3-methyl-1-phenylbut-2-en-1-one

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

Procedure: Compound 1 (0.68 g, 4.41 mmol) was dissolved in DMF (5 mL). NaH (60% in mineral oil, 0.19 g, 4.7 mmol) was added at room temperature affording rapid gas evolution. The reaction stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1-one (0.50 g, 3.15 mmol) was added. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH4 (1.19 g) were added. The solution was brought to 60° C. for 0.5 h. and then cooled to room temperature. The solution was quenched with water, extracted with Et2O (3 times), dried (Na2SO4) and concentrated. Flash chromatography (10% AcOEt) to give the desired product as a tan solid (0.60 g, 63% yield). MS Calcd.: 298. Found 299 (M+H). affording rapid gas evolution was added were added The solution was quenched with water extracted with Et2O (3 times) dried (Na2SO4) concentrated

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

Procedure: A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 was treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated to reflux for 5 h. The reaction was concentrated in vacuo to give crude 4-(3-benzylpyrrolidine-1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanol containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture was refluxed for three days then concentrated and purified by flash chromatography eluting with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine that was found to be only 90% pure by HPLC analysis. This material was then dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 90 min at room temperature, the catalyst was removed via filtration and the filtrate concentrated to an oil. Purification by flash chromatography eluting with 75% hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H), 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s, 1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s, 1H). MS Calcd.: 450. Found: 451 (M+H). was added The mixture was refluxed for three days then concentrated purified by flash chromatography eluting with 60% hexanes/AcOEt

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

Procedure: Compound 1 (0.68 g, 4.41 mmol) was dissolved in DMF (5 mL). NaH (60% in mineral oil, 0.19 g, 4.7 mmol) was added at room temperature affording rapid gas evolution. The reaction stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1-one (0.50 g, 3.15 mmol) was added. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH4 (1.19 g) were added. The solution was brought to 60° C. for 0.5 h. and then cooled to room temperature. The solution was quenched with water, extracted with Et2O (3 times), dried (Na2SO4) and concentrated. Flash chromatography (10% AcOEt) to give the desired product as a tan solid (0.60 g, 63% yield). MS Calcd.: 298. Found 299 (M+H). affording rapid gas evolution was added were added The solution was quenched with water extracted with Et2O (3 times) dried (Na2SO4) concentrated

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

Procedure: A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 was treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated to reflux for 5 h. The reaction was concentrated in vacuo to give crude 4-(3-benzylpyrrolidine-1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanol containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture was refluxed for three days then concentrated and purified by flash chromatography eluting with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine that was found to be only 90% pure by HPLC analysis. This material was then dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 90 min at room temperature, the catalyst was removed via filtration and the filtrate concentrated to an oil. Purification by flash chromatography eluting with 75% hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H), 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s, 1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s, 1H). MS Calcd.: 450. Found: 451 (M+H). was added The mixture was refluxed for three days then concentrated purified by flash chromatography eluting with 60% hexanes/AcOEt

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

Procedure: Compound 1 (0.68 g, 4.41 mmol) was dissolved in DMF (5 mL). NaH (60% in mineral oil, 0.19 g, 4.7 mmol) was added at room temperature affording rapid gas evolution. The reaction stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1-one (0.50 g, 3.15 mmol) was added. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH4 (1.19 g) were added. The solution was brought to 60° C. for 0.5 h. and then cooled to room temperature. The solution was quenched with water, extracted with Et2O (3 times), dried (Na2SO4) and concentrated. Flash chromatography (10% AcOEt) to give the desired product as a tan solid (0.60 g, 63% yield). MS Calcd.: 298. Found 299 (M+H). affording rapid gas evolution was added were added The solution was quenched with water extracted with Et2O (3 times) dried (Na2SO4) concentrated

