1-bromo-3-fluoro-5-[(2-methylpropan-2-yl)oxy]benzene

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

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

Procedure: 1-Bromo-3-tert-butoxy-5-fluorobenzene (56.1 g), benzophenone (50.9 g), NaOMe (50.5 g) and 2,2′-Bis-diphenylphosphanyl-[1,1′]binaphthalenyl (17.5 g) are dissolved in toluene (500 ml). The reaction mixture is flushed with argon, Pd2(dba)3 (5.4 g) is added and the reaction mixture is heated to 80° C. for 40 hours. The reaction mixture is quenched with water. The organics are separated, dried over MgSO4, filtered and the solvent removed in vacuo. The intermediate is obtained by flash column chromatography (silica, eluent dichloromethane). The resulting product is then dissolved in MeOH (1 L). NaOAc (46.1 g), hydroxylamine hydrochloride (29.1 g) are added and the reaction mixture is stirred at room temperature for 2.5 hours. The reaction mixture is quenched with 0.1M NaOH, extracted into DCM (2×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 6.20 (m, 3H), 3.75 (br s, 2H), 1.4 (s, 9H). The reaction mixture is flushed with argon, Pd2(dba)3 (5.4 g) is added The reaction mixture is quenched with water The organics are separated dried over MgSO4 filtered the solvent removed in vacuo The intermediate is obtained by flash column chromatography (silica, eluent dichloromethane) The reaction mixture is quenched with 0.1M NaOH extracted into DCM (2×) dried over MgSO4 filtered the solvent removed in vacuo

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

Procedure: tert-Butanol (28.2 g) is dissolved in dimethyl acetamide (200 ml). NaH (15.6 g, 60% dispersion in oil) is added over 15 minutes. The reaction mixture is stirred at room temperature for 2 hours. 3,5-difluorobromobenzene (50 g) is added drop wise over 30 minutes. The reaction mixture is stirred at room temperature until shown to be complete by HPLC. The reastion mixture is quenched by addition of water (10 ml), washed with water (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.00 (ddd, 1H), 6.95 (dd, 1H), 6.68 (ddd, 1H), 1.4 (s, 9H). The reaction mixture is stirred at room temperature The reastion mixture is quenched by addition of water (10 ml) washed with water (1×) dried over MgSO4 filtered the solvent removed in vacuo

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

Procedure: tert-Butanol (28.2 g) is dissolved in dimethyl acetamide (200 ml). NaH (15.6 g, 60% dispersion in oil) is added over 15 minutes. The reaction mixture is stirred at room temperature for 2 hours. 3,5-difluorobromobenzene (50 g) is added drop wise over 30 minutes. The reaction mixture is stirred at room temperature until shown to be complete by HPLC. The reastion mixture is quenched by addition of water (10 ml), washed with water (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.00 (ddd, 1H), 6.95 (dd, 1H), 6.68 (ddd, 1H), 1.4 (s, 9H). The reaction mixture is stirred at room temperature The reastion mixture is quenched by addition of water (10 ml) washed with water (1×) dried over MgSO4 filtered the solvent removed in vacuo

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

Procedure: 1-Bromo-3-tert-butoxy-5-fluorobenzene (56.1 g), benzophenone (50.9 g), NaOMe (50.5 g) and 2,2′-Bis-diphenylphosphanyl-[1,1′]binaphthalenyl (17.5 g) are dissolved in toluene (500 ml). The reaction mixture is flushed with argon, Pd2(dba)3 (5.4 g) is added and the reaction mixture is heated to 80° C. for 40 hours. The reaction mixture is quenched with water. The organics are separated, dried over MgSO4, filtered and the solvent removed in vacuo. The intermediate is obtained by flash column chromatography (silica, eluent dichloromethane). The resulting product is then dissolved in MeOH (1 L). NaOAc (46.1 g), hydroxylamine hydrochloride (29.1 g) are added and the reaction mixture is stirred at room temperature for 2.5 hours. The reaction mixture is quenched with 0.1M NaOH, extracted into DCM (2×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 6.20 (m, 3H), 3.75 (br s, 2H), 1.4 (s, 9H). The reaction mixture is flushed with argon, Pd2(dba)3 (5.4 g) is added The reaction mixture is quenched with water The organics are separated dried over MgSO4 filtered the solvent removed in vacuo The intermediate is obtained by flash column chromatography (silica, eluent dichloromethane) The reaction mixture is quenched with 0.1M NaOH extracted into DCM (2×) dried over MgSO4 filtered the solvent removed in vacuo

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

Procedure: tert-Butanol (28.2 g) is dissolved in dimethyl acetamide (200 ml). NaH (15.6 g, 60% dispersion in oil) is added over 15 minutes. The reaction mixture is stirred at room temperature for 2 hours. 3,5-difluorobromobenzene (50 g) is added drop wise over 30 minutes. The reaction mixture is stirred at room temperature until shown to be complete by HPLC. The reastion mixture is quenched by addition of water (10 ml), washed with water (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.00 (ddd, 1H), 6.95 (dd, 1H), 6.68 (ddd, 1H), 1.4 (s, 9H). The reaction mixture is stirred at room temperature The reastion mixture is quenched by addition of water (10 ml) washed with water (1×) dried over MgSO4 filtered the solvent removed in vacuo