methanesulfonohydrazide

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: To solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.67 g, 2.42 mmol) in dry DCM (60 mL) were added methanesulfonohydrazide 187 (0.40 g, 3.63 mmol), 1-hydroxybenzotriazole (0.44 g, 3.63 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.72 g, 3.63 mmol) and 4-(dimethylamino)pyridine (0.44 g, 3.63 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5R)-6-(benzyloxy)-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 188 (0.37 g, 42%) as a white solid. concentrated under vacuum The residue was purified by column chromatography

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

Procedure: A mixture of 2-amino-5-oxazol-5-yl-4-trifluoromethyl-benzoic acid methyl ester (248 mg, 0.866 mmol) and 4-chlorophenyl chloroformate (121 μL, 0.886 mmol) in dioxane (4 mL) was heated to 80° C. for 1 h. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in dioxane (4 mL) and treated with CH3SO2NHNH2 (191 mg, 1.732 mmol) and i-Pr2NEt (454 μL, 2.60 mmol). After heating at 80° C. for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by two successive flash chromatographies (70 g of silica gel, 2% MeOH in DCM), then (20 g silica gel, DCM→MeOH in DCM (1% to 3%)) to give the title compound (65 mg) as an off-white powder. This solid was further purified by sonication in DCM to provide 24 mg of pure product. The filtrate was concentrated in vacuo and sonicated in Et2O to give a further 27.8 mg of title product, for a total of 51.8 mg (15%) of the title compound as an off-white powder. API-ES: m/z 408.0 [M+NH4]+, rt 2.89 min. The reaction mixture was concentrated in vacuo The crude residue was dissolved in dioxane (4 mL) After heating at 80° C. for 1 h the reaction mixture was concentrated in vacuo The residue was purified by two successive flash chromatographies (70 g of silica gel, 2% MeOH in DCM)

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

Procedure: A mixture of 2-amino-5-oxazol-5-yl-4-trifluoromethyl-benzoic acid methyl ester (248 mg, 0.866 mmol) and 4-chlorophenyl chloroformate (121 μL, 0.886 mmol) in dioxane (4 mL) was heated to 80° C. for 1 h. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in dioxane (4 mL) and treated with CH3SO2NHNH2 (191 mg, 1.732 mmol) and i-Pr2NEt (454 μL, 2.60 mmol). After heating at 80° C. for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by two successive flash chromatographies (70 g of silica gel, 2% MeOH in DCM), then (20 g silica gel, DCM→MeOH in DCM (1% to 3%)) to give the title compound (65 mg) as an off-white powder. This solid was further purified by sonication in DCM to provide 24 mg of pure product. The filtrate was concentrated in vacuo and sonicated in Et2O to give a further 27.8 mg of title product, for a total of 51.8 mg (15%) of the title compound as an off-white powder. API-ES: m/z 408.0 [M+NH4]+, rt 2.89 min. The reaction mixture was concentrated in vacuo The crude residue was dissolved in dioxane (4 mL) After heating at 80° C. for 1 h the reaction mixture was concentrated in vacuo The residue was purified by two successive flash chromatographies (70 g of silica gel, 2% MeOH in DCM)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-5-pyridazin-3-yl-4-trifluoromethyl-benzoic acid methyl ester (79 mg, 0.266 mmol) in dioxane (4 mL) under argon was added 4-chlorophenyl chloroformate (44.6 μL, 0.319 mmol). The solution was stirred at 85° C. for 30 min and cooled to r.t. CH3SO2NHNH2 (58.5 mg, 0.531 mmol) and i-Pr2NEt (46.4 μL, 0.266 mmol) were added and the reaction mixture was heated back to 85° C. for 3 h. The mixture was concentrated in vacuo and the residue was purified by two consecutive flash chromatographies (silica gel, DCM→5% MeOH in DCM) then (silica gel, 7:3 EtOAc/hexanes). The product was suspended in a minimum amount of EtOAc, sonicated then taken into hexanes. The solid was collected by vacuum filtration to furnish the title compound (13 mg, 12%) as a white solid. API-ES: m/z 402.0 [M+H]+, rt 3.36 min, Method N—05—100: 5%→100% (6 min), 100% (1.5 min), 100%→5% (0.5 min) cooled to r.t the reaction mixture was heated back to 85° C. for 3 h The mixture was concentrated in vacuo the residue was purified by two consecutive flash chromatographies (silica gel, DCM→5% MeOH in DCM) sonicated The solid was collected by vacuum filtration

