3-bromo-4-(trifluoromethoxy)aniline

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

Procedure: 4-Trifluoromethoxynitrobenzene (4.1 g) was suspended in water (16 ml) and concentrated sulfuric acid (16 ml) and warmed to 80° C. with stirring. Potassium bromate (3.7 g) was added portionwise over 3 hours. The resulting mixture was heated at 80° C. for a further 2 hours, cooled to room temperature and poured onto ice (100 g). The mixture was extracted with ethyl acetate, dried (MgSO4), filtered, and the solvent removed in vacuo. The recovered solid (1.0 g) was taken up in acetic acid (2.5 ml) and water (10 ml) and iron powder (2.0 g) added. The resulting mixture was warmed to reflux for 2 hours, cooled to room temperature and filtered through Celite™. The filtrate was extracted with ethyl acetate, the organic layers separated, dried (MgSO4), filtered and the solvent removed in vacuo. Chromatography on silica gel (ethyl acetate:hexane 1:3) afforded the title compound as a yellow oil. 1H NMR (CDCl3) δ6.57 (1H, dd), 6.9 (1H, d), 7.06 (1H, dd). cooled to room temperature poured onto ice (100 g) The mixture was extracted with ethyl acetate dried (MgSO4) filtered the solvent removed in vacuo water (10 ml) and iron powder (2.0 g) added The resulting mixture was warmed to reflux for 2 hours cooled to room temperature filtered through Celite™ The filtrate was extracted with ethyl acetate the organic layers separated dried (MgSO4) filtered the solvent removed in vacuo

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

Procedure: Sodium nitrite (359 mg, 5.2 mmol) in water (5 ml) was added dropwise to a stirred, cooled (0° C.) suspension of 3-bromo-4-trifluoromethoxyaniline (Description 19) (1.02 g, 4 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then added dropwise to a stirred, cooled (-5° C.) suspension of tin (II) chloride dihydrate (4.06 g, 18 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then at room temperature for 30 min. The mixture was poured into cooled (0° C.) aqueous sodium hydroxide (4M, 200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), cooled in ice and ethanolic hydrogen chloride (5M, 0.76 ml, 3.8 mmol) was added. The solvent was evaporated under reduced pressure, ethanol (50 ml) and malonaldehyde bis(dimethyl acetal) (0.63 ml, 0.62 g, 3.8 mmol) were added. The mixture was heated under reflux for 30 min., cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (92:8) to give the title compound as a yellow oil (801 mg, 65%). 1H NMR (360 MHz, CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.90 (1H, d, J=2.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.68 (1H, dd, J=8.9, 2.6 Hz), 7.39 (1H, d, J=8.9 Hz), and 6.50 (1H, dd, J=2-4, 1.8 Hz). m/z (ES+) 307, 309 (M+1). cooled added dropwise to a stirred cooled The mixture was stirred at 0° C. for 30 min. at room temperature for 30 min The mixture was poured extracted with ethyl acetate (3×100 ml) The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml) dried (MgSO4) evaporated under reduced pressure The residue was dissolved in ethanol (10 ml) cooled in ice were added The mixture was heated under reflux for 30 min. cooled the solvent was evaporated under reduced pressure Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added the mixture was extracted with ethyl acetate (3×50 ml) The combined organic fractions were washed with brine (50 ml) dried (MgSO4) evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (92:8)

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

Procedure: Sodium nitrite (359 mg, 5.2 mmol) in water (5 ml) was added dropwise to a stirred, cooled (0° C.) suspension of 3-bromo-4-trifluoromethoxyaniline (Description 19) (1.02 g, 4 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then added dropwise to a stirred, cooled (-5° C.) suspension of tin (II) chloride dihydrate (4.06 g, 18 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then at room temperature for 30 min. The mixture was poured into cooled (0° C.) aqueous sodium hydroxide (4M, 200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), cooled in ice and ethanolic hydrogen chloride (5M, 0.76 ml, 3.8 mmol) was added. The solvent was evaporated under reduced pressure, ethanol (50 ml) and malonaldehyde bis(dimethyl acetal) (0.63 ml, 0.62 g, 3.8 mmol) were added. The mixture was heated under reflux for 30 min., cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (92:8) to give the title compound as a yellow oil (801 mg, 65%). 1H NMR (360 MHz, CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.90 (1H, d, J=2.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.68 (1H, dd, J=8.9, 2.6 Hz), 7.39 (1H, d, J=8.9 Hz), and 6.50 (1H, dd, J=2-4, 1.8 Hz). m/z (ES+) 307, 309 (M+1). cooled added dropwise to a stirred cooled The mixture was stirred at 0° C. for 30 min. at room temperature for 30 min The mixture was poured extracted with ethyl acetate (3×100 ml) The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml) dried (MgSO4) evaporated under reduced pressure The residue was dissolved in ethanol (10 ml) cooled in ice were added The mixture was heated under reflux for 30 min. cooled the solvent was evaporated under reduced pressure Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added the mixture was extracted with ethyl acetate (3×50 ml) The combined organic fractions were washed with brine (50 ml) dried (MgSO4) evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (92:8)

