N'-hydroxybutanimidamide

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 93 g of methyl pentynoate and 82 g butyramidoxime are mixed together without solvent and heated to 50° C for 24 hours. 400 mL xylene was added and water was azaeotropically removed for 6 hours. The reaction was then distilled (140° C. at 0.2 torr) to give 44 g product. water was azaeotropically removed for 6 hours The reaction was then distilled (140° C. at 0.2 torr)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 93 g of methyl pentynoate and 82 g butyramidoxime are mixed together without solvent and heated to 50° C for 24 hours. 400 mL xylene was added and water was azaeotropically removed for 6 hours. The reaction was then distilled (140° C. at 0.2 torr) to give 44 g product. water was azaeotropically removed for 6 hours The reaction was then distilled (140° C. at 0.2 torr)

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

Procedure: 41.20 g (112.1 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole and 12.6 g (123.4 mmol) of butyramidoxime are stirred at 60° for 2.5 hours in 200 ml of N,N-dimethylformamide. The cooled suspension is then filtered; the filter residue is rinsed with ether and dried. The product obtained is stirred at 1120° for 3 hours with 350 ml of glacial acetic acid. The reaction mixture is evaporated and the residue is dissolved in methylene chloride. The solution is washed with a saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(3-propyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one of melting point 176°-178°. The cooled suspension is then filtered the filter residue is rinsed with ether dried The product obtained The reaction mixture is evaporated the residue is dissolved in methylene chloride The solution is washed with a saturated sodium bicarbonate solution dried over magnesium sulphate evaporated By recrystallization of the residue from methylene chloride and ethyl acetate

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

Procedure: A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.60 g), 4-methylmorpholine (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g), 1-hydroxybenzotriazole monohydrate (0.17 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 min, N′-hydroxybutanimidamide (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Xylene (50 mL) was added to the residue, and the mixture was heated under reflux for 24 hrs. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give 5-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-3-propyl-1,2,4-oxadiazole as colorless crystals (0.12 g, yield 18%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 192-193° C. the mixture was further stirred at room temperature for 15 hrs the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated Xylene (50 mL) was added to the residue the mixture was heated under reflux for 24 hrs The reaction mixture was concentrated

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

Procedure: A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.60 g), 4-methylmorpholine (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g), 1-hydroxybenzotriazole monohydrate (0.17 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 min, N′-hydroxybutanimidamide (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Xylene (50 mL) was added to the residue, and the mixture was heated under reflux for 24 hrs. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give 5-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-3-propyl-1,2,4-oxadiazole as colorless crystals (0.12 g, yield 18%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 192-193° C. the mixture was further stirred at room temperature for 15 hrs the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated Xylene (50 mL) was added to the residue the mixture was heated under reflux for 24 hrs The reaction mixture was concentrated

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

Procedure: A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.60 g), 4-methylmorpholine (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g), 1-hydroxybenzotriazole monohydrate (0.17 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 min, N′-hydroxybutanimidamide (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Xylene (50 mL) was added to the residue, and the mixture was heated under reflux for 24 hrs. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give 5-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-3-propyl-1,2,4-oxadiazole as colorless crystals (0.12 g, yield 18%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 192-193° C. the mixture was further stirred at room temperature for 15 hrs the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated Xylene (50 mL) was added to the residue the mixture was heated under reflux for 24 hrs The reaction mixture was concentrated

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

Procedure: Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 108 mg, 2.7 mmol) and butyramidoxime (276 mg, 2.7 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (1.04 g, 2.7 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-n-propyl-1,2,4-oxadiazol-5-yl)pyrimidine 785 mg (67%). This product was dissolved in triflouroacetic acid (2 ml), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 240 mg (43%) white crystals, mp 126-128° C. identified by 300 MHz nmr. dried round bottom flask After 15 minutes stirring the ice bath was removed the grey suspension refluxed 45 minutes to give a white suspension reflux The solvents were evaporated in vacuo the residue was chromatographed (silica, chloroform/methanol, 9:1)

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

Procedure: Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 108 mg, 2.7 mmol) and butyramidoxime (276 mg, 2.7 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (1.04 g, 2.7 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-n-propyl-1,2,4-oxadiazol-5-yl)pyrimidine 785 mg (67%). This product was dissolved in triflouroacetic acid (2 ml), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 240 mg (43%) white crystals, mp 126°-128° C. identified by 300 MHz nmr. dried round bottom flask After 15 minutes stirring the ice bath was removed the grey suspension refluxed 45 minutes to give a white suspension reflux The solvents were evaporated in vacuo the residue was chromatographed (silica, chloroform/methanol, 9:1)

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

Procedure: 150 mg (0.373 mmol) of the compound from Example 44A and 70 mg (0.746 mmol) of N′-hydroxybutanimidamide were reacted according to the General Method 2. Yield: 174 mg (93% of theory).

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

Procedure: 66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 22 mg (0.22 mmol, 1.1 eq.) of N′-hydroxybutanimidamide were reacted according to the General Method 1. Yield: 12 mg (15% of theory)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 93 g of methyl pentynoate and 82 g butyramidoxime are mixed together without solvent and heated to 50° C for 24 hours. 400 mL xylene was added and water was azaeotropically removed for 6 hours. The reaction was then distilled (140° C. at 0.2 torr) to give 44 g product. water was azaeotropically removed for 6 hours The reaction was then distilled (140° C. at 0.2 torr)

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

Procedure: 41.20 g (112.1 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole and 12.6 g (123.4 mmol) of butyramidoxime are stirred at 60° for 2.5 hours in 200 ml of N,N-dimethylformamide. The cooled suspension is then filtered; the filter residue is rinsed with ether and dried. The product obtained is stirred at 1120° for 3 hours with 350 ml of glacial acetic acid. The reaction mixture is evaporated and the residue is dissolved in methylene chloride. The solution is washed with a saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(3-propyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one of melting point 176°-178°. The cooled suspension is then filtered the filter residue is rinsed with ether dried The product obtained The reaction mixture is evaporated the residue is dissolved in methylene chloride The solution is washed with a saturated sodium bicarbonate solution dried over magnesium sulphate evaporated By recrystallization of the residue from methylene chloride and ethyl acetate