(tetrahydro-pyran-4-yl)-hydrazine hydrochloride

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Tetrahydro-pyran-4-yl)-hydrazine hydrochloride (1.975 g, 12.94 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.958 g, 11.57 mmol) and sodium acetate (1.370 g; 16.70 mmol) were combined in ethanol (16 mL). The mixture was heated at 80-85° C. for 17 hours. After cooling to room temperature, the reaction was concentrated and the residue was partitioned between methylene chloride and water. The organic phase was separated and washed with water and then brine. Each aqueous phase was back extracted with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes to give 5-amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.554 g, 92%). After cooling to room temperature the reaction was concentrated the residue was partitioned between methylene chloride and water The organic phase was separated washed with water Each aqueous phase was back extracted with methylene chloride dried over sodium sulfate concentrated in vacuo The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes

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

Procedure: N′-(Tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester (5.210 g, 24.32 mmol) was dissolved in a mixture of dry tetrahydrofuran (22 mL) and dry methanol (30 mL). Sodium cyanoborohydride was added to the solution resulting in effervescence. When the effervescence subsided, the mixture was heated to reflux for 5-10 minutes. After cooling to room temperature 6N HCl (10.5 mL) was slowly added and then the mixture was heated to reflux for 20 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was triturated with hot isopropanol and then cooled to room temperature, diluted with ether and chilled. The solid was collected by filtration and was found to be the reduced material but not completely deprotected. The solid was dissolved in the same THF-methanol mixture and treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was then concentrated in vacuo. Isopropanol was added to the residue and solid quickly began to crystallize out of solution. After chilling overnight, ether was added followed by additional chilling. The solid was then collected by filtration, washed with ether and dried in vacuo to give (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (2.22 g, 60%). resulting in effervescence the mixture was heated to reflux for 5-10 minutes was slowly added the mixture was heated to reflux for 20 minutes the solvent was removed in vacuo The residue was triturated with hot isopropanol cooled to room temperature diluted with ether chilled The solid was collected by filtration The solid was dissolved in the same THF-methanol mixture treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours After cooling to room temperature the reaction mixture was filtered to remove a small amount of insoluble material The filtrate was then concentrated in vacuo Isopropanol was added to the residue and solid to crystallize out of solution After chilling overnight ether was added The solid was then collected by filtration washed with ether dried in vacuo

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Tetrahydro-pyran-4-yl)-hydrazine hydrochloride (1.975 g, 12.94 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.958 g, 11.57 mmol) and sodium acetate (1.370 g; 16.70 mmol) were combined in ethanol (16 mL). The mixture was heated at 80-85° C. for 17 hours. After cooling to room temperature, the reaction was concentrated and the residue was partitioned between methylene chloride and water. The organic phase was separated and washed with water and then brine. Each aqueous phase was back extracted with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes to give 5-amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.554 g, 92%). After cooling to room temperature the reaction was concentrated the residue was partitioned between methylene chloride and water The organic phase was separated washed with water Each aqueous phase was back extracted with methylene chloride dried over sodium sulfate concentrated in vacuo The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes

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

Procedure: N′-(Tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester (5.210 g, 24.32 mmol) was dissolved in a mixture of dry tetrahydrofuran (22 mL) and dry methanol (30 mL). Sodium cyanoborohydride was added to the solution resulting in effervescence. When the effervescence subsided, the mixture was heated to reflux for 5-10 minutes. After cooling to room temperature 6N HCl (10.5 mL) was slowly added and then the mixture was heated to reflux for 20 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was triturated with hot isopropanol and then cooled to room temperature, diluted with ether and chilled. The solid was collected by filtration and was found to be the reduced material but not completely deprotected. The solid was dissolved in the same THF-methanol mixture and treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was then concentrated in vacuo. Isopropanol was added to the residue and solid quickly began to crystallize out of solution. After chilling overnight, ether was added followed by additional chilling. The solid was then collected by filtration, washed with ether and dried in vacuo to give (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (2.22 g, 60%). resulting in effervescence the mixture was heated to reflux for 5-10 minutes was slowly added the mixture was heated to reflux for 20 minutes the solvent was removed in vacuo The residue was triturated with hot isopropanol cooled to room temperature diluted with ether chilled The solid was collected by filtration The solid was dissolved in the same THF-methanol mixture treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours After cooling to room temperature the reaction mixture was filtered to remove a small amount of insoluble material The filtrate was then concentrated in vacuo Isopropanol was added to the residue and solid to crystallize out of solution After chilling overnight ether was added The solid was then collected by filtration washed with ether dried in vacuo

