3-[4-bromo-2-(trifluoromethyl)phenyl]sulfanylpropanamide

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

Procedure: 3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (160 g, 488 mmol) was dissolved under Ar in N,N-dimethylformamide (1.5 L) before 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (143 g, 687 mmol), potassium carbonate (160 g, 1.16 mol), and water (130 mL) were added. The solution was degassed and tetrakis-(triphenylphosphine)palladium(0) (24.0 g, 20.8 mmol) was added. The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was poured onto water (5 L) and extracted with ethyl acetate (1×3 L, 2×1 L). The combined organic extracts were washed with brine (1 L), the volume was reduced in vacuo to ca. 2 L and dried over sodium sulfate. The resulting filtrate was further reduced in vacuo until precipitation occurred and a homogeneous slurry was formed. Tert-butyl methyl ether (1 L) was then added in portions to the distillation, keeping the overall volume constant (solvent exchange). The suspension was cooled to 5° C. (ice bath) and filtered. The precipitate was washed with tert-butyl methyl ether (500 mL) and dried in vacuo to provide 141 g of the title compound as brown crystalline solid (88%). MS (ESI & APCI): m/z=330.1 [M+H]. 1H NMR (CDCl3, 600 MHz): δ 2.54 (t, J=7.4 Hz, 2H), 3.27 (t, J=7.4 Hz, 2H), 5.39 (bs, 1H), 5.52 (bs, 1H), 7.56 (s, 1H), 7.57 (s, 1H), 7.66 (s, 1H), 7.73 (bs, 1H), 7.77 (d, J=0.7 Hz, 1H). were added The solution was degassed After cooling to room temperature the mixture was poured onto water (5 L) extracted with ethyl acetate (1×3 L, 2×1 L) The combined organic extracts were washed with brine (1 L) dried over sodium sulfate The resulting filtrate was further reduced in vacuo until precipitation a homogeneous slurry was formed The suspension was cooled to 5° C. (ice bath) filtered The precipitate was washed with tert-butyl methyl ether (500 mL) dried in vacuo

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

Procedure: 3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (160 g, 488 mmol) was dissolved under Ar in N,N-dimethylformamide (1.5 L) before 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (143 g, 687 mmol), potassium carbonate (160 g, 1.16 mol), and water (130 mL) were added. The solution was degassed and tetrakis-(triphenylphosphine)palladium(0) (24.0 g, 20.8 mmol) was added. The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was poured onto water (5 L) and extracted with ethyl acetate (1×3 L, 2×1 L). The combined organic extracts were washed with brine (1 L), the volume was reduced in vacuo to ca. 2 L and dried over sodium sulfate. The resulting filtrate was further reduced in vacuo until precipitation occurred and a homogeneous slurry was formed. Tert-butyl methyl ether (1 L) was then added in portions to the distillation, keeping the overall volume constant (solvent exchange). The suspension was cooled to 5° C. (ice bath) and filtered. The precipitate was washed with tert-butyl methyl ether (500 mL) and dried in vacuo to provide 141 g of the title compound as brown crystalline solid (88%). MS (ESI & APCI): m/z=330.1 [M+H]. 1H NMR (CDCl3, 600 MHz): δ 2.54 (t, J=7.4 Hz, 2H), 3.27 (t, J=7.4 Hz, 2H), 5.39 (bs, 1H), 5.52 (bs, 1H), 7.56 (s, 1H), 7.57 (s, 1H), 7.66 (s, 1H), 7.73 (bs, 1H), 7.77 (d, J=0.7 Hz, 1H). were added The solution was degassed After cooling to room temperature the mixture was poured onto water (5 L) extracted with ethyl acetate (1×3 L, 2×1 L) The combined organic extracts were washed with brine (1 L) dried over sodium sulfate The resulting filtrate was further reduced in vacuo until precipitation a homogeneous slurry was formed The suspension was cooled to 5° C. (ice bath) filtered The precipitate was washed with tert-butyl methyl ether (500 mL) dried in vacuo

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

Procedure: 4-Bromo-2-methylpyridine (6.0 g, 34.9 mmol) was dissolved in dimethylformamide (60 mL) before potassium acetate (10.0 g, 102 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (10 g, 39.4 mmol) were added at room temperature. The solution was degassed and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 547 mol) was added. The brown reaction mixture was stirred for 22 h at 80° C. After cooling to room temperature, 3-(4-bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (8.0 g, 24.4 mmol), potassium carbonate (8.0 g, 57.9 mmol), dimethylformamide (20 mL), and water (16 mL) were added. The mixture was degassed, stirred for 30 min at room temperature and further [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 547·mol) was added. The resulting brown reaction mixture was stirred for 20 h at 60° C. After cooling to room temperature, it was poured onto water (150 mL) and extracted with ethyl acetate (1×80 mL, 2×40 mL). The combined organic extracts were washed with brine/water (1:1 v/v, mL) and brine (20 mL), methanol (16 mL) was added and the mixture was dried over sodium sulfate. Silica gel (16 g) was added, the slurry was filtered and washed with ethyl acetate/methanol (9:1 v/v, 40 mL). The combined filtrates were concentrated in vacuo. The residue was treated with toluene/n-heptane (1:1 v/v, 24 mL) and the resulting suspension was stirred for 30 min at room temperature. After filtration, the precipitate was washed with toluene/n-heptane (4:1 v/v, 10 mL) and n-heptane (10 mL) and dried in vacuo to afford the title compound as brown crystals (5.7 g, 71%). MS (EI): m/z=341.1 [M+H]+. 1H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J=7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J=1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J=9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J=5.1 Hz, 1H). were added at room temperature The solution was degassed After cooling to room temperature The mixture was degassed stirred for 30 min at room temperature further [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 547·mol) was added The resulting brown reaction mixture was stirred for 20 h at 60° C After cooling to room temperature it was poured onto water (150 mL) extracted with ethyl acetate (1×80 mL, 2×40 mL) The combined organic extracts were washed with brine/water (1:1 v/v, mL) and brine (20 mL), methanol (16 mL) was added the mixture was dried over sodium sulfate Silica gel (16 g) was added the slurry was filtered washed with ethyl acetate/methanol (9:1 v/v, 40 mL) The combined filtrates were concentrated in vacuo The residue was treated with toluene/n-heptane (1:1 v/v, 24 mL) the resulting suspension was stirred for 30 min at room temperature After filtration the precipitate was washed with toluene/n-heptane (4:1 v/v, 10 mL) and n-heptane (10 mL) dried in vacuo

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

Procedure: 3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (300 g, 914 mmol) was dissolved in N,N-dimethylformamide (3.0 L) and potassium carbonate (300 g, 2.17 mol). Then, 2-methylpyridine-4-boronic acid pinacol ester (285 g, 1.3 mol) and water (240 mL) were added. The solution was degassed and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 g, 41 mmol) was added. The mixture was stirred for 20 h at 50° C. After cooling to room temperature, it was poured onto ice cold water (5° C., 5 L) and extracted with ethyl acetate (1×3.5 L, 2×1.5 L). The combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added and the mixture was dried over sodium sulfate. Silica gel (400 g) was added, the slurry was filtered and washed with ethyl acetate/methanol (9:1 v/v, 1.5 L). The combined filtrates were concentrated in vacuo. The residue was suspended in toluene (600 mL) and n-heptane (300 mL) and stirred for 5 min at 60° C. and for 1 h at room temperature. The precipitate was filtered off, washed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL), and dried in vacuo to afford 230.3 g of brown crystalline material. The crystals were further purified by trituration in isopropanol/heptane (1:1 v/v, 600 mL) for 30 min at room temperature and 30 min at 0-4° C. (ice bath). The precipitate was filtered off, washed with n-heptane/isopropanol (4:1 v/v, 300 mL), and dried in vacuo at 65° C. to yield the title compound as a light brown crystalline solid (215.7 g, 69%). MS (EI): m/z=341.1 [M+H]. 1H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J=7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J=1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J=9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J=5.1 Hz, 1H). The solution was degassed After cooling to room temperature it was poured onto ice cold water (5° C., 5 L) extracted with ethyl acetate (1×3.5 L, 2×1.5 L) The combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added the mixture was dried over sodium sulfate Silica gel (400 g) was added the slurry was filtered washed with ethyl acetate/methanol (9:1 v/v, 1.5 L) The combined filtrates were concentrated in vacuo n-heptane (300 mL) and stirred for 5 min at 60° C. and for 1 h at room temperature The precipitate was filtered off washed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL) dried in vacuo

