1-benzyl-4-methylpiperidin-4-amine

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

Procedure: 39.4 g of 4-acetylamino-1-benzyl-4-methylpiperidine are heated to boiling in 400 ml of concentrated hydrochloric acid for 3 days. After evaporation to half the volume in a rotary evaporator, the pH is adjusted to 12 with 50% strength sodium hydroxide solution while cooling. The mixture is extracted three times with methylene chloride. The combined organic phases are then dried over sodium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is employed without further purification in the next reaction. After evaporation to half the volume in a rotary evaporator while cooling The mixture is extracted three times with methylene chloride The combined organic phases are then dried over sodium sulphate the solvent is distilled off in a rotary evaporator The residue is employed without further purification in the next reaction

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.6 g 1-fluor-2-nitrobenzene and 82.7 g potassiumcarbonate were added to 5.3 g 1-benzyl-4-methyl-piperidin-4-ylamine in 50 mL DMSO and the mixture was stirred at 150° C. 24 h. The reaction was diluted with water and the aqueous layer was extracted with ethylacetate. The organic layer was evaporated and the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1) to give 5.9 g of the desired product. 24 h the aqueous layer was extracted with ethylacetate The organic layer was evaporated the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1)

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

Procedure: A mixture of N-(1-benzyl-4-methyl-4-piperidinyl)acetamide obtained in Example 10-2 (3.45 g) and conc. HCl (41 mL) was heated under reflux with stirring for 72 hrs. After cooling, the mixture was quenched by adding 3N potassium hydroxide solution, and the resulting solution (pH11) was extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound as a pale brown oil (2.86 g). was heated under reflux After cooling the mixture was quenched by adding 3N potassium hydroxide solution the resulting solution (pH11) was extracted with chloroform The organic layer was washed with brine dried over MgSO4 concentrated

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

Procedure: 39.4 g of 4-acetylamino-1-benzyl-4-methylpiperidine are heated to boiling in 400 ml of concentrated hydrochloric acid for 3 days. After evaporation to half the volume in a rotary evaporator, the pH is adjusted to 12 with 50% strength sodium hydroxide solution while cooling. The mixture is extracted three times with methylene chloride. The combined organic phases are then dried over sodium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is employed without further purification in the next reaction. After evaporation to half the volume in a rotary evaporator while cooling The mixture is extracted three times with methylene chloride The combined organic phases are then dried over sodium sulphate the solvent is distilled off in a rotary evaporator The residue is employed without further purification in the next reaction

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

Procedure: 39.4 g of 4-acetylamino-1-benzyl-4-methylpiperidine are heated to boiling in 400 ml of concentrated hydrochloric acid for 3 days. After evaporation to half the volume in a rotary evaporator, the pH is adjusted to 12 with 50% strength sodium hydroxide solution while cooling. The mixture is extracted three times with methylene chloride. The combined organic phases are then dried over sodium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is employed without further purification in the next reaction. After evaporation to half the volume in a rotary evaporator while cooling The mixture is extracted three times with methylene chloride The combined organic phases are then dried over sodium sulphate the solvent is distilled off in a rotary evaporator The residue is employed without further purification in the next reaction

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.6 g 1-fluor-2-nitrobenzene and 82.7 g potassiumcarbonate were added to 5.3 g 1-benzyl-4-methyl-piperidin-4-ylamine in 50 mL DMSO and the mixture was stirred at 150° C. 24 h. The reaction was diluted with water and the aqueous layer was extracted with ethylacetate. The organic layer was evaporated and the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1) to give 5.9 g of the desired product. 24 h the aqueous layer was extracted with ethylacetate The organic layer was evaporated the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (215 mg), DIPEA (313 μL) and 1-benzyl-4-methyl-piperidin-4-ylamine (175 mg) in dichloroethane (7 mL), which was being stirred at 40° C., was added BEP (200 mg). The mixture was stirred at 40° C. for 60 min, then at r.t. overnight. Water was added and the mixture was extracted with dichloromethane. To the dichloromethane phase 30% sodium methoxide in methanol (0.4 mL) was added and stirred for 30 min. The mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica (dichloromethane/methanol gradient) to give 1420 g (43%) of the title compound. was added BEP (200 mg) The mixture was stirred at 40° C. for 60 min at r.t. overnight the mixture was extracted with dichloromethane To the dichloromethane phase 30% sodium methoxide in methanol (0.4 mL) was added stirred for 30 min The mixture was filtered the filtrate was washed with water dried over magnesium sulfate concentrated The residue was chromatographed over silica (dichloromethane/methanol gradient)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (215 mg), DIPEA (313 μL) and 1-benzyl-4-methyl-piperidin-4-ylamine (175 mg) in dichloroethane (7 mL), which was being stirred at 40° C., was added BEP (200 mg). The mixture was stirred at 40° C. for 60 min, then at r.t. overnight. Water was added and the mixture was extracted with dichloromethane. To the dichloromethane phase 30% sodium methoxide in methanol (0.4 mL) was added and stirred for 30 min. The mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica (dichloromethane/methanol gradient) to give 1420 g (43%) of the title compound. was added BEP (200 mg) The mixture was stirred at 40° C. for 60 min at r.t. overnight the mixture was extracted with dichloromethane To the dichloromethane phase 30% sodium methoxide in methanol (0.4 mL) was added stirred for 30 min The mixture was filtered the filtrate was washed with water dried over magnesium sulfate concentrated The residue was chromatographed over silica (dichloromethane/methanol gradient)

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

Procedure: A mixture of N-(1-benzyl-4-methyl-4-piperidinyl)acetamide obtained in Example 10-2 (3.45 g) and conc. HCl (41 mL) was heated under reflux with stirring for 72 hrs. After cooling, the mixture was quenched by adding 3N potassium hydroxide solution, and the resulting solution (pH11) was extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound as a pale brown oil (2.86 g). was heated under reflux After cooling the mixture was quenched by adding 3N potassium hydroxide solution the resulting solution (pH11) was extracted with chloroform The organic layer was washed with brine dried over MgSO4 concentrated

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

Procedure: 39.4 g of 4-acetylamino-1-benzyl-4-methylpiperidine are heated to boiling in 400 ml of concentrated hydrochloric acid for 3 days. After evaporation to half the volume in a rotary evaporator, the pH is adjusted to 12 with 50% strength sodium hydroxide solution while cooling. The mixture is extracted three times with methylene chloride. The combined organic phases are then dried over sodium sulphate, and the solvent is distilled off in a rotary evaporator. The residue is employed without further purification in the next reaction. After evaporation to half the volume in a rotary evaporator while cooling The mixture is extracted three times with methylene chloride The combined organic phases are then dried over sodium sulphate the solvent is distilled off in a rotary evaporator The residue is employed without further purification in the next reaction

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.6 g 1-fluor-2-nitrobenzene and 82.7 g potassiumcarbonate were added to 5.3 g 1-benzyl-4-methyl-piperidin-4-ylamine in 50 mL DMSO and the mixture was stirred at 150° C. 24 h. The reaction was diluted with water and the aqueous layer was extracted with ethylacetate. The organic layer was evaporated and the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1) to give 5.9 g of the desired product. 24 h the aqueous layer was extracted with ethylacetate The organic layer was evaporated the residue purified by column chromatographie on silica gel (heptane/ethylacetate:9/1)