate (1.4 g, 6.79 mmol), and XPhosPalladacycle (178 mg, 0.23 mmol), followed by addition of DMF (11 mL). The vial was purged with N2 for 5 minutes and the reaction mixture was heated at 50° C. in the microwave for 16 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel to afford tert-butyl 4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-1H-pyrazole-1-carboxylate (700 mg) MS [M+H+]=307.5. The vial was purged with N2 for 5 minutes The reaction mixture was concentrated in vacuo the crude product was purified by silica gel

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

Procedure: According to the procedure of example 20(a) except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 4-fluoronitrobenzene (210 μL; 2 mmol) and 2-methoxy-4-ethylphenol for 4-bromo-5-fluoro-2-methoxyphenol (444 mg; 2 mmol), the title compound (527 mg; 77%) was prepared as a light yellow solid after purification on silica gel (cyclohexane/ethyl acetate: 95/5). after purification on silica gel (cyclohexane/ethyl acetate: 95/5)

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

Procedure: According to the procedure of example 20(a) except substituting 2-methoxy-4-propylphenol for 4-bromo-5-fluoro-2-methoxyphenol (441 mg; 2 mmol), and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 2,6-Difluoropyridine (0.18 mL; 2 mmol), the title compound was prepared as a yellow oil (246 mg; 39%), after purification on silica gel (cyclohexane/ethyl acetate: 95/5). after purification on silica gel (cyclohexane/ethyl acetate: 95/5)

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

Procedure: According to the procedure of example 20(a) except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 4-fluoronitrobenzene (210 μL; 2 mmol) and 2-methoxy-4-ethylphenol for 4-bromo-5-fluoro-2-methoxyphenol (444 mg; 2 mmol), the title compound (527 mg; 77%) was prepared as a light yellow solid after purification on silica gel (cyclohexane/ethyl acetate: 95/5). after purification on silica gel (cyclohexane/ethyl acetate: 95/5)

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

Procedure: According to the procedure of example 20(a) except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 4-fluoronitrobenzene (210 μL; 2 mmol) and 2-methoxy-4-ethylphenol for 4-bromo-5-fluoro-2-methoxyphenol (444 mg; 2 mmol), the title compound (527 mg; 77%) was prepared as a light yellow solid after purification on silica gel (cyclohexane/ethyl acetate: 95/5). after purification on silica gel (cyclohexane/ethyl acetate: 95/5)

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

Procedure: According to the procedure of example 20(a) except substituting 2-methoxy-4-propylphenol for 4-bromo-5-fluoro-2-methoxyphenol (441 mg; 2 mmol), and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 2,6-Difluoropyridine (0.18 mL; 2 mmol), the title compound was prepared as a yellow oil (246 mg; 39%), after purification on silica gel (cyclohexane/ethyl acetate: 95/5). after purification on silica gel (cyclohexane/ethyl acetate: 95/5)

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

Procedure: 4-Bromo-5-fluoro-2-methoxyphenol (500 mg, 0.002 mol), phenylboronic acid (0.73 g, 0.0060 mol), TEA (2.0 mL, 0.014 mol), cupric acetate (0.70 g, 0.0038 mol) and DCM (20 mL, 0.4 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.83 (s, 3H), 6.73 (d, J=9.09 Hz, 1H), 6.94-7.00 (m, 2H), 7.07-7.15 (m, 2H), 7.34 (dd, J=8.59, 7.58 Hz, 2H). dried flask Reaction mixture was then filtered through celite The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography eluting with 5% EtOAc in hexane

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-bromo-5-fluoro-2-methoxyphenol (2.82 g, 12.25 mmol) in N,N-dimethylformamide (50 mL) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (2.50 g, 12.86 mmol) and potassium carbonate (5.08 g, 36.75 mmol). The reaction mixture was heated to 100° C. After 2 h, the mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (0-33% ethyl acetate/hexanes elute) afforded 2.76 g (66%) of 5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine as an oil. to cool to room temperature The mixture was extracted with ethyl acetate (3×25 mL) The combined organic phases were washed with brine dried over magnesium sulfate filtered concentrated Chromatographic purification (0-33% ethyl acetate/hexanes elute)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To CH2Cl2 (30 mL) in a 50 mL round bottom flask was added 4-bromo-5-fluoro-2-methoxyphenol (2 g, 9.05 mmol). The reaction mixture was cooled to 0° C. in an ice/water bath. Boron tribromide (1.027 mL, 10.86 mmol) was slowly added via syringe over 5 min, and the ice/water bath was removed. The reaction mixture was allowed to warm to room temperature and was stirred for 18 h. The reaction mixture was placed in an ice/water bath and methanol (30 mL) was slowly added via syringe. Upon removal of the ice/water bath, the reaction mixture was allowed to warm to room temperature. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate (200 mL) and washed with water (200 mL). The organic layer was dried over Na2SO4 and filtered. Concentration of the organic solution gave 4-bromo-5-fluorobenzene-1,2-diol as a dark brown oil (1.8 g, 96%): 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=6.5 Hz, 1H), 6.72 (dd, J=8.3, 3.5 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −115.91 (s); ESIMS m/z 207 ([M+H]+), 206 ([M−H]−). the ice/water bath was removed to warm to room temperature The reaction mixture was placed in an ice/water bath methanol (30 mL) was slowly added via syringe Upon removal of the ice/water bath to warm to room temperature The reaction mixture was transferred to a separatory funnel diluted with ethyl acetate (200 mL) washed with water (200 mL) The organic layer was dried over Na2SO4 filtered

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

Procedure: To a reaction flask was added 4-bromo-5-fluoro-2-methoxyphenol (500 mg, 2.26 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (998 mg, 3.39 mmol), potassium phosphate (1.4 g, 6.79 mmol), and XPhosPalladacycle (178 mg, 0.23 mmol), followed by addition of DMF (11 mL). The vial was purged with N2 for 5 minutes and the reaction mixture was heated at 50° C. in the microwave for 16 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel to afford tert-butyl 4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-1H-pyrazole-1-carboxylate (700 mg) MS [M+H+]=307.5. The vial was purged with N2 for 5 minutes The reaction mixture was concentrated in vacuo the crude product was purified by silica gel