(3-chloro-2-fluorophenyl)boronic acid

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

Procedure: The titled compound was synthesized by steps analogous to those described in method AA5 above, but using (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (prepared using the same procedures as described in Method CC6 but using 4-iodophenol) 3-chloro-2-fluorophenylboronic acid and trimethyl((3-methyloxetan-3-yl)ethynyl)silane. MS m/z=476.1 [M+H]+. Calculated for C26H19ClFN3O3: 475.11. 1H NMR (400 MHz, DMSO-d6) δ=8.45 (br. s., 1 H), 7.67 (br. s., 2 H), 7.65-7.60 (m, 2H), 7.58-7.50 (m, 1 H), 7.47-7.39 (m, 1 H), 7.38-7.31 (m, 1 H), 4.78 (d, J=5.5 Hz, 4 H), 4.46 (d, J=5.6 Hz, 2 H), 1.66 (s, 3 H) prepared

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 N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 3-chloro-2-fluorophenylboronic acid (CAS RN 352535-82-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (64%). MS (ESI): m/z=477.061 [M+H]+. for the chromatographic purification

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 (3-chloro-2-fluorophenyl)boronic acid gave 338. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.47-8.06 (m, 1H), 7.86 (s, 1H), 7.66-7.55 (m, 1H), 7.52 (s, 2H), 7.30 (t, J=8.1 Hz, 1H), 4.83 (dd, J=10.5, 3.6 Hz, 1H), 4.58-4.37 (m, 1H), 4.36-4.22 (m, 1H), 4.18-3.97 (m, 1H), 3.76 (s, 3H), 2.10-2.00 (m, 1H), 1.89-1.60 (m, 4H). 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 ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-chloro-2-fluorophenyl)boronic acid gave 248. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.59 (s, 1H), 8.30-8.21 (m, 1H), 7.86-7.77 (m, 2H), 7.52-7.43 (m, 1H), 5.05-4.77 (m, 2H), 4.16 (ddd, J=24.7, 13.6, 4.7 Hz, 1H), 3.99 (ddd, J=17.9, 13.5, 4.8 Hz, 1H), 3.77 (s, 3H), 3.27-3.22 (m, 1H), 2.18-2.09 (m, 1H), 1.88-1.78 (m, 2H), 1.71-1.60 (m, 3H). 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 ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-chloro-2-fluorophenyl)boronic acid gave 248. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.59 (s, 1H), 8.30-8.21 (m, 1H), 7.86-7.77 (m, 2H), 7.52-7.43 (m, 1H), 5.05-4.77 (m, 2H), 4.16 (ddd, J=24.7, 13.6, 4.7 Hz, 1H), 3.99 (ddd, J=17.9, 13.5, 4.8 Hz, 1H), 3.77 (s, 3H), 3.27-3.22 (m, 1H), 2.18-2.09 (m, 1H), 1.88-1.78 (m, 2H), 1.71-1.60 (m, 3H). LCMS (ES+) m/z 468 (M+1).

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

Procedure: Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (3-chloro-2-fluorophenyl)boronic acid gave the title compound.

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

Procedure: The titled compound was synthesized by steps analogous to those described in method AA5 above, but using (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (prepared using the same procedures as described in Method CC6 but using 4-iodophenol) 3-chloro-2-fluorophenylboronic acid and trimethyl((3-methyloxetan-3-yl)ethynyl)silane. MS m/z=476.1 [M+H]+. Calculated for C26H19ClFN3O3: 475.11. 1H NMR (400 MHz, DMSO-d6) δ=8.45 (br. s., 1 H), 7.67 (br. s., 2 H), 7.65-7.60 (m, 2H), 7.58-7.50 (m, 1 H), 7.47-7.39 (m, 1 H), 7.38-7.31 (m, 1 H), 4.78 (d, J=5.5 Hz, 4 H), 4.46 (d, J=5.6 Hz, 2 H), 1.66 (s, 3 H) prepared

