2-bromo-3-methylbenzonitrile

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

Procedure: A solution of 35 g (0.18 mole) of cyanobromotoluene and 16.18 g (0.19 mole) of piperidine in 300 mL of anhydrous DMF was treated with 73 g (0.5 mole) of K2CO3 at 50° C. for 2 hr. The reaction mixture was filtered through a plug of Celite, washed with 400 mL of ethyl acetate, and the filtrate was partitioned between ethyl acetate and ½ saturated brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo, yielding 36 g (0.18 mole) 100% of 2-Piperidin-1-ylmethyl-benzonitrile. 1H NMR (300 MHz, CDCl3) 7.6 (m, 3H), 7.24 (m, 1H), 3.6 (s, 2H), 2.4 (m, 4H), 1.5 (m, 6H). The reaction mixture was filtered through a plug of Celite washed with 400 mL of ethyl acetate the filtrate was partitioned between ethyl acetate and ½ saturated brine The organic layer was dried over anhydrous Na2SO4 concentrated in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-3-methylbenzonitrile (0.744 g, 3.79 mmol), N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.60 g, 1.265 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.121 g, 0.253 mmol), potassium phosphate, anhydrous (0.524 mL, 6.32 mmol), and Pd2(dba)3 (0.116 g, 0.126 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and degassed water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a yellow solid as (2-(2-(4-methoxybenzylamino)-3-(tetrahydro-2H-pyran-4-yl) quinolin-6-yl)-3-methylbenzonitrile. was purged with N2 followed by the addition of degassed dioxane (2 mL) degassed water (1.0 mL) was filtered concentrated chromatographed on silica gel using gradient 2:1 hexanes/EtOAc

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-3-methylbenzonitrile (0.744 g, 3.79 mmol), N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.60 g, 1.265 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.121 g, 0.253 mmol), potassium phosphate, anhydrous (0.524 mL, 6.32 mmol), and Pd2(dba)3 (0.116 g, 0.126 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and degassed water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a yellow solid as (2-(2-(4-methoxybenzylamino)-3-(tetrahydro-2H-pyran-4-yl) quinolin-6-yl)-3-methylbenzonitrile. was purged with N2 followed by the addition of degassed dioxane (2 mL) degassed water (1.0 mL) was filtered concentrated chromatographed on silica gel using gradient 2:1 hexanes/EtOAc

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of potassium phosphate (5.98 g, 28.2 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.54 g, 1.13 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), 2-bromo-3-methylbenzonitrile (2.21 g, 11.26 mmol) and 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (2.00 g, 5.63 mmