1-(2-methylpropyl)piperazine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.060 g, 0.29 mmol) and isopropanol (4.5 ml) was added 1-isobutyl-piperazine (0.045 g, 0.32 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.06 ml, 0.32 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as an orange solid (0.054 g, 60%); 1H-NMR (500 MHz, DMSO-d6) 0.87 (d, J=6.57 Hz, 6H, CH(CH3)2), 1.77 (m, 1H, CH(CH3)2), 2.08 (d, J=7.39 Hz, 2H, N—CH2), 2.45 (br s, 4H, piperazine N(CH2)2), 3.05 (br s, 4H, piperazine N(CH2)2), 6.94 (s, 2H, NH2), 8.06 (s, 1H, 6-H); to cool to room temperature concentrated in vacuo The residue was absorbed on silica gel was eluted with ethyl acetate/dichloromethane (v/v; 1:1)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-isobutylpiperazine (0.078 g, 0.55 mmol) with the aid of isopropanol (5 ml) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.112 g, 63%). 1H-NMR (500 MHz, DMSO-d6) 0.87 (d, J=6.56 Hz, 6H, CH(CH3)2), 1.77 (m, 1H, CH(CH3)2), 2.08 (d, J=7.35 Hz, 2H, N—CH2), 2.47 (br s, 4H, piperazine N(CH2)2), 3.04 (br s, 4H, piperazine N(CH2)2), 6.96 (s, 2H, NH2), 8.15 (s, 1H, 6-H); to cool to room temperature The precipitate was collected by filtration washed with isopropanol and diethyl ether

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A suspension of 2-chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine dihydrochloride (1.07 g, 2.6 mmol), N-isobutylpiperazine (0.95 g, 6.72 mmol), potassium carbonate (0.5 g, 3.62 mmol), and potassium iodide (0.5 g, 0.54 mmol) in xylenes (5 mL) was heated to reflux under a nitrogen atmosphere for 24 hours. The reaction mixture was then cooled to ambient temperature and a solution of potassium carbonate (19) in water (10 mL) and cyclohexane (10 mL) were added. The mixture was stirred vigorously for 15 min, and the precipitate was collected by filtration. The filter cake was washed with water (10 mL) and triturated with methyl tert-butyl ether (4 mL) to provide 1-{5-[5(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isobutyl-piperazine (2.07 mmol). was heated to reflux under a nitrogen atmosphere for 24 hours the precipitate was collected by filtration The filter cake was washed with water (10 mL) triturated with methyl tert-butyl ether (4 mL)

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

Procedure: A suspension of 2-chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine dihydrochloride (1.07 g, 2.6 mmol), N-isobutylpiperazine (0.95 g, 6.72 mmol), potassium carbonate (0.5 g, 3.62 mmol), and potassium iodide (0.5 g, 0.54 mmol) in xylenes (5 mL) was heated to reflux under a nitrogen atmosphere for 24 hours. The reaction mixture was then cooled to ambient temperature and a solution of potassium carbonate (19) in water (10 mL) and cyclohexane (10 mL) were added. The mixture was stirred vigorously for 15 min, and the precipitate was collected by filtration. The filter cake was washed with water (10 mL) and triturated with methyl tert-butyl ether (4 mL) to provide 1-{5-[5(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isobutyl-piperazine (2.07 mmol). was heated to reflux under a nitrogen atmosphere for 24 hours the precipitate was collected by filtration The filter cake was washed with water (10 mL) triturated with methyl tert-butyl ether (4 mL)

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

Procedure: A suspension of 2-chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine dihydrochloride (1.07 g, 2.6 mmol), N-isobutylpiperazine (0.95 g, 6.72 mmol), potassium carbonate (0.5 g, 3.62 mmol), and potassium iodide (0.5 g, 0.54 mmol) in xylenes (5 mL) was heated to reflux under a nitrogen atmosphere for 24 hours. The reaction mixture was then cooled to ambient temperature and a solution of potassium carbonate (g) in water (10 mL) and cyclohexane (10 mL) were added. The mixture was stirred vigorously for 15 min, and the precipitate was collected by filtration. The filter cake was washed with water (10 mL) and triturated with methyl tert-butyl ether (4 mL) to provide 1-{5-[5-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isobutyl-piperazine (2.07 mmol). MS m/z 430 (M++1). was heated to reflux under a nitrogen atmosphere for 24 hours the precipitate was collected by filtration The filter cake was washed with water (10 mL) triturated with methyl tert-butyl ether (4 mL)

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

Procedure: A suspension of 2-chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine dihydrochloride (1.07 g, 2.6 mmol), N-isobutylpiperazine (0.95 g, 6.72 mmol), potassium carbonate (0.5 g, 3.62 mmol), and potassium iodide (0.5 g, 0.54 mmol) in xylenes (5 mL) was heated to reflux under a nitrogen atmosphere for 24 hours. The reaction mixture was then cooled to ambient temperature and a solution of potassium carbonate (g) in water (10 mL) and cyclohexane (10 mL) were added. The mixture was stirred vigorously for 15 min, and the precipitate was collected by filtration. The filter cake was washed with water (10 mL) and triturated with methyl tert-butyl ether (4 mL) to provide 1-{5-[5-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isobutyl-piperazine (2.07 mmol). MS m/z 430 (M++1). was heated to reflux under a nitrogen atmosphere for 24 hours the precipitate was collected by filtration The filter cake was washed with water (10 mL) triturated with methyl tert-butyl ether (4 mL)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.108 g, 0.36 mmol) in N,N-dimethylformamide (1.5 mL) was added K2CO3 (0.15 g, 1.07 mmol) and 1-isobutyl-piperazine (88.9 μL, 0.54 mmol). The resulting mixture was heated at 110° C. for 6 h. After that time N,N-dimethylacetamide (1.5 mL) was added and heating was continued for 20 h. After that time the reaction mixture was cooled to rt, diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with water, and dried under high vacuum. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) to give 2-(6-(4-isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.052 g, 34%) as a yellow solid: mp 188-189° C.; 1H NMR (400 MHz, CDCl3) δ 10.33 (br s, 1H), 7.83 (d, J=7.42 Hz, 1H), 7.65 (dd, J=8.59, 7.42, 1H), 6.76-6.88 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.64 (t, J=4.88 Hz, 4H), 2.55 (t, J=4.88 Hz, 4H), 2.17 (d, J=7.42 Hz, 2H), 1.75-1.95 (m, 1H), 0.95 (d, J=6.64 Hz, 6H); ESI MS m/z 424 [M+H]+. heating After that time the reaction mixture was cooled to rt filtered The filtrate was concentrated under reduced pressure the residue was washed with water dried under high vacuum The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol)

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

Procedure: In 30 ml of chloroform were added 1.42 g of 1-isobutylpiperazine and 2.76 g of potassium carbonate, and to the mixture was added dropwise 50 ml of a chloroform solution containing 2.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred at a temperature of 15° C. to 25° C. for two hours, and then the reaction solution was washed with 20 ml of a 1N aqueous sodium hydroxide solution and extracted twice with a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted three time with 30 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, the residue obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: 2% methanol-chloroform) to give 2.60 g of 1-(5-isoquinolinesulfonyl)-4-isobutylpiperazine, i.e., Compound (47) in a yield of 78%. under cooling with ice the mixed solution thus obtained the reaction solution was washed with 20 ml of a 1N aqueous sodium hydroxide solution extracted twice with a 5N aqueous hydrochloric acid solution extracted three time with 30 ml of chloroform the chloroform layer extracted was washed with water dried with anhydrous magnesium sulfate After the chloroform was distilled under reduced pressure, the residue obtained