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

Procedure: In a 200-mL three-neck flask were put 5.8 g (26 mmol) of 1-bromo-2-naphthol, 4.5 g (26 mmol) of 3-chloro-2-fluorobenzeneboronic acid, and 0.40 g (1.3 mmol) of tri(ortho-tolyl)phosphine, and the air in the flask was replaced with nitrogen. To this mixture, 150 mL of toluene, 50 mL of ethanol, and 21 mL of an aqueous solution of potassium carbonate (2.0 mol/L) were added. The mixture was degassed by being stirred while the pressure in the flask was reduced; then, the air in the flask was replaced with nitrogen. To this mixture was added 58 mg (0.26 mmol) of palladium(II)acetate, and the resulting mixture was stirred at 90° C. under a nitrogen stream for 7 hours. After stirring, the organic layer of the mixture was washed with water and the aqueous layer was subjected to extraction with toluene. The solution of the extract combined with the organic layer was washed with a saturated aqueous solution of sodium chloride, and the organic layer was dried over magnesium sulfate. The resulting mixture was gravity-filtered, and the resulting filtrate was concentrated to give a brown liquid. The liquid was purified by silica gel column chromatography using a mixed solvent (toluene: hexane=9:1) as a developing solvent, so that 3.1 g of a brown liquid of a target substance was produced in a yield of 44%. In a 200-mL three-neck flask were put The mixture was degassed the resulting mixture was stirred at 90° C. under a nitrogen stream for 7 hours After stirring the organic layer of the mixture was washed with water the aqueous layer was subjected to extraction with toluene was washed with a saturated aqueous solution of sodium chloride the organic layer was dried over magnesium sulfate The resulting mixture was gravity-filtered the resulting filtrate was concentrated to give a brown liquid The liquid was purified by silica gel column chromatography

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

Procedure: In a 200-mL three-neck flask were put 5.8 g (26 mmol) of 1-bromo-2-naphthol, 4.5 g (26 mmol) of 3-chloro-2-fluorobenzeneboronic acid, and 0.40 g (1.3 mmol) of tri(ortho-tolyl)phosphine, and the air in the flask was replaced with nitrogen. To this mixture, 150 mL of toluene, 50 mL of ethanol, and 21 mL of an aqueous solution of potassium carbonate (2.0 mol/L) were added. The mixture was degassed by being stirred while the pressure in the flask was reduced; then, the air in the flask was replaced with nitrogen. To this mixture was added 58 mg (0.26 mmol) of palladium(II)acetate, and the resulting mixture was stirred at 90° C. under a nitrogen stream for 7 hours. After stirring, the organic layer of the mixture was washed with water and the aqueous layer was subjected to extraction with toluene. The solution of the extract combined with the organic layer was washed with a saturated aqueous solution of sodium chloride, and the organic layer was dried over magnesium sulfate. The resulting mixture was gravity-filtered, and the resulting filtrate was concentrated to give a brown liquid. The liquid was purified by silica gel column chromatography using a mixed solvent (toluene: hexane=9:1) as a developing solvent, so that 3.1 g of a brown liquid of a target substance was produced in a yield of 44%. In a 200-mL three-neck flask were put The mixture was degassed the resulting mixture was stirred at 90° C. under a nitrogen stream for 7 hours After stirring the organic layer of the mixture was washed with water the aqueous layer was subjected to extraction with toluene was washed with a saturated aqueous solution of sodium chloride the organic layer was dried over magnesium sulfate The resulting mixture was gravity-filtered the resulting filtrate was concentrated to give a brown liquid The liquid was purified by silica gel column chromatography

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

Procedure: In a 200-mL three-neck flask were put 5.8 g (26 mmol) of 1-bromo-2-naphthol, 4.5 g (26 mmol) of 3-chloro-2-fluorobenzeneboronic acid, and 0.40 g (1.3 mmol) of tri(ortho-tolyl)phosphine, and the air in the flask was replaced with nitrogen. To this mixture, 150 mL of toluene, 50 mL of ethanol, and 21 mL of an aqueous solution of potassium carbonate (2.0 mol/L) were added. The mixture was degassed by being stirred while the pressure in the flask was reduced; then, the air in the flask was replaced with nitrogen. To this mixture was added 58 mg (0.26 mmol) of palladium(II)acetate, and the resulting mixture was stirred at 90° C. under a nitrogen stream for 7 hours. After stirring, the organic layer of the mixture was washed with water and the aqueous layer was subjected to extraction with toluene. The solution of the extract combined with the organic layer was washed with a saturated aqueous solution of sodium chloride, and the organic layer was dried over magnesium sulfate. The resulting mixture was gravity-filtered, and the resulting filtrate was concentrated to give a brown liquid. The liquid was purified by silica gel column chromatography using a mixed solvent (toluene: hexane=9:1) as a developing solvent, so that 3.1 g of a brown liquid of a target substance was produced in a yield of 44%. In a 200-mL three-neck flask were put The mixture was degassed the resulting mixture was stirred at 90° C. under a nitrogen stream for 7 hours After stirring the organic layer of the mixture was washed with water the aqueous layer was subjected to extraction with toluene was washed with a saturated aqueous solution of sodium chloride the organic layer was dried over magnesium sulfate The resulting mixture was gravity-filtered the resulting filtrate was concentrated to give a brown liquid The liquid was purified by silica gel column chromatography

Conditions: temp:-80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500-mL three-neck flask was put 16 g (72 mmol) of 1-bromo-3-chloro-2-fluorobenzene, and the air in the flask was replaced with nitrogen; then, 200 mL of tetrahydrofuran was added and the solution was cooled down to −80° C. under a nitrogen stream. To this solution, 48 mL (76 mmol) of n-butyl lithium (a 1.6 mol/L hexane solution) was added dropwise with a syringe, and then the mixture was stirred for 1.5 hours at the same temperature. After stirring, 9.0 mL (80 mmol) of trimethyl borate was added to this mixture. While the temperature was raised to room temperature, the mixture was stirred for about 19 hours. After stirring, about 100 mL of a 1 mol/L hydrochloric acid was added to the resulting solution and the mixture was stirred. The organic layer of this mixture was washed with water and the aqueous layer was subjected to extraction with toluene twice. The solution of the extract and the organic layer were combined and washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over magnesium sulfate, and this mixture was gravity-filtered. The resulting filtrate was concentrated to give 4.5 g of a pale yellow solid of a target substance, in a yield of 35%. In a 500-mL three-neck flask was put After stirring While the temperature was raised to room temperature the mixture was stirred for about 19 hours After stirring the mixture was stirred The organic layer of this mixture was washed with water the aqueous layer was subjected to extraction with toluene twice The solution of the extract washed with a saturated aqueous solution of sodium chloride The resulting organic layer was dried over magnesium sulfate this mixture was gravity-filtered The resulting filtrate was concentrated

Conditions: temp:-80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500-mL three-neck flask was put 16 g (72 mmol) of 1-bromo-3-chloro-2-fluorobenzene, and the air in the flask was replaced with nitrogen; then, 200 mL of tetrahydrofuran was added and the solution was cooled down to −80° C. under a nitrogen stream. To this solution, 48 mL (76 mmol) of n-butyl lithium (a 1.6 mol/L hexane solution) was added dropwise with a syringe, and then the mixture was stirred for 1.5 hours at the same temperature. After stirring, 9.0 mL (80 mmol) of trimethyl borate was added to this mixture. While the temperature was raised to room temperature, the mixture was stirred for about 19 hours. After stirring, about 100 mL of a 1 mol/L hydrochloric acid was added to the resulting solution and the mixture was stirred. The organic layer of this mixture was washed with water and the aqueous layer was subjected to extraction with toluene twice. The solution of the extract and the organic layer were combined and washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over magnesium sulfate, and this mixture was gravity-filtered. The resulting filtrate was concentrated to give 4.5 g of a pale yellow solid of a target substance, in a yield of 35%. In a 500-mL three-neck flask was put After stirring While the temperature was raised to room temperature the mixture was stirred for about 19 hours After stirring the mixture was stirred The organic layer of this mixture was washed with water the aqueous layer was subjected to extraction with toluene twice The solution of the extract washed with a saturated aqueous solution of sodium chloride The resulting organic layer was dried over magnesium sulfate this mixture was gravity-filtered The resulting filtrate was concentrated