4-chloro-2-iodo-1-methoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-2-iodo-1-methoxybenzene (542 mg, 2.02 mmol), (2-chloropyridin-4-yl)boronic acid (400 mg, 2 mmol), and sodium carbonate (860.2 mg, 8.116 mmol) in 1,4-dioxane (8.4 mL, 110 mmol) and water (2.8 mL, 160 mmol) was sparged 5 minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (139.9 mg, 0.1210 mmol) was added and the reaction vial was capped. The reaction mixture was heated at 90° C. After 3 hours, the reaction mixture was cooled to ambient temperature and poured into water. The mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (24 g SiO2, hexanes to 3:1 hexanes-ethyl acetate) to afford the product as a light yellow powder. was sparged 5 minutes with argon the reaction vial was capped the reaction mixture was cooled to ambient temperature The mixture was extracted with ethyl acetate (3×) The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo concentrated onto diatomaceous earth purified by automated flash chromatography (24 g SiO2, hexanes to 3:1 hexanes-ethyl acetate)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged aqueous solution of sodium carbonate (2M, 14 mL) and ethylene glycol dimethyl ether (25 mL) was added 4-chloro-2-iodoanisole (2.50 g, 0.00931 mol), 2-chloropyridine-4-boronic acid (1.61 g, 0.0102 mol) and bis(triphenylphosphine)palladium (II) dichloride (327 mg, 0.00047 mol). The reaction mixture was warmed to 50° C. and stirred for 5 hours. Following LCMS analysis the reaction was warmed to 75° C. and stirred for 5 hours before cooling to room temperature. The reaction was partitioned between ethyl acetate (100 mL) and a 10% w/v aqueous solution of citric acid (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude product as an orange oil (2.95 g). The material was purified using an ISCO™ companion (120 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as an off white solid (1.10 g). Following LCMS analysis the reaction was warmed to 75° C. stirred for 5 hours before cooling to room temperature The reaction was partitioned between ethyl acetate (100 mL) The organic layer was washed with water (50 mL) dried over anhydrous magnesium sulphate filtered the solvents removed in vacuo to give the crude product as an orange oil (2.95 g) The material was purified an ISCO™ companion (120 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate) Fractions containing product concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-2-iodo-1-methoxybenzene (542 mg, 2.02 mmol), (2-chloropyridin-4-yl)boronic acid (400 mg, 2 mmol), and sodium carbonate (860.2 mg, 8.116 mmol) in 1,4-dioxane (8.4 mL, 110 mmol) and water (2.8 mL, 160 mmol) was sparged 5 minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (139.9 mg, 0.1210 mmol) was added and the reaction vial was capped. The reaction mixture was heated at 90° C. After 3 hours, the reaction mixture was cooled to ambient temperature and poured into water. The mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (24 g SiO2, hexanes to 3:1 hexanes-ethyl acetate) to afford the product as a light yellow powder. was sparged 5 minutes with argon the reaction vial was capped the reaction mixture was cooled to ambient temperature The mixture was extracted with ethyl acetate (3×) The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo concentrated onto diatomaceous earth purified by automated flash chromatography (24 g SiO2, hexanes to 3:1 hexanes-ethyl acetate)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged aqueous solution of sodium carbonate (2M, 14 mL) and ethylene glycol dimethyl ether (25 mL) was added 4-chloro-2-iodoanisole (2.50 g, 0.00931 mol), 2-chloropyridine-4-boronic acid (1.61 g, 0.0102 mol) and bis(triphenylphosphine)palladium (II) dichloride (327 mg, 0.00047 mol). The reaction mixture was warmed to 50° C. and stirred for 5 hours. Following LCMS analysis the reaction was warmed to 75° C. and stirred for 5 hours before cooling to room temperature. The reaction was partitioned between ethyl acetate (100 mL) and a 10% w/v aqueous solution of citric acid (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude product as an orange oil (2.95 g). The material was purified using an ISCO™ companion (120 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as an off white solid (1.10 g). Following LCMS analysis the reaction was warmed to 75° C. stirred for 5 hours before cooling to room temperature The reaction was partitioned between ethyl acetate (100 mL) The organic layer was washed with water (50 mL) dried over anhydrous magnesium sulphate filtered the solvents removed in vacuo to give the crude product as an orange oil (2.95 g) The material was purified an ISCO™ companion (120 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate) Fractions containing product concentrated in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Boron tribromide (1349 g) was added to a solution of 4-chloro-2-iodoanisole (1025 g) in dichloromethane (10.3 L) under nitrogen at such a rate that the temperature remained at 0-5° C. The solution was then warmed to 20° C. and stirred for c. 19 h until the reaction was complete by HPLC. This organic solution was added to water (8.2 L) and the mixture was cooled to 5° C. to 10° C. DCM (770 ml) was added and the resulting biphasic mixture was then stirred at 5° C. for 15 min before being warmed to 22° C. and then finally stirred at 22° C. for 20 min before separating the phases. The separated organic phase was washed with aqueous saturated sodium bicarbonate (3.1 L), water (3.1 L) and then evaporated on a Buchi to give the title compound. (963.6 g) remained at 0-5° C 19 h the mixture was cooled to 5° C. to 10° C the resulting biphasic mixture was then stirred at 5° C. for 15 min before being warmed to 22° C. finally stirred at 22° C. for 20 min before separating the phases The separated organic phase was washed with aqueous saturated sodium bicarbonate (3.1 L), water (3.1 L) evaporated on a Buchi

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

Procedure: 109.4 g (0.436 mol) of boron tribromide were added over 10 minutes to a stirred solution of 90 g (0.335 mol) of 4-chloro-2-iodoanisole in dichloromethane (900 ml) at −78° C. under nitrogen. Cooling was removed and allowed to warm to room temperature and stirred for 5 hours. Poured onto ice and diluted with a further 800 ml of water. The organic phase was separated, the aqueous extracted with dichloromethane and the combined organics washed with saturated sodium bicarbonate, dried and evaporated to give 84.87 g of off-white solid. Cooling was removed Poured onto ice diluted with a further 800 ml of water The organic phase was separated the aqueous extracted with dichloromethane the combined organics washed with saturated sodium bicarbonate dried evaporated

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

Procedure: 109.4 g (0.436 mol) of boron tribromide were added over 10 minutes to a stirred solution of 90 g (0.335 mol) of 4-chloro-2-iodoanisole in dichloromethane (900 ml) at −78° C. under nitrogen. Cooling was removed and allowed to warm to room temperature and stirred for 5 hours. Poured onto ice and diluted with a further 800 ml of water. The organic phase was separated, the aqueous extracted with dichloromethane and the combined organics washed with saturated sodium bicarbonate, dried and evaporated to give 84.87 g of off-white solid. Cooling was removed Poured onto ice diluted with a further 800 ml of water The organic phase was separated the aqueous extracted with dichloromethane the combined organics washed with saturated sodium bicarbonate dried evaporated

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

Procedure: 109.4 g (0.436 mol) of boron tribromide were added over 10 minutes to a stirred solution of 90 g (0.335 mol) of 4-chloro-2-iodoanisole in dichloromethane (900 ml) at −78° C. under nitrogen. Cooling was removed and allowed to warm to room temperature and stirred for 5 hours. Poured onto ice and diluted with a further 800 ml of water. The organic phase was separated, the aqueous extracted with dichloromethane and the combined organics washed with saturated sodium bicarbonate, dried and evaporated to give 84.87 g of off-white solid. Cooling was removed Poured onto ice diluted with a further 800 ml of water The organic phase was separated the aqueous extracted with dichloromethane the combined organics washed with saturated sodium bicarbonate dried evaporated