2-bromo-1,3-difluoro-5-methoxybenzene

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

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

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

Procedure: In an oven-dried, N2-purged round bottom, 4-bromo-3,5-difluoroanisole (500 mg, 2.24 mmol) was dissolved in anhydrous THF (11 mL) and brought to −78° C. nBuLi (0.96 mL, 2.44 M in THF, 2.35 mmol) was added over 2 min. This was stirred for 5 min and then a solution di-tert-butyl azodicarboxylate (542 mg, 2.35 mmol) in anhydrous THF (3 mL) in an oven-dried, N2-purged pear flask was added in one portion via syringe. The reaction was removed from the ice bath and allowed to warm to room temperature over 30 min. The reaction, a clear solution, was quenched by the addition of aq. sat. NH4Cl. The material was extracted with two portions of ethyl acetate and the combined organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (0.868 g, impure with ethyl acetate) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 6.48 (d, J=10.1 Hz, 2H) 3.73-3.85 (m, 3H) 1.36-1.60 (m, 18H). In an oven-dried, N2-purged round bottom brought to −78° C. was added over 2 min was added in one portion via syringe The reaction was removed from the ice bath The reaction a clear solution, was quenched by the addition of aq. sat. NH4Cl The material was extracted with two portions of ethyl acetate the combined organics were dried over MgSO4 concentrated in vacuo Purification by silica gel flash chromatography (ethyl acetate in heptane)

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

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

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-3,5-difluoroanisole (645 mg, 2.89 mmol) and 2-chloro-4-(2-methoxy-2-oxoethyl)phenylboronic acid (Intermediate 2-6; 859 mg, 3.76 mmol) and sodium carbonate (2.89 mL, 5.78 mmol), tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.18 mmol) in DME (20 mL) was degassed and then stirred at 85° C. for 17 hours. The reaction mixture was allowed to cool, evaporated and partitioned between EtOAc (75 mL), water (40 mL) and saturated brine (15 mL), The aqueous phase was acidified with 2M HCl and extracted into EtOAc (2×125 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(2-chloro-2′,6′-difluoro-4′-methoxybiphenyl-4-yl)acetic acid (654 mg, 72.4%) as a white solid, which was used without further purification. to cool evaporated partitioned between EtOAc (75 mL), water (40 mL) and saturated brine (15 mL) extracted into EtOAc (2×125 mL) The organic layer was dried over MgSO4 filtered evaporated

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

Procedure: In an oven-dried, N2-purged round bottom, 4-bromo-3,5-difluoroanisole (500 mg, 2.24 mmol) was dissolved in anhydrous THF (11 mL) and brought to −78° C. nBuLi (0.96 mL, 2.44 M in THF, 2.35 mmol) was added over 2 min. This was stirred for 5 min and then a solution di-tert-butyl azodicarboxylate (542 mg, 2.35 mmol) in anhydrous THF (3 mL) in an oven-dried, N2-purged pear flask was added in one portion via syringe. The reaction was removed from the ice bath and allowed to warm to room temperature over 30 min. The reaction, a clear solution, was quenched by the addition of aq. sat. NH4Cl. The material was extracted with two portions of ethyl acetate and the combined organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (0.868 g, impure with ethyl acetate) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 6.48 (d, J=10.1 Hz, 2H) 3.73-3.85 (m, 3H) 1.36-1.60 (m, 18H). In an oven-dried, N2-purged round bottom brought to −78° C. was added over 2 min was added in one portion via syringe The reaction was removed from the ice bath The reaction a clear solution, was quenched by the addition of aq. sat. NH4Cl The material was extracted with two portions of ethyl acetate the combined organics were dried over MgSO4 concentrated in vacuo Purification by silica gel flash chromatography (ethyl acetate in heptane)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl malonate (0.505 mol) is added to a mixture of sodium hydride (0.412 mol) and 1,4-dioxane (230 ml) at 40° C. within 3 hours. The mixture is stirred for 90 minutes at 60° C. and copper(I) bromide (0.402 mol) is added. A mixture of 2,6-difluoro-4-methoxybromobenzene (0.2 mol) and 1,4-dioxane (50 ml) is added. The reaction mixture is heated at 100° C. for 14 hours and cooled to 15° C. Hydrochloric acid (12N, 350 ml) is added slowly at 15 to 20° C. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (250 ml) and toluene (200 ml). The combined organic phases are concentrated in vacuo. The residue is filtered over silica gel, washed with petroleum ether/ethyl acetate (15:1) and the solvent is distilled off. The residue is distilled in vacuo to yield 44.8 g of the product as an oil, 128-136° C. at 0.018 mbar. is added The reaction mixture is heated at 100° C. for 14 hours cooled to 15° C The organic phase is separated off the aqueous phase is extracted with ethyl acetate (250 ml) and toluene (200 ml) The combined organic phases are concentrated in vacuo The residue is filtered over silica gel washed with petroleum ether/ethyl acetate (15:1) the solvent is distilled off The residue is distilled in vacuo

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

Procedure: In an oven-dried, N2-purged round bottom, 4-bromo-3,5-difluoroanisole (500 mg, 2.24 mmol) was dissolved in anhydrous THF (11 mL) and brought to −78° C. nBuLi (0.96 mL, 2.44 M in THF, 2.35 mmol) was added over 2 min. This was stirred for 5 min and then a solution di-tert-butyl azodicarboxylate (542 mg, 2.35 mmol) in anhydrous THF (3 mL) in an oven-dried, N2-purged pear flask was added in one portion via syringe. The reaction was removed from the ice bath and allowed to warm to room temperature over 30 min. The reaction, a clear solution, was quenched by the addition of aq. sat. NH4Cl. The material was extracted with two portions of ethyl acetate and the combined organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (0.868 g, impure with ethyl acetate) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 6.48 (d, J=10.1 Hz, 2H) 3.73-3.85 (m, 3H) 1.36-1.60 (m, 18H). In an oven-dried, N2-purged round bottom brought to −78° C. was added over 2 min was added in one portion via syringe The reaction was removed from the ice bath The reaction a clear solution, was quenched by the addition of aq. sat. NH4Cl The material was extracted with two portions of ethyl acetate the combined organics were dried over MgSO4 concentrated in vacuo Purification by silica gel flash chromatography (ethyl acetate in heptane)

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

Procedure: In an oven-dried, N2-purged round bottom, 4-bromo-3,5-difluoroanisole (500 mg, 2.24 mmol) was dissolved in anhydrous THF (11 mL) and brought to −78° C. nBuLi (0.96 mL, 2.44 M in THF, 2.35 mmol) was added over 2 min. This was stirred for 5 min and then a solution di-tert-butyl azodicarboxylate (542 mg, 2.35 mmol) in anhydrous THF (3 mL) in an oven-dried, N2-purged pear flask was added in one portion via syringe. The reaction was removed from the ice bath and allowed to warm to room temperature over 30 min. The reaction, a clear solution, was quenched by the addition of aq. sat. NH4Cl. The material was extracted with two portions of ethyl acetate and the combined organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (0.868 g, impure with ethyl acetate) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 6.48 (d, J=10.1 Hz, 2H) 3.73-3.85 (m, 3H) 1.36-1.60 (m, 18H). In an oven-dried, N2-purged round bottom brought to −78° C. was added over 2 min was added in one portion via syringe The reaction was removed from the ice bath The reaction a clear solution, was quenched by the addition of aq. sat. NH4Cl The material was extracted with two portions of ethyl acetate the combined organics were dried over MgSO4 concentrated in vacuo Purification by silica gel flash chromatography (ethyl acetate in heptane)