1-bromo-4-(difluoromethoxy)benzene

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

Procedure: 22.2 g of 4-ethoxystyrene, 33.5 g of 4-(difluoromethoxy)bromobenzene (available from 4-bromophenol analogously to Example 1)), 0.67 g of palladium(II) acetate, 20.8 ml of triethylamine and 1.83 g of tri-o-tolylphosphine are heated to boiling in 225 ml of acetonitrile for 24 hours. After cooling to 0° C., the crystals are filtered off with suction and washed with acetonitrile and water. m.p.: 177° C. the crystals are filtered off with suction washed with acetonitrile and water

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

Procedure: 22.2 g of 4-ethoxystyrene, 33.5 g of 4-(difluoromethoxy)bromobenzene (available from 4-bromophenol analogously to Example 1)), 0.67 g of palladium(II) acetate, 20.8 ml of triethylamine and 1.83 g of tri-o-tolylphosphine are heated to boiling in 225 ml of acetonitrile for 24 hours. After cooling to 0° C., the crystals are filtered off with suction and washed with acetonitrile and water. m.p.: 177° C. the crystals are filtered off with suction washed with acetonitrile and water

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

Procedure: 10.0 g (44.8 mmol) of 4-(difluoromethoxy)bromobenzene were reacted according to General Method 1A with 14.6 g (67.3 mmol) of [5-(methoxycarbonyl)pyridin-3-yl]boronic acid hydrochloride. The release of the hydrochloride was achieved by additional addition of 6.80 g (49.3 mmol) of potassium carbonate. Yield: 8.6 g (67% of theory)

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

Procedure: A solution of (4-bromophenoxy)difluoromethane (3 g) and triisopropyl borate (3.42 ml) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (1.59M hexane solution, 3.42 ml). The mixture was stirred at room temperature overnight. Added thereto was 6N aqueous hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with cold hexane to give 4-(difluoromethoxy)phenylboronic acid (1.88 g) as colorless solid. Added at 0° C. the mixture was extracted with ethyl acetate The extract was washed with brine dried over magnesium sulfate The solvent was evaporated under reduced pressure the residue was triturated with cold hexane

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

Procedure: To a stirred solution of 1-bromo-4-(difluoromethoxy)-benzene (1.18 g) and triisopropyl borate (1.34 ml) in tetra-hydrofuran (6 ml) was added dropwise n-butyl lithium (1.58 M hexane solution, 3.68 ml) at −78° C. over 10 minutes under argon atmosphere, then the reaction mixture was allowed to warm to room temperature. After being starred at room temperature for 3 hours, the mixture was cooled to 0° C., and thereto were added a 6 N aqueous hydrochloric acid solution and water. The resultant mixture was extracted with ethyl acetate (30 ml) twice, and the combined organic layer was washed with brine (10 ml), dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residual solid was triturated with cold hexane to give the titled compound as a colorless solid. 1H-NMR (DMSO-d6) δ 7.12 (d, J=8.4 Hz, 2H), 7.27 (t, J=74.1 Hz, 1H), 7.83 (d, J=8.6 Hz, 2H), 8.08 (br-s, 2H). the mixture was cooled to 0° C. The resultant mixture was extracted with ethyl acetate (30 ml) twice the combined organic layer was washed with brine (10 ml) dried over sodium sulfate The insoluble materials were filtered off the filtrate was evaporated under reduced pressure The residual solid was triturated with cold hexane

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

Procedure: 22.2 g of 4-ethoxystyrene, 33.5 g of 4-(difluoromethoxy)bromobenzene (available from 4-bromophenol analogously to Example 1)), 0.67 g of palladium(II) acetate, 20.8 ml of triethylamine and 1.83 g of tri-o-tolylphosphine are heated to boiling in 225 ml of acetonitrile for 24 hours. After cooling to 0° C., the crystals are filtered off with suction and washed with acetonitrile and water. m.p.: 177° C. the crystals are filtered off with suction washed with acetonitrile and water

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

Procedure: A solution of (4-bromophenoxy)difluoromethane (3 g) and triisopropyl borate (3.42 ml) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (1.59 M hexane solution, 3.42 ml). The mixture was stirred at room temperature overnight. Added thereto was 6N aqueous hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with cold hexane to give 4-(difluoromethoxy)phenylboronic acid (1.88 g) as colorless solid. Added at 0° C. the mixture was extracted with ethyl acetate The extract was washed with brine dried over magnesium sulfate The solvent was evaporated under reduced pressure the residue was triturated with cold hexane