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

Procedure: A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 was treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated to reflux for 5 h. The reaction was concentrated in vacuo to give crude 4-(3-benzylpyrrolidine-1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanol containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture was refluxed for three days then concentrated and purified by flash chromatography eluting with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine that was found to be only 90% pure by HPLC analysis. This material was then dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 90 min at room temperature, the catalyst was removed via filtration and the filtrate concentrated to an oil. Purification by flash chromatography eluting with 75% hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H), 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s, 1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s, 1H). MS Calcd.: 450. Found: 451 (M+H). was added The mixture was refluxed for three days then concentrated purified by flash chromatography eluting with 60% hexanes/AcOEt

Conditions: temp:112.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 0.96 g (6.00 mmol) of 3-methyl-1-phenyl-2-buten-1-one and 0.84 g (5.00 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (25 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver and a condenser tube. Toluene (5 ml) as the solvent and butanol (0.5 ml) were added, and 0.12 g (0.50 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 8 hours while agitating at an internal temperature of 112° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was recrystallized with 5 ml of ethyl acetate to give 0.42 g of 2-benzenesulfonyl-4-methyl-6-phenylpyridine with the following properties as colorless crystals (purity of 99%, yield of 28% based on benzenesulfonyl cyanide). equipped with a thermometer, a magnetic stirrer a Dean-Stark water type distilling receiver and a condenser tube Toluene (5 ml) as the solvent and butanol (0.5 ml) were added Then the mixture was heated under reflux for 8 hours separating removing water that was produced After this solution was cooled to room temperature the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the The crude product was recrystallized with 5 ml of ethyl acetate

Conditions: temp:112.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 0.96 g (6.00 mmol) of 3-methyl-l-phenyl-2-buten-1-one and 0.84 g (5.00 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (25 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver and a condenser tube. Toluene (5 ml) as the solvent and butanol (0.5 ml) were added, and 0.12 g (0.50 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 8 hours while agitating at an internal temperature of 112° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was recrystallized with 5 ml of ethyl acetate to give 0.42 g of 2-benzenesulfonyl-4-methyl-6-phenylpyridine with the following properties as colorless crystals (purity of 99%, yield of 28% based on benzenesulfonyl cyanide). equipped with a thermometer, a magnetic stirrer a Dean-Stark water type distilling receiver and a condenser tube Toluene (5 ml) as the solvent and butanol (0.5 ml) were added Then the mixture was heated under reflux for 8 hours separating removing water that was produced After this solution was cooled to room temperature the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the The crude product was recrystallized with 5 ml of ethyl acetate

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

Procedure: Compound 1 (0.68 g, 4.41 mmol) was dissolved in DMF (5 mL). NaH (60% in mineral oil, 0.19 g, 4.7 mmol) was added at room temperature affording rapid gas evolution. The reaction stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1-one (0.50 g, 3.15 mmol) was added. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH4 (1.19 g) were added. The solution was brought to 60° C. for 0.5 h. and then cooled to room temperature. The solution was quenched with water, extracted with Et2O (3 times), dried (Na2SO4) and concentrated. Flash chromatography (10% AcOEt) to give the desired product as a tan solid (0.60 g, 63% yield). MS Calcd.: 298. Found 299 (M+H). affording rapid gas evolution was added were added The solution was quenched with water extracted with Et2O (3 times) dried (Na2SO4) concentrated

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

Procedure: A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 was treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated to reflux for 5 h. The reaction was concentrated in vacuo to give crude 4-(3-benzylpyrrolidine-1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanol containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture was refluxed for three days then concentrated and purified by flash chromatography eluting with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine that was found to be only 90% pure by HPLC analysis. This material was then dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 90 min at room temperature, the catalyst was removed via filtration and the filtrate concentrated to an oil. Purification by flash chromatography eluting with 75% hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H), 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s, 1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s, 1H). MS Calcd.: 450. Found: 451 (M+H). was added The mixture was refluxed for three days then concentrated purified by flash chromatography eluting with 60% hexanes/AcOEt