2-[4-(3-aminopropyl)piperazin-1-yl]ethanol

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

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

Procedure: To a solution of potasium hydroxide (1.5 g) in methanol (11 ml) was added 3-[4-(2-hydroxyethyl)-1-piperazinyl]propylamine (5.0 g) and thereto was added carbon disulfide (2.0 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 2 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (10 ml), washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (3.8 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling, extracted with ethyl acetate, dried over magnesium sulfate and then evaporated to give methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]dithio-carbamate (4.8 g). The reaction mixture was evaporated under reduced pressure The residual oil was dissolved in water (10 ml) washed with diethyl ether cooled was added methyl iodide (3.8 g) with stirring The resulting mixture was stirred for 2 hours under ice- cooling extracted with ethyl acetate dried over magnesium sulfate evaporated

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

Procedure: To a solution of potasium hydroxide (1.5 g) in methanol (11 ml) was added 3-[4-(2-hydroxyethyl)-1-piperazinyl]propylamine (5.0 g) and thereto was added carbon disulfide (2.0 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 2 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (10 ml), washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (3.8 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling, extracted with ethyl acetate, dried over magnesium sulfate and then evaporated to give methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]dithio-carbamate (4.8 g). The reaction mixture was evaporated under reduced pressure The residual oil was dissolved in water (10 ml) washed with diethyl ether cooled was added methyl iodide (3.8 g) with stirring The resulting mixture was stirred for 2 hours under ice- cooling extracted with ethyl acetate dried over magnesium sulfate evaporated

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

Procedure: To a solution of potasium hydroxide (1.5 g) in methanol (11 ml) was added 3-[4-(2-hydroxyethyl)-1-piperazinyl]propylamine (5.0 g) and thereto was added carbon disulfide (2.0 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 2 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (10 ml), washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (3.8 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling, extracted with ethyl acetate, dried over magnesium sulfate and then evaporated to give methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]dithio-carbamate (4.8 g). The reaction mixture was evaporated under reduced pressure The residual oil was dissolved in water (10 ml) washed with diethyl ether cooled was added methyl iodide (3.8 g) with stirring The resulting mixture was stirred for 2 hours under ice- cooling extracted with ethyl acetate dried over magnesium sulfate evaporated

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

Procedure: A 50 mL chloroform solution of 6.21 g. (0.025 1 mol) of myristoyl chloride was added dropwise under argon to an ice cold 75 mL chloroform solution of 4.79 g. (0.0256 mol) of N-(3-aminopropyl)-N'-(2-hydroxyethyl)piperazine. After stirring for two hours, 100 mL of aqueous sodium carbonate was added and stirred for 30 minutes. The layers were separated and the chloroform layer was washed with aqueous sodium carbonate (2×125 mL) followed by water (2×75 mL). The chloroform layer was concentrated in vacuo and the remaining amber liquid was crystallized successively from ethyl acetate to yield 4.56 g. (45.6%) of the subject compound. stirred for 30 minutes The layers were separated the chloroform layer was washed with aqueous sodium carbonate (2×125 mL) The chloroform layer was concentrated in vacuo the remaining amber liquid was crystallized successively from ethyl acetate to yield 4.56 g

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

Procedure: A 50 mL chloroform solution of 2.45 g. (0.0112 mol) of dodecanoyl chloride was added dropwise under argon to an ice cold 50 mL chloroform solution of 2.12 g. (0.0113 mol) of N-(3-aminopropyl)-N'-(2-hydroxyethyl) piperazine and stirred for one hour maintaining the temperature between 2°-4° C. This reaction mixture was then treated with 100 mL of aqueous sodium bicarbonate and extracted with chloroform (2×50 mL). The combined chloroform layers were washed with aqueous sodium bicarbonate (2×50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The remaining solid was crystallized in ethyl acetate/hexane to yield 1.69 g. (40.8%)of the subject product. maintaining the temperature between 2°-4° C extracted with chloroform (2×50 mL) The combined chloroform layers were washed with aqueous sodium bicarbonate (2×50 mL) dried (MgSO4) filtered concentrated in vacuo The remaining solid was crystallized in ethyl acetate/hexane to yield 1.69 g

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

Procedure: To a mixture of 0.051 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0494 g (0.13 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.6 mL of dichloromethane, 0.6 mL of dimethylformamide, 0.12 mL of triethylamine was added followed by 0.0235 g (0.13 mmole) of 2-[4-(3-amino-propyl)-piperazin-1-yl]-ethanol. After stirring 1.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-water (gradient, 5:95-0:100) to give 0.0054 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-3-methoxy-benzamide (I-96). was added the mixture was concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with acetonitrile-water (gradient, 5:95-0:100)

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

Procedure: To a solution of potasium hydroxide (1.5 g) in methanol (11 ml) was added 3-[4-(2-hydroxyethyl)-1-piperazinyl]propylamine (5.0 g) and thereto was added carbon disulfide (2.0 g) under ice cooling over a perod of 10 minutes. The resulting mixture was stirred for 2 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (10 ml), washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (3.8 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling, extracted with ethyl acetate, dried over magnesium sulfate and then evaporated to give methyl-N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]dithio-carbamate (4.8 g). The reaction mixture was evaporated under reduced pressure The residual oil was dissolved in water (10 ml) washed with diethyl ether cooled was added methyl iodide (3.8 g) with stirring The resulting mixture was stirred for 2 hours under ice- cooling extracted with ethyl acetate dried over magnesium sulfate evaporated

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

Procedure: To a solution of potasium hydroxide (1.5 g) in methanol (11 ml) was added 3-[4-(2-hydroxyethyl)-1-piperazinyl]propylamine (5.0 g) and thereto was added carbon disulfide (2.0 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 2 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (10 ml), washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (3.8 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling, extracted with ethyl acetate, dried over magnesium sulfate and then evaporated to give methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]dithio-carbamate (4.8 g). The reaction mixture was evaporated under reduced pressure The residual oil was dissolved in water (10 ml) washed with diethyl ether cooled was added methyl iodide (3.8 g) with stirring The resulting mixture was stirred for 2 hours under ice- cooling extracted with ethyl acetate dried over magnesium sulfate evaporated