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-5-pyridazin-3-yl-4-trifluoromethyl-benzoic acid methyl ester (79 mg, 0.266 mmol) in dioxane (4 mL) under argon was added 4-chlorophenyl chloroformate (44.6 μL, 0.319 mmol). The solution was stirred at 85° C. for 30 min and cooled to r.t. CH3SO2NHNH2 (58.5 mg, 0.531 mmol) and i-Pr2NEt (46.4 μL, 0.266 mmol) were added and the reaction mixture was heated back to 85° C. for 3 h. The mixture was concentrated in vacuo and the residue was purified by two consecutive flash chromatographies (silica gel, DCM→5% MeOH in DCM) then (silica gel, 7:3 EtOAc/hexanes). The product was suspended in a minimum amount of EtOAc, sonicated then taken into hexanes. The solid was collected by vacuum filtration to furnish the title compound (13 mg, 12%) as a white solid. API-ES: m/z 402.0 [M+H]+, rt 3.36 min, Method N—05—100: 5%→100% (6 min), 100% (1.5 min), 100%→5% (0.5 min) cooled to r.t the reaction mixture was heated back to 85° C. for 3 h The mixture was concentrated in vacuo the residue was purified by two consecutive flash chromatographies (silica gel, DCM→5% MeOH in DCM) sonicated The solid was collected by vacuum filtration

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

Procedure: A solution of 2-amino-5-pyrimidin-5-yl-4-trifluoromethyl-benzoic acid methyl ester (518 mg, 1.74 mmol) and 4-chlorophenyl chloroformate (244 μL, 1.74 mmol) in dioxane (8 mL) was stirred at 80° C. for 2 h. After cooling to r.t., CH3SO2NHNH2 (230.4 mg, 2.1 mmol) and i-Pr2NEt (609 μL, 3.49 mmol) were added. The mixture was heated to 80° C. for 4 h and, cooled to r.t., and the solvent was removed in vacuo. The residue was purified by flash chromatography (120 g silica gel, DCM→MeOH in DCM (2% to 5%)). The product was sonicated in MeOH/Et2O to furnish the title compound (252 mg, 36%) as a beige powder. API-ES: m/z 402 [M+H]+, rt 2.52 min. The mixture was heated to 80° C. for 4 h cooled to r.t. the solvent was removed in vacuo The residue was purified by flash chromatography (120 g silica gel, DCM→MeOH in DCM (2% to 5%)) The product was sonicated in MeOH/Et2O

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

Procedure: A solution of 2-amino-5-pyrazin-2-yl-4-trifluoromethyl-benzoic acid methyl ester (235 mg, 0.79 mmol) and 4-chlorophenyl chloroformate (133 μL, 0.95 mmol) in dioxane (8 mL) was stirred at 80° C. for 105 min. After cooling to r.t., CH3SO2NHNH2 (130.6 mg, 1.19 mmol) and i-Pr2NEt (276 μL, 1.58 mmol) were added. The mixture was heated to 80° C. for 45 min, cooled to r.t., and the solvent was removed in vacuo. The residue was purified by flash chromatography (50 g silica gel, DCM→MeOH in DCM (2% to 5%)) to provide the title compound (241.5 mg, 76%) as a white powder. API-ES: m/z 402 [M+H]+, rt 2.69 min. The mixture was heated to 80° C. for 45 min cooled to r.t. the solvent was removed in vacuo The residue was purified by flash chromatography (50 g silica gel, DCM→MeOH in DCM (2% to 5%))

