2-cyano-3,3-bis(methylsulfanyl)prop-2-enamide

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

Procedure: A mixture of bis(methythio)methylenecyanoacetamide (7.800 g, 50 mmol) and 2,4,6-trichlorophenylhydrazine (10.575 g, 50 mmol) in 250 ml of methanol was heated at reflux for 2.5 hours. The mixture was cooled and water was added. Precipitate formed and filtered to give 14.323 g (81.5% yield) of the title compound as a white solid. 1H NMR(CDCl3): 2.6 (s,3H), 5.5(brs, 2H), 7.5(s,2H) ppm. Recrystallization of a small portion of the solid from chloroform gave white crystals; m. p. 198-199° C. Anal. Calc. for C11H9Cl3N4OS: C, 37.57; H, 2.58; N, 15.93; Found: C, 37.54; H, 2.51; N, 15.73. was heated at reflux for 2.5 hours The mixture was cooled Precipitate formed filtered

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylamide 12 (100 mg, 0.574 mmol) in ethanol (5 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.183 g, 0.574 mmol) and diisopropylethylamine (0.100 ml, 0.574 mmol). The mixture was heated to 65° C. for 18 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc was added to the residue and a solid precipitated. The solid was collected on a fritted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide 13. HPLC (4 minute 10-90 gradient) tR 1.98 min; MS m/z 439.08 [M+H]+; 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (d, J=3.7, 1 H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1 H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2 H), 6.30 (s, 2 H), 2.86 (m, 1 H), 2.45 (s, 3 H), 2.11 (s, 3 H), 0.68 (m, 2 H), 0.57 (m, 2 H) ppm. The mixture was cooled to room temperature Solvents were removed in vacuo EtOAc was added to the residue a solid precipitated The solid was collected on a fritted funnel was washed with EtOAc and ether

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylamide 12 (100 mg, 0.574 mmol) in ethanol (5 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.183 g, 0.574 mmol) and diisopropylethylamine (0.100 ml, 0.574 mmol). The mixture was heated to 65° C. for 18 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc was added to the residue and a solid precipitated. The solid was collected on a fritted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide 13. HPLC (4 minute 10-90 gradient) tR 1.98 min; MS m/z 439.08 [M+H]+; 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (d, J=3.7, 1 H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1 H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2 H), 6.30 (s, 2 H), 2.86 (m, 1 H), 2.45 (s, 3 H), 2.11 (s, 3 H), 0.68 (m, 2 H), 0.57 (m, 2 H) ppm. The mixture was cooled to room temperature Solvents were removed in vacuo EtOAc was added to the residue a solid precipitated The solid was collected on a fritted funnel was washed with EtOAc and ether

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 1-(4-aminophenyl)-4-(1-pyrrolidinyl)piperidine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 1-(4-aminophenyl)-4-(1-pyrrolidinyl)piperidine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-(5-amino-2-pyridinyl)morpholine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-Methylsulphonylbenzylamine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(methylsulfonyl)benzyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-Methylsulphonylbenzylamine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(methylsulfonyl)benzyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added Sulfanilamide (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-sulfamoylphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-methyl-1-(4-aminophenyl)-1H-imidazole (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-methyl-1′-[(4-aminophenyl) 1,4′-bipiperidine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-Nitroaniline (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. reaction at 75° C. Once complete (18 hrs), reaction was brought to room temperature filtered to obtain a light yellow powder as product to dry under vacuum for 1 hr Reaction (18 hrs), reaction was brought to room temperature filtered