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

Procedure: 10.0 g (44.8 mmol) of 4-(difluoromethoxy)bromobenzene were reacted according to General Method 3A with 14.6 g (67.3 mmol) of [5-(methoxycarbonyl)pyridin-3-yl]boronic acid hydrochloride. The release of the hydrochloride was achieved by additional addition of 6.80 g (49.3 mmol) of potassium carbonate. Yield: 8.6 g (67% of theory)

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

Procedure: A solution of (4-bromophenoxy)difluoromethane (3 g) and triisopropyl borate (3.42 ml) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (1.59 M hexane solution, 3.42 ml). The mixture was stirred at room temperature overnight. Added thereto was 6N aqueous hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with cold hexane to give 4-(difluoromethoxy)phenylboronic acid (1.88 g) as colorless solid. Added at 0° C. the mixture was extracted with ethyl acetate The extract was washed with brine dried over magnesium sulfate The solvent was evaporated under reduced pressure the residue was triturated with cold hexane

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

Procedure: 10.0 g (44.8 mmol) of 4-(difluoromethoxy)bromobenzene were reacted according to General Method 3A with 14.6 g (67.3 mmol) of [5-(methoxycarbonyl)pyridin-3-yl]boronic acid hydrochloride. The release of the hydrochloride was achieved by additional addition of 6.80 g (49.3 mmol) of potassium carbonate. Yield: 8.6 g (67% of theory)

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

Procedure: In a 0.5-2 ml Biotage conical microwave vial equipped with magnetic spin vane was dissolved 4-(5-ethynyl-2-fluorophenyl)morpholine (540 mg, 1.50 mmol) in triethylamine (1.5 mL). Copper iodide (54 mg, 0.283 mmol) and Tetrakis(triphenylphosphine) palladium (105 mg, 0.091 mmol) were added. Lastly 1-bromo-4-(difluoromethoxy)benzene (0.750 g, 3.36 mmol) was added, the vial was covered with a teflon septa, an aluminum cap was crimped in place, and the assembly was set on a Biotage Emrys microwave instrument to irradiate at 80° C. for 30 minutes. The crude reaction was diluted with diethylether, washed with saturated ammonium chloride, and purified via column chromatography on a Yamazen W-Prep 2XY using 25% EtOAc in hexanes. Concentration by rotary evaporation afforded 500 mg of oil (96%); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.03 (t, J=4.6 Hz, 4H) 3.73 (t, J=4.6 Hz, 4H) 7.13-7.14 (m, 1H) 7.16 (d, J=2.6 Hz, 1H) 7.17-7.19 (m, 2H) 7.22 (d, J=8.8 Hz, 2H) 7.24 (t, J=73.8 Hz, 1H) 7.60 (d, J=8.8 Hz, 2H); MS (ES) m/z 348.2 [M+H]+ In a 0.5-2 ml Biotage conical microwave vial equipped with magnetic spin vane to irradiate at 80° C. for 30 minutes The crude reaction washed with saturated ammonium chloride purified via column chromatography on a Yamazen W-Prep Concentration by rotary evaporation

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

Procedure: In a 0.5-2 ml Biotage conical microwave vial equipped with magnetic spin vane was dissolved 4-(5-ethynyl-2-fluorophenyl)morpholine (540 mg, 1.50 mmol) in triethylamine (1.5 mL). Copper iodide (54 mg, 0.283 mmol) and Tetrakis(triphenylphosphine) palladium (105 mg, 0.091 mmol) were added. Lastly 1-bromo-4-(difluoromethoxy)benzene (0.750 g, 3.36 mmol) was added, the vial was covered with a teflon septa, an aluminum cap was crimped in place, and the assembly was set on a Biotage Emrys microwave instrument to irradiate at 80° C. for 30 minutes. The crude reaction was diluted with diethylether, washed with saturated ammonium chloride, and purified via column chromatography on a Yamazen W-Prep 2XY using 25% EtOAc in hexanes. Concentration by rotary evaporation afforded 500 mg of oil (96%); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.03 (t, J=4.6 Hz, 4H) 3.73 (t, J=4.6 Hz, 4H) 7.13-7.14 (m, 1H) 7.16 (d, J=2.6 Hz, 1H) 7.17-7.19 (m, 2H) 7.22 (d, J=8.8 Hz, 2H) 7.24 (t, J=73.8 Hz, 1H) 7.60 (d, J=8.8 Hz, 2H); MS (ES) m/z 348.2 [M+H]+ In a 0.5-2 ml Biotage conical microwave vial equipped with magnetic spin vane to irradiate at 80° C. for 30 minutes The crude reaction washed with saturated ammonium chloride purified via column chromatography on a Yamazen W-Prep Concentration by rotary evaporation