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

Procedure: A solution of 2-amino-4-isopropyl-5-pyridazin-4-yl-benzoic acid methyl ester (220 mg, 0.81 mmol) and 4-chlorophenyl chloroformate (170 μL, 1.22 mmol) in dioxane (10 mL) was stirred at r.t. for 10 min and at 80° C. for 30 min. After cooling to r.t., CH3SO2NHNH2 (178.6 mg, 1.6 mmol) and i-Pr2NEt (425 μL, 2.43 mmol) were added. The mixture was heated at 80° C. for 1.5 h, cooled to r.t., and the solvent was removed in vacuo. The residue was purified by flash chromatography (100 g silica gel, DCM→MeOH in DCM (2.5% to 5%)). The fractions containing the product were combined and concentrated in vacuo and the residue was further purified by trituration in MeOH-Et2O. After filtration and drying, the title compound (156 mg, 51%) was isolated as a white powder. API-ES: m/z 376 [M+H]+, rt 2.12 min. The mixture was heated at 80° C. for 1.5 h cooled to r.t. the solvent was removed in vacuo The residue was purified by flash chromatography (100 g silica gel, DCM→MeOH in DCM (2.5% to 5%)) The fractions containing the product concentrated in vacuo the residue was further purified by trituration in MeOH-Et2O After filtration drying

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

Procedure: A solution of 2-amino-4-isopropyl-5-pyridazin-4-yl-benzoic acid methyl ester (220 mg, 0.81 mmol) and 4-chlorophenyl chloroformate (170 μL, 1.22 mmol) in dioxane (10 mL) was stirred at r.t. for 10 min and at 80° C. for 30 min. After cooling to r.t., CH3SO2NHNH2 (178.6 mg, 1.6 mmol) and i-Pr2NEt (425 μL, 2.43 mmol) were added. The mixture was heated at 80° C. for 1.5 h, cooled to r.t., and the solvent was removed in vacuo. The residue was purified by flash chromatography (100 g silica gel, DCM→MeOH in DCM (2.5% to 5%)). The fractions containing the product were combined and concentrated in vacuo and the residue was further purified by trituration in MeOH-Et2O. After filtration and drying, the title compound (156 mg, 51%) was isolated as a white powder. API-ES: m/z 376 [M+H]+, rt 2.12 min. The mixture was heated at 80° C. for 1.5 h cooled to r.t. the solvent was removed in vacuo The residue was purified by flash chromatography (100 g silica gel, DCM→MeOH in DCM (2.5% to 5%)) The fractions containing the product concentrated in vacuo the residue was further purified by trituration in MeOH-Et2O After filtration drying

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

Procedure: A solution containing 2-amino-5-pyridazin-4-yl-4-trifluoromethyl-benzoic acid methyl ester (65.5 mg, 0.22 mmol) and 4-chlorophenyl chloroformate (34 μL, 0.24 mmol) in dioxane (3 mL) was heated at 80° C. for 1.5 h. After allowing the reaction mixture to cool down to r.t., CH3SO2NHNH2 (48.5 mg, 0.44 mmol) and i-Pr2NEt (38.5 μL, 0.22 mmol) were added. The mixture was heated to 80° C. for 1 h and, after cooling to r.t., the solvent was removed in vacuo. The residue was dissolved in DCM and the product was precipitated by addition of Et2O. Filtration and drying provided the title product (34.4 mg, 39%) as a white solid. API-ES: m/z 402 [M+H]+, rt 2.02 min. to cool down to r.t. The mixture was heated to 80° C. for 1 h after cooling to r.t. the solvent was removed in vacuo The residue was dissolved in DCM the product was precipitated by addition of Et2O Filtration drying