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

Procedure: 4-Trifluoromethoxynitrobenzene (4.1 g) was suspended in water (16 ml) and concentrated sulfuric acid (16 ml) and warmed to 80° C. with stirring. Potassium bromate (3.7 g) was added portionwise over 3 hours. The resulting mixture was heated at 80° C. for a further 2 hours, cooled to room temperature and poured onto ice (100 g). The mixture was extracted with ethyl acetate, dried (MgSO4), filtered, and the solvent removed in vacuo. The recovered solid (1.0 g) was taken up in acetic acid (2.5 ml) and water (10 ml) and iron powder (2.0 g) added. The resulting mixture was warmed to reflux for 2 hours, cooled to room temperature and filtered through Celite™. The filtrate was extracted with ethyl acetate, the organic layers separated, dried (MgSO4), filtered and the solvent removed in vacuo. Chromatography on silica gel (ethyl acetate:hexane 1:3) afforded the title compound as a yellow oil. 1H NMR (CDCl3) δ6.57 (1H, dd), 6.9 (1H, d), 7.06 (1H, dd). cooled to room temperature poured onto ice (100 g) The mixture was extracted with ethyl acetate dried (MgSO4) filtered the solvent removed in vacuo water (10 ml) and iron powder (2.0 g) added The resulting mixture was warmed to reflux for 2 hours cooled to room temperature filtered through Celite™ The filtrate was extracted with ethyl acetate the organic layers separated dried (MgSO4) filtered the solvent removed in vacuo

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

Procedure: 4-Trifluoromethoxynitrobenzene (4.1 g) was suspended in water (16 ml) and concentrated sulfuric acid (16 ml) and warmed to 80° C. with stirring. Potassium bromate (3.7 g) was added portionwise over 3 hours. The resulting mixture was heated at 80° C. for a further 2 hours, cooled to room temperature and poured onto ice (100 g). The mixture was extracted with ethyl acetate, dried (MgSO4), filtered, and the solvent removed in vacuo. The recovered solid (1.0 g) was taken up in acetic acid (2.5 ml) and water (10 ml) and iron powder (2.0 g) added. The resulting mixture was warmed to reflux for 2 hours, cooled to room temperature and filtered through Celite™. The filtrate was extracted with ethyl acetate, the organic layers separated, dried (MgSO4), filtered and the solvent removed in vacuo. Chromatography on silica gel (ethyl acetate:hexane 1:3) afforded the title compound as a yellow oil. 1H NMR (CDCl3) δ6.57 (1H, dd), 6.9 (1H, d), 7.06 (1H, dd). cooled to room temperature poured onto ice (100 g) The mixture was extracted with ethyl acetate dried (MgSO4) filtered the solvent removed in vacuo water (10 ml) and iron powder (2.0 g) added The resulting mixture was warmed to reflux for 2 hours cooled to room temperature filtered through Celite™ The filtrate was extracted with ethyl acetate the organic layers separated dried (MgSO4) filtered the solvent removed in vacuo

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

Procedure: The title compound was prepared from 3-bromo-4-[(trifluoromethyl)oxy]aniline and 4-iodobenzenesulfonyl chloride using a similar method to that described for Examples 82-100. MS (ES−) m/e 520/522 [M−H]−.

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

Procedure: The title compound was prepared from 3-bromo-4-[(trifluoromethyl)oxy]aniline and 4-iodobenzenesulfonyl chloride using a similar method to that described for Examples 82-100. MS (ES−) m/e 520/522 [M−H]−.

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

Procedure: 6-(bromomethyl)benzofuran-2-carbonitrile (0.5 g, 2.12 mmol) was dissolved in DMF (21.2 ml). K2CO3 (0.44 g, 3.18 mmol) was added, followed by 3-bromo-4-(trifluoromethoxy)aniline (314 μL, 2.12 mmol), and the mixture was stirred at RT for 18 hr. The reaction was diluted with EtOAc and water. The organic layer was washed with water×6, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was diluted with DCM and silica gel was added. The mixture was concentrated under reduced pressure to dry-load material for purification. The crude mixture was purified via silica gel FCC, 100% Heptane-50% EtOAc/50% Heptane to give 6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg). LCMS retention time=1.57 minutes (LC method 1); MS (m+1)=412.1. 1H NMR (400 MHz, DMSO-d6) δ 4.46 (d, J=6.0 Hz, 2H), 6.62 (dd, J=9.0, 2.8 Hz, 1H), 6.88-6.95 (m, 2H), 7.17 (dq, J=9.0, 1.3 Hz, 1H), 7.44 (dd, J=8.2, 1.4 Hz, 1H), 7.70 (s, 1H), 7.80 (dd, J=8.1, 0.7 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H). The organic layer was washed with water×6, brine dried over Na2SO4 filtered concentrated under reduced pressure The crude mixture was diluted with DCM and silica gel was added The mixture was concentrated under reduced pressure to dry-load material for purification The crude mixture was purified via silica gel FCC, 100% Heptane-50% EtOAc/50% Heptane

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

Procedure: The title compound was prepared as described in general reductive amination procedure, starting from 3-bromo-4-(trifluoromethoxy)aniline and 6-formyl-3-methylbenzofuran-2-carbonitrile, Intermediate 4. LCMS retention time=1.64 minutes (LC method 3); MS (m+1)=426.0.