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

Procedure: 3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (300 g, 914 mmol) was dissolved in N,N-dimethylformamide (3.0 L) and potassium carbonate (300 g, 2.17 mol). Then, 2-methylpyridine-4-boronic acid pinacol ester (285 g, 1.3 mol) and water (240 mL) were added. The solution was degassed and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 g, 41 mmol) was added. The mixture was stirred for 20 h at 50° C. After cooling to room temperature, it was poured onto ice cold water (5° C., 5 L) and extracted with ethyl acetate (1×3.5 L, 2×1.5 L). The combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added and the mixture was dried over sodium sulfate. Silica gel (400 g) was added, the slurry was filtered and washed with ethyl acetate/methanol (9:1 v/v, 1.5 L). The combined filtrates were concentrated in vacuo. The residue was suspended in toluene (600 mL) and n-heptane (300 mL) and stirred for 5 min at 60° C. and for 1 h at room temperature. The precipitate was filtered off, washed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL), and dried in vacuo to afford 230.3 g of brown crystalline material. The crystals were further purified by trituration in isopropanol/heptane (1:1 v/v, 600 mL) for 30 min at room temperature and 30 min at 0-4° C. (ice bath). The precipitate was filtered off, washed with n-heptane/isopropanol (4:1 v/v, 300 mL), and dried in vacuo at 65° C. to yield the title compound as a light brown crystalline solid (215.7 g, 69%). MS (EI): m/z=341.1 [M+H]. 1H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J=7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J=1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J=9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J=5.1 Hz, 1H). The solution was degassed After cooling to room temperature it was poured onto ice cold water (5° C., 5 L) extracted with ethyl acetate (1×3.5 L, 2×1.5 L) The combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added the mixture was dried over sodium sulfate Silica gel (400 g) was added the slurry was filtered washed with ethyl acetate/methanol (9:1 v/v, 1.5 L) The combined filtrates were concentrated in vacuo n-heptane (300 mL) and stirred for 5 min at 60° C. and for 1 h at room temperature The precipitate was filtered off washed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL) dried in vacuo

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

Procedure: 4-Bromo-2-trifluoromethyl-benzenethiol (259.2 g, 1.01 mol) was dissolved in methanol (1.3 L) and water (2.6 L), then acrylamide (130 g, 1.82 mol), followed by sodium tetraborate (25.9 g, 129 mmol) were added at room temperature. The suspension was stirred for 40 h. After filtration, the solid was washed with water (2.6 L) and n-heptane (2.6 L) and dried in vacuo to yield the title compound as a white powder (325.6 g, 98%). MS (EI): m/z=330.0, 328.0 [M+H]+. 1H NMR (d6-DMSO, 400 MHz): δ 2.40 (t, J=7.2 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 6.92 (bs, 1H), 7.37 (bs, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.82-7.88 (m, 2H). were added at room temperature After filtration the solid was washed with water (2.6 L) and n-heptane (2.6 L) dried in vacuo

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

Procedure: 4-Bromo-2-trifluoromethyl-benzenethiol (259.2 g, 1.01 mol) was dissolved in methanol (1.3 L) and water (2.6 L), then acrylamide (130 g, 1.82 mol), followed by sodium tetraborate (25.9 g, 129 mmol) were added at room temperature. The suspension was stirred for 40 h. After filtration, the solid was washed with water (2.6 L) and n-heptane (2.6 L) and dried in vacuo to yield the title compound as a white powder (325.6 g, 98%). MS (EI): m/z=330.0, 328.0 [M+H]+. 1H NMR (d6-DMSO, 400 MHz): δ 2.40 (t, J=7.2 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 6.92 (bs, 1H), 7.37 (bs, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.82-7.88 (m, 2H). were added at room temperature After filtration the solid was washed with water (2.6 L) and n-heptane (2.6 L) dried in vacuo