4,5-DIFLUORO-2-METHOXYPHENYLBORONIC ACID

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

Procedure: The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (82%). MS (ESI): m/z=309.104 [M+H]+. for the chromatographic purification

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

Procedure: The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of CH2Cl2:methanol (100:0 to 85:15) for the chromatographic purification. Light brown foam (76%). MS (ESI): m/z=343.09 [M+H]+. for the chromatographic purification

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

Procedure: The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of CH2Cl2:methanol (100:0 to 85:15) for the chromatographic purification. Light brown foam (76%). MS (ESI): m/z=343.09 [M+H]+. for the chromatographic purification

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

Procedure: The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (73%). MS (ESI): m/z=301.10 [M+H]+. for the chromatographic purification

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

Procedure: The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester and (example 85, intermediate c) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (79%). MS (ESI): m/z=419.139 [M+H]. for the chromatographic purification

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

Procedure: The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic separation. Light brown solid (91%). MS (ESI): m/z=251.099 [M+H]+. for the chromatographic separation

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

Procedure: The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4,5-difluoro-2-methoxy phenylboronic acid (CAS RN 870777-32-5) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=491.4 [M+H]+. as reaction solvent

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

Procedure: The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4,5-difluoro-2-methoxy phenylboronic acid (CAS RN 870777-32-5) and using DMF as reaction solvent. Off-white solid (27%). MS (ESI): m/z=491.4 [M+H]+. as reaction solvent

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,5-Difluoro-2-methoxyphenyl-boronic acid (8.8 g, 46.82 mmol) and 4-iodophenol (6.86 g, 31.21 mmol) were suspended in 165 ml of DMF. H2O (40 mL) was added and the mixture was degassed with argon. Finely ground potassium carbonate (13 g, 93.63 mmol) and tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.29 mmol) were added. The reaction was stirred at 80-85° C. for 1 hr under argon and cooled. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried and solvents were evaporated. The crude product was purified by flash chromatography, eluting with 0-8% ethyl acetate in hexanes to yield 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (6.58 g, 89.3%). LR-MS (ES) calculated for C13H10F2O2, 236.22; found m/z 235 (M−H). the mixture was degassed with argon cooled The organic layer was washed with brine dried solvents were evaporated The crude product was purified by flash chromatography eluting with 0-8% ethyl acetate in hexanes

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,5-Difluoro-2-methoxyphenyl-boronic acid (8.8 g, 46.82 mmol) and 4-iodophenol (6.86 g, 31.21 mmol) were suspended in 165 ml of DMF. H2O (40 mL) was added and the mixture was degassed with argon. Finely ground potassium carbonate (13 g, 93.63 mmol) and tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.29 mmol) were added. The reaction was stirred at 80-85° C. for 1 hr under argon and cooled. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried and solvents were evaporated. The crude product was purified by flash chromatography, eluting with 0-8% ethyl acetate in hexanes to yield 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (6.58 g, 89.3%). LR-MS (ES) calculated for C13H10F2O, 236.22; found m/z 235 [M−H]−. the mixture was degassed with argon cooled The organic layer was washed with brine dried solvents were evaporated The crude product was purified by flash chromatography eluting with 0-8% ethyl acetate in hexanes

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,5-Difluoro-2-methoxyphenyl-boronic acid (8.8 g, 46.82 mmol) and 4-iodophenol (6.86 g, 31.21 mmol) were suspended in 165 ml of DMF. H2O (40 mL) was added and the mixture was degassed with argon. Finely ground potassium carbonate (13 g, 93.63 mmol) and tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.29 mmol) were added. The reaction was stirred at 80-85° C. for 1 hr under argon and cooled. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried and solvents were evaporated. The crude product was purified by flash chromatography, eluting with 0-8% ethyl acetate in hexanes to yield 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (6.58 g, 89.3%). LR-MS (ES) calculated for C13H10F2O2, 236.22; found m/z 235 [M−H]−. the mixture was degassed with argon cooled The organic layer was washed with brine dried solvents were evaporated The crude product was purified by flash chromatography eluting with 0-8% ethyl acetate in hexanes

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

Procedure: To a mixture of 4-fluoro-3-(4-iodophenoxy)methylbenzoic acid methyl ester (1.1 g, 2.85 mmol) and 4,5-difluoro-2-methoxyphenylboronic acid (0.642 g, 3.4 mmol) in DMF (15 mL) and water (2.5 mL) was added Pd(dppf)Cl2 (220 mg, 0.27 mmol) and potassium carbonate (1.24 g, 9.0 mmol). The mixture was stirred at 45° C. overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried and concentrated. The residue was purified through flash column chromatography (120 g silica gel, 5% to 40% ethyl acetate in hexanes over 25 minutes) to give a white solid as 3-(4′,5′-difluoro-2′-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid methyl ester (0.76 g, 67%). solvents were evaporated The residue was extracted with ethyl acetate and water The organic layer was dried concentrated The residue was purified through flash column chromatography (120 g silica gel, 5% to 40% ethyl acetate in hexanes over 25 minutes)