(2-chloro-6-fluorophenyl)boronic acid

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

Procedure: Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 328. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 (s, 1H), 7.58-7.51 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.33 (m, 1H), 7.00-6.60 (m, 2H), 4.74 (dd, J=11.1, 3.6 Hz, 1H), 4.41-4.23 (m, 1H), 4.16-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.69 (d, J=9.1 Hz, 2H). LCMS (ES+) m/z 483 (M+1).

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

Procedure: Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 328. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 (s, 1H), 7.58-7.51 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.33 (m, 1H), 7.00-6.60 (m, 2H), 4.74 (dd, J=11.1, 3.6 Hz, 1H), 4.41-4.23 (m, 1H), 4.16-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.69 (d, J=9.1 Hz, 2H). LCMS (ES+) m/z 483 (M+1).

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

Procedure: Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 284. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.66 (s, 1H), 7.72 (s, 1H), 7.64 (td, J=8.3, 6.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.50-7.40 (m, 1H), 4.77 (dd, J=10.9, 3.7 Hz, 1H), 4.38-4.17 (m, 1H), 4.17-4.03 (m, 1H), 4.02-3.83 (m, 1H), 3.78 (s, 3H), 3.23-3.09 (m, 1H), 2.10-1.98 (m, 1H), 1.91-1.76 (m, 1H), 1.70-1.56 (m, 4H). LCMS (ES+) m/z 468 (M+1).

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

Procedure: Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 280. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.89 (s, 1H), 7.61-7.46 (m, 4H), 7.40 (ddd, J=9.6, 8.2, 1.4 Hz, 1H), 5.06 (t, J=5.2 Hz, 1H), 3.68 (d, J=2.8 Hz, 5H), 3.33-3.17 (m, 2H), 2.82 (s, 3H), 1.66-1.49 (m, 4H). LCMS (ES+) m/z 495 (M+1).

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (250 mg, 1.21 mmol) in DME (4 mL) and water (1 mL) was added 2-chloro-6-fluorophenylboronic acid (230 mg, 1.32 mmol), potassium phosphate tribasic (306 mg, 1.44 mmol), potassium hydrogenfluoride (188 mg, 2.4 mmol) and Pd(PPh3)4 (69 mg, 0.06 mmol). The reaction mixture was heated to 120° C. under microwave irradiation for 1 h. The product was diluted with EtOAc (30 mL) and washed with water (10 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (SiO2, 0-50% EtOAc in heptane) followed by preparative HPLC (Method 1) gave a white solid. To a solution of this solid (150 mg) in DCM (7 mL) was added phosphorus tribromide (0.2 mL, 2.48 mmol). The mixture was stirred at r.t. for 3 h and partitioned between DCM (50 mL) and 10% aqueous K2CO3 solution (20 mL). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to give a clear oil. To a solution of this oil in DMF (7 mL) was added K2CO3 (72 mg, 0.52 mmol) and 6-mercaptopurine (88 mg, 0.52 mmol) and the mixture stirred at r.t. for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (7×30 mL). The organic layer was separated, dried (MgSO4) and the solvent was removed in vacuo to give the title compound (102 mg, 19%) as a white solid. δH (DMSO-d6) 13.46 (br s, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.41 (s, 1H), 7.89 (d, J 6 Hz, 1H), 7.65 (d, J 6 Hz, 1H), 7.56 (t, J 6 Hz, 1H), 7.40-7.50 (m, 2H), 7.24-7.30 (m, 1H), 4.64-4.72 (m, 2H), 2.64 (s, 3H). LCMS (ES+) 436.2 (M+H)+, RT 3.77 minutes (Method 3). washed with water (10 mL) The organic layer was separated dried (MgSO4) filtered concentrated in vacuo to give a yellow oil Purification by column chromatography (SiO2, 0-50% EtOAc in heptane) gave a white solid partitioned between DCM (50 mL) and 10% aqueous K2CO3 solution (20 mL) The organic layer was separated dried (MgSO4) the solvent removed in vacuo to give a clear oil the mixture stirred at r.t. for 18 h washed with water (7×30 mL) The organic layer was separated dried (MgSO4) the solvent was removed in vacuo

