3-fluoro-5-[(2-methylpropan-2-yl)oxy]aniline

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

Procedure: Thiophosgene (33.6 g) in CHCl3 (250 ml) and K2CO3 (64.7 g) in H2O (450 ml) are added, separately and simultaneously, drop wise to a solution of 3-tert-Butoxy-5-fluoro-phenyl-amine (42.9 g) in CHCl3 (350 ml) at 0° C. The reaction mixture is warmed to room temperature over night. The organics are separated and washed with water (3×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, eluent dichloromethane/iso-hexane 1:3). 1H nmr (CDCl3, 400 MHz); 6.70 (m, 3H), 1.40 (s, 9H). The organics are separated washed with water (3×), brine (1×) dried over MgSO4 filtered the solvent removed in vacuo

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

Procedure: Thiophosgene (33.6 g) in CHCl3 (250 ml) and K2CO3 (64.7 g) in H2O (450 ml) are added, separately and simultaneously, drop wise to a solution of 3-tert-Butoxy-5-fluoro-phenyl-amine (42.9 g) in CHCl3 (350 ml) at 0° C. The reaction mixture is warmed to room temperature over night. The organics are separated and washed with water (3×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, eluent dichloromethane/iso-hexane 1:3). 1H nmr (CDCl3, 400 MHz); 6.70 (m, 3H), 1.40 (s, 9H). The organics are separated washed with water (3×), brine (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:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1′-Thiocarbonyldiimidazole (423 g, 2.37 mol) was dissolved in dichloromethane (3200 ml). The mixture was stirred under N2 atmosphere while a solution of 3-tert-butoxy-5-fluoroaniline (435 g, 2.37 mol) in dichloromethane (800 ml) was added slowly within 2 h. Then the mixture was kept stirring at 20° C. for 16 h. The mixture was diluted with water (3000 ml). The separated dichloromethane phase was washed again with water (3000 ml) before dried with anhydrous Na2SO4 for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to remove solvent to give 1-tert-butoxy-3-fluoro-5-isothiocyanato-benzene (499 g). 1H-NMR (400 MHz, CDCl3): 6.63-6.68 (m, 3H), 1.37 (s, 9H). was added slowly within 2 h The separated dichloromethane phase was washed again with water (3000 ml) before dried with anhydrous Na2SO4 for 2 h The mixture was filtered the filtrate was concentrated under vacuum to remove solvent

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

Procedure: Thiophosgene (33.6 g) in CHCl3 (250 ml) and K2CO3 (64.7 g) in H2O (450 ml) are added, separately and simultaneously, drop wise to a solution of 3-tert-Butoxy-5-fluoro-phenyl-amine (42.9 g) in CHCl3 (350 ml) at 0° C. The reaction mixture is warmed to room temperature over night. The organics are separated and washed with water (3×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, eluent dichloromethane/iso-hexane 1:3). The organics are separated washed with water (3×), brine (1×) dried over MgSO4 filtered the solvent removed in vacuo

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

Procedure: Thiophosgene (33.6 g) in CHCl3 (250 ml) and K2CO3 (64.7 g) in H2O (450 ml) are added, separately and simultaneously, drop wise to a solution of 3-tert-Butoxy-5-fluoro-phenyl-amine (42.9 g) in CHCl3 (350 ml) at 0° C. The reaction mixture is warmed to room temperature over night. The organics are separated and washed with water (3×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, eluent dichloromethane/iso-hexane 1:3). 1H nmr (CDCl3, 400 MHz); 6.70 (m, 3H), 1.40 (s, 9H). The organics are separated washed with water (3×), brine (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