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

Procedure: 6-(bromomethyl)benzofuran-2-carbonitrile (0.5 g, 2.12 mmol) was dissolved in DMF (21.2 ml). K2CO3 (0.44 g, 3.18 mmol) was added, followed by 3-bromo-4-(trifluoromethoxy)aniline (314 μL, 2.12 mmol), and the mixture was stirred at RT for 18 hr. The reaction was diluted with EtOAc and water. The organic layer was washed with water×6, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was diluted with DCM and silica gel was added. The mixture was concentrated under reduced pressure to dry-load material for purification. The crude mixture was purified via silica gel FCC, 100% Heptane-50% EtOAc/50% Heptane to give 6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg). LCMS retention time=1.57 minutes (LC method 1); MS (m+1)=412.1. 1H NMR (400 MHz, DMSO-d6) δ 4.46 (d, J=6.0 Hz, 2H), 6.62 (dd, J=9.0, 2.8 Hz, 1H), 6.88-6.95 (m, 2H), 7.17 (dq, J=9.0, 1.3 Hz, 1H), 7.44 (dd, J=8.2, 1.4 Hz, 1H), 7.70 (s, 1H), 7.80 (dd, J=8.1, 0.7 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H). The organic layer was washed with water×6, brine dried over Na2SO4 filtered concentrated under reduced pressure The crude mixture was diluted with DCM and silica gel was added The mixture was concentrated under reduced pressure to dry-load material for purification The crude mixture was purified via silica gel FCC, 100% Heptane-50% EtOAc/50% Heptane

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

Procedure: 4-Trifluoromethoxynitrobenzene (4.1 g) was suspended in water (16 ml) and concentrated sulfuric acid (16 ml) and warmed to 80° C. with stirring. Potassium bromate (3.7 g) was added portionwise over 3 h., and the mixture was heated at 80° C. for a further 2 h. The mixture was cooled to room temperature and poured onto ice (100 g). The mixture was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue) was dissolved in acetic acid (2.5 ml) and water (10 ml) and iron powder (2.0 g) was added. The mixture was heated under reflux for 2 h., cooled to room temperature and filtered through Celite™. The filtrate was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (3:1) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ6.57 (1H, dd), 6.9 (1H, d), 7.06 (1H, dd). The mixture was cooled to room temperature poured onto ice (100 g) The mixture was extracted with ethyl acetate the combined organic fractions were dried (MgSO4) the solvent was evaporated under reduced pressure The residue) was dissolved in acetic acid (2.5 ml) water (10 ml) and iron powder (2.0 g) was added The mixture was heated under reflux for 2 h. cooled to room temperature filtered through Celite™ The filtrate was extracted with ethyl acetate the combined organic fractions were dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (3:1)

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

Procedure: Sodium nitrite (359 mg, 5.2 mmol) in water (5 ml) was added dropwise to a stirred, cooled (0° C.) suspension of 3-bromo-4-trifluoromethoxyaniline (Description 19) (1.02 g, 4 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then added dropwise to a stirred, cooled (-5° C.) suspension of tin (II) chloride dihydrate (4.06 g, 18 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then at room temperature for 30 min. The mixture was poured into cooled (0° C.) aqueous sodium hydroxide (4M, 200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), cooled in ice and ethanolic hydrogen chloride (5M, 0.76 ml, 3.8 mmol) was added. The solvent was evaporated under reduced pressure, ethanol (50 ml) and malonaldehyde bis(dimethyl acetal) (0.63 ml, 0.62 g, 3.8 mmol) were added. The mixture was heated under reflux for 30 min., cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (92:8) to give the title compound as a yellow oil (801 mg, 65%). 1H NMR (360 MHz, CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.90 (1H, d, J=2.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.68 (1H, dd, J=8.9, 2.6 Hz), 7.39 (1H, d, J=8.9 Hz), and 6.50 (1H, dd, J=2-4, 1.8 Hz). m/z (ES+) 307, 309 (M+1). cooled added dropwise to a stirred cooled The mixture was stirred at 0° C. for 30 min. at room temperature for 30 min The mixture was poured extracted with ethyl acetate (3×100 ml) The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml) dried (MgSO4) evaporated under reduced pressure The residue was dissolved in ethanol (10 ml) cooled in ice were added The mixture was heated under reflux for 30 min. cooled the solvent was evaporated under reduced pressure Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added the mixture was extracted with ethyl acetate (3×50 ml) The combined organic fractions were washed with brine (50 ml) dried (MgSO4) evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (92:8)