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

Procedure: 83 mg of 2-chloro-6-fluorophenylboronic acid, 0.10 g of sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of wafer and 23 mg of tetrakis(triphenylphosphine)palladium(0) were added to 2.1 mL of toluene solution containing 0.15 g of tert-butyl 2-(benzamido)-4-bromobenzoate, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 21 mg of 2-chloro-6-fluorophenylboronic acid and 23 mg tetrakis(triphenylphosphine)palladium(0) were added and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, toluene and a saturated sodium, hydrogen carbonate aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=10:1] to obtain tert-butyl 2-(benzamido)-4-(2-chloro-6-fluorophenyl)benzoate. the resulting mixture was heated to reflux for 2 hours the resulting mixture was heated to reflux for 2 hours After the reaction mixture was cooled to room temperature The organic layer was separated dried over anhydrous magnesium sulfate after washed with saturated sodium chloride aqueous solution the solvent was evaporated under reduced pressure The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=10:1]

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-3-nitrobenzene [585-79-5] (400 mg, 1.98 mmol) and 2-chloro-6-fluorophenylboronic acid [313545-32-3] (414 mg, 2.37 mmol) in dioxane (12 mL) and water (3 mL) was added potassium fluoride (460 mg, 7.92 mmol) and Pd(PPh3)4 (229 mg, 0.20 mmol). The solution was heated for 60 min at 120° C. under microwave irradiation. More 2-chloro-6-fluorophenylboronic acid (414 mg, 2.37 mmol) was added to the mixture followed by heating at 120° C. for 45 min under microwave irradiation. The reaction mixture was then diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO3 solution and brine, the organics were then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 50 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give the title compound. tR (HPLC conditions c): 5.42 min. by heating at 120° C. for 45 min under microwave irradiation the resulting solution was washed successively with saturated aqueous NaHCO3 solution and brine the organics were then dried (Phase separator) concentrated under reduced pressure The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 50 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA)

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

Procedure: Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted 2-chloro-6-fluorophenylboronic acid (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-6′-fluoro-biphenyl-2-carboxylic acid (3 mg, 3%). 1H NMR (300 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.28-8.38 (m, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.39-7.57 (m, 3H), 7.33 (d, J=9.2 Hz, 1H). the acid was purified

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

Procedure: Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 328. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 (s, 1H), 7.58-7.51 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.33 (m, 1H), 7.00-6.60 (m, 2H), 4.74 (dd, J=11.1, 3.6 Hz, 1H), 4.41-4.23 (m, 1H), 4.16-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.89-1.77 (m, 1H), 1.69 (d, J=9.1 Hz, 2H). LCMS (ES+) m/z 483 (M+1).

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

Procedure: Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 284. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.66 (s, 1H), 7.72 (s, 1H), 7.64 (td, J=8.3, 6.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.50-7.40 (m, 1H), 4.77 (dd, J=10.9, 3.7 Hz, 1H), 4.38-4.17 (m, 1H), 4.17-4.03 (m, 1H), 4.02-3.83 (m, 1H), 3.78 (s, 3H), 3.23-3.09 (m, 1H), 2.10-1.98 (m, 1H), 1.91-1.76 (m, 1H), 1.70-1.56 (m, 4H). LCMS (ES+) m/z 468 (M+1).

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

Procedure: Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 280. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.89 (s, 1H), 7.61-7.46 (m, 4H), 7.40 (ddd, J=9.6, 8.2, 1.4 Hz, 1H), 5.06 (t, J=5.2 Hz, 1H), 3.68 (d, J=2.8 Hz, 5H), 3.33-3.17 (m, 2H), 2.82 (s, 3H), 1.66-1.49 (m, 4H). LCMS (ES+) m/z 495 (M+1).