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

Procedure: To a solution of 3.37 g of tetrahydro-2H-pyran-4-ylhydrazine hydrochloride in 120 mL of ethanol was added 3.82 g of powdery potassium carbonate, followed by stirring at room temperature for 30 minutes. To a mixture was added 6 g of N-{4-bromo-2-[(2E)-3-(dimethylamino)prop-2-enoyl]-5-methylphenyl}acetamide, followed by stirring at 80° C. for 16 hours and cooling to room temperature. The mixture was poured into a mixture of water/ethyl acetate, and the aqueous layer was separated. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 3.96 g of N-{4-bromo-5-methyl-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]phenyl}acetamide. by stirring at 80° C. for 16 hours cooling to room temperature the aqueous layer was separated The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate)

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with (tetrahydropyran-4-yl)hydrazine hydrochloride (CAS Reg. No. 194543-22-1) to give the title compound as orange oil. MS (ESI): m/z=468.1 [M+H]+.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate was reacted with (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (CAS Reg. No. 116312-69-7) to give the title compound as yellow solid. MS (ESI): m/z=486.2 [M+H]+.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 388 d) was reacted with (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (CAS Reg. No. 116312-69-7) to give the title compound as brown solid. MS (ESI): m/z=520.3 [M+H]+.

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

Procedure: In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with (tetrahydropyran-4-yl)hydrazine hydrochloride (CAS Reg. No. 194543-22-1) to give the title compound as orange oil. MS (ESI): m/z=502.1 [M+H]+.

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Tetrahydro-pyran-4-yl)-hydrazine hydrochloride (1.975 g, 12.94 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.958 g, 11.57 mmol) and sodium acetate (1.370 g; 16.70 mmol) were combined in ethanol (16 mL). The mixture was heated at 80-85° C. for 17 hours. After cooling to room temperature, the reaction was concentrated and the residue was partitioned between methylene chloride and water. The organic phase was separated and washed with water and then brine. Each aqueous phase was back extracted with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes to give 5-amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.554 g, 92%). After cooling to room temperature the reaction was concentrated the residue was partitioned between methylene chloride and water The organic phase was separated washed with water Each aqueous phase was back extracted with methylene chloride dried over sodium sulfate concentrated in vacuo The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes

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

Procedure: N′-(Tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester (5.210 g, 24.32 mmol) was dissolved in a mixture of dry tetrahydrofuran (22 mL) and dry methanol (30 mL). Sodium cyanoborohydride was added to the solution resulting in effervescence. When the effervescence subsided, the mixture was heated to reflux for 5-10 minutes. After cooling to room temperature 6N HCl (10.5 mL) was slowly added and then the mixture was heated to reflux for 20 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was triturated with hot isopropanol and then cooled to room temperature, diluted with ether and chilled. The solid was collected by filtration and was found to be the reduced material but not completely deprotected. The solid was dissolved in the same THF-methanol mixture and treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was then concentrated in vacuo. Isopropanol was added to the residue and solid quickly began to crystallize out of solution. After chilling overnight, ether was added followed by additional chilling. The solid was then collected by filtration, washed with ether and dried in vacuo to give (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (2.22 g, 60%). resulting in effervescence the mixture was heated to reflux for 5-10 minutes was slowly added the mixture was heated to reflux for 20 minutes the solvent was removed in vacuo The residue was triturated with hot isopropanol cooled to room temperature diluted with ether chilled The solid was collected by filtration The solid was dissolved in the same THF-methanol mixture treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours After cooling to room temperature the reaction mixture was filtered to remove a small amount of insoluble material The filtrate was then concentrated in vacuo Isopropanol was added to the residue and solid to crystallize out of solution After chilling overnight ether was added The solid was then collected by filtration washed with ether dried in vacuo