5-chloro-2,4-difluorobenzenesulfonyl chloride

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

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

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

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: The reaction and aftertreatment were conducted in the same manner as in Example 86a by using the 2-(benzyloxy)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50 g, 1.42 mmol) prepared in Example 153a, 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.36 g, 1.57 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.71 mL, 1.71 mmol) and THF (5.0 mL), to yield the title compound (487.8 mg, 61%) as a colorless solid. The reaction and aftertreatment

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

Procedure: To a solution of N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (WO 2010/079443; 5.00 g, 19.9 mmol) in THF (60 mL), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 24.0 mL, 24.0 mmol) was added at −78° C. The reaction solution was stirred at room temperature for 10 minutes, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (5.41 g, 21.9 mmol) in THF (15 mL) was then added thereto at −78° C. The reaction solution was stirred at room temperature for 2 hours, and water (100 mL) was then added to the reaction solution, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was washed with saturated saline (100 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1) to yield the title compound (5.31 g, 58%) as a colorless solid. at −78° C The reaction solution was stirred at room temperature for 2 hours followed by extraction with ethyl acetate (100 mL) The thus obtained organic layer was washed with saturated saline (100 mL) dried over anhydrous sodium sulfate After vacuum concentration the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1)

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

Procedure: The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (150 mg, 0.611 mmol) prepared in Example 14, 5-chloro-2,4-difluorobenzenesulfonyl chloride (302 mg, 1.22 mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0 mL), to yield the title compound (71.7 mg, 26%) as a colorless oil. The reaction and aftertreatment

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

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

Procedure: A solution of (2,4-dimethoxybenzyl)-pyrimidin-2-yl-amine (Preparation 38, 736 mg, 3 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to −78° C. before the addition of lithium(hexamethyldisilazane) (1M solution in tetrahydrofuran, 3.30 mL, 3.30 mmol). The reaction was allowed to warm to 0° C. for 30 minutes before cooling again to −78° C. The resulting solution was added to a solution of 3-chloro-4,6-difluorobenzenesulfonyl chloride (890 mg, 3.6 mmol) in tetrahydrofuran (10 mL) at −78° C. After 30 minutes at this temperature the reaction was warmed to room temperature and stirred for 24 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography (50-100% dichloromethane in heptane gradient elution) to afford the title compound as a white solid (260 mg, 19%). before cooling again to −78° C After 30 minutes at this temperature the reaction was warmed to room temperature The reaction was quenched by the addition of saturated aqueous ammonium chloride solution extracted into ethyl acetate The organic layer was washed with brine dried over magnesium sulfate concentrated in vacuo The residue was purified silica gel column chromatography (50-100% dichloromethane in heptane gradient elution)

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 19, 203.4 g, 0.809 mol) was dissolved in 2-methyltetrahydrofuran (1.63 L) and the yellow suspension cooled to between −38° C. and −45° C. Lithium bis(trimethylsilyl)amide (890 mL of 1M solution in tetrahydrofuran, 0.890 mol) was added slowly over 15 minutes keeping the temperature between −38° C. and −45° C. to give an orange suspension. This orange suspension was stirred at −38° C. to −45° C. for 45 minutes and then a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride, (200 g, 0.809 mol) in 2-methyltetrahydrofuran (407 mL) added slowly over 20 minutes keeping the temperature between −38° C. and −45° C. The mixture was warmed to 15° C. over 1 hour. The reaction was quenched with a solution of ammonium chloride (203.4 g, 3.80 mol) in water (1.02 L) and stirred vigorously for 5 minutes. The layers were separated and the organic layer washed with water (813.6 mL) and concentrated in vacuo to give an orange solid which was triturated with isopropyl acetate (1.22 L) to afford the title compound as a yellow-orange solid (218.6 g, 58%). the yellow suspension cooled to between −38° C. and −45° C the temperature between −38° C. and −45° C. to give an orange suspension the temperature between −38° C. and −45° C stirred vigorously for 5 minutes The layers were separated the organic layer washed with water (813.6 mL) concentrated in vacuo to give an orange solid which was triturated with isopropyl acetate (1.22 L)

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

Procedure: The reaction and aftertreatment were conducted in the same manner as in Example 86a by using the 2-(benzyloxy)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50 g, 1.42 mmol) prepared in Example 153a, 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.36 g, 1.57 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.71 mL, 1.71 mmol) and THF (5.0 mL), to yield the title compound (487.8 mg, 61%) as a colorless solid. The reaction and aftertreatment