2-bromo-4-chloro-1-(difluoromethoxy)benzene

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (preparation described in WO2011003065) (46.5 g, 191 mmol) in DMA (350 mL) was added 2-bromo-4-chloro-1-difluoromethoxybenzene (64.0 g, 248 mmol), palladium (II) acetate (2.15 g, 9.6 mmol), di-(adamantyl)-n-butylphosphine (5.0 g, 13.4 mmol), potassium carbonate (79.2 g, 573 mmol) and trimethylacetic acid (5.27 g, 51.6 mmol). The mixture was degassed with nitrogen for 10 minutes then heated at 130° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water and brine, dried (MgSO4), filtered and evaporated. The resultant crude material was purified by flash chromatography on silica eluting with 0-10% EtOAc in cyclohexane to afford 5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (62.4 g, 78%). 1H NMR (400 MHz, CDCl3) δ: (ppm) 8.24 (s, 1H), 7.52-7.53 (m, 2H), 6.39 (t, 1H), 5.29-5.30 (m, 2H), 3.63-3.64 (m, 2H), 0.90 (s, 9H). The mixture was degassed with nitrogen for 10 minutes to cool to room temperature diluted with ethyl acetate washed with water and brine dried (MgSO4) filtered evaporated The resultant crude material was purified by flash chromatography on silica eluting with 0-10% EtOAc in cyclohexane

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

Procedure: To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in DMF (25 mL) was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and water (2.5 mL). The reaction was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic portion washed with brine, dried (MgSO4), and evaporated. The crude product was purified by flash chromatography on silica eluting with 0-20% EtOAc in heptanes to yield 2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil (2.98 g, 48%). LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H). The reaction mixture was partitioned between ethyl acetate and water the organic portion washed with brine dried (MgSO4) evaporated The crude product was purified by flash chromatography on silica eluting with 0-20% EtOAc in heptanes

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

Procedure: 417 mg (2.19 mmol, 1.2 eq.) of 2,5-dimethoxypyridin-4-ylboronic acid and 494 mg (1.82 mmol) of 2-bromo-4-chlorophenyl difluoromethyl ether in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%). Yield: 170 mg (purity 90%, 27% of theory) The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%)

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

Procedure: 36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added dropwise with vigorous stirring. The reaction mixture was stirred for 5 min and diluted with 200 ml of water. The aqueous phase was extracted twice with in each case 150 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ether. The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80% of theory) the mixture was cooled in an ice bath The aqueous phase was extracted twice with in each case 150 ml of diethyl ether The combined organic phases were dried (sodium sulphate) filtered concentrated under reduced pressure dried The aqueous phase was once more extracted with diethyl ether The organic phase was dried (sodium sulphate) filtered concentrated under reduced pressure dried

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

Procedure: 417 mg (2.19 mmol, 1.2 eq.) of 2,5-dimethoxypyridin-4-ylboronic acid and 494 mg (1.82 mmol) of 2-bromo-4-chlorophenyl difluoromethyl ether in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%). Yield: 170 mg (purity 90%, 27% of theory) The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%)

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

Procedure: 36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added dropwise with vigorous stirring. The reaction mixture was stirred for 5 min and diluted with 200 ml of water. The aqueous phase was extracted twice with in each case 150 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ether. The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80% of theory) the mixture was cooled in an ice bath The aqueous phase was extracted twice with in each case 150 ml of diethyl ether The combined organic phases were dried (sodium sulphate) filtered concentrated under reduced pressure dried The aqueous phase was once more extracted with diethyl ether The organic phase was dried (sodium sulphate) filtered concentrated under reduced pressure dried

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

Procedure: To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in 25 mL DMF was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and 2.5 mL water. The reaction was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 20% ethyl acetate in heptanes) to yield 2.98 g (48%) of 2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H). The reaction mixture was partitioned between ethyl acetate and water the organic portion washed with brine dried over magnesium sulfate concentrated The crude product was purified by flash chromatography on silica gel (0 to 20% ethyl acetate in heptanes)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (preparation described in WO2011003065) (46.5 g, 191 mmol) in DMA (350 mL) was added 2-bromo-4-chloro-1-difluoromethoxybenzene (64.0 g, 248 mmol), palladium (II) acetate (2.15 g, 9.6 mmol), di-(adamantyl)-n-butylphosphine (5.0 g, 13.4 mmol), potassium carbonate (79.2 g, 573 mmol) and trimethylacetic acid (5.27 g, 51.6 mmol). The mixture was degassed with nitrogen for 10 minutes then heated at 130° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water and brine, dried (MgSO4), filtered and evaporated. The resultant crude material was purified by flash chromatography on silica eluting with 0-10% EtOAc in cyclohexane to afford 5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (62.4 g, 78%). 1H NMR (400 MHz, CDCl3) δ: (ppm) 8.24 (s, 1H), 7.52-7.53 (m, 2H), 6.39 (t, 1H), 5.29-5.30 (m, 2H), 3.63-3.64 (m, 2H), 0.90 (s, 9H). The mixture was degassed with nitrogen for 10 minutes to cool to room temperature diluted with ethyl acetate washed with water and brine dried (MgSO4) filtered evaporated The resultant crude material was purified by flash chromatography on silica eluting with 0-10% EtOAc in cyclohexane

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

Procedure: To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in DMF (25 mL) was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and water (2.5 mL). The reaction was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic portion washed with brine, dried (MgSO4), and evaporated. The crude product was purified by flash chromatography on silica eluting with 0-20% EtOAc in heptanes to yield 2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil (2.98 g, 48%). LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H). The reaction mixture was partitioned between ethyl acetate and water the organic portion washed with brine dried (MgSO4) evaporated The crude product was purified by flash chromatography on silica eluting with 0-20% EtOAc in heptanes

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

Procedure: 417 mg (2.19 mmol, 1.2 eq.) of 2,5-dimethoxypyridin-4-ylboronic acid and 494 mg (1.82 mmol) of 2-bromo-4-chlorophenyl difluoromethyl ether in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%). Yield: 170 mg (purity 90%, 27% of theory) The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%)

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

Procedure: 36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added dropwise with vigorous stirring. The reaction mixture was stirred for 5 min and diluted with 200 ml of water. The aqueous phase was extracted twice with in each case 150 ml of diethyl ether. The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ether. The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80% of theory) the mixture was cooled in an ice bath The aqueous phase was extracted twice with in each case 150 ml of diethyl ether The combined organic phases were dried (sodium sulphate) filtered concentrated under reduced pressure dried The aqueous phase was once more extracted with diethyl ether The organic phase was dried (sodium sulphate) filtered concentrated under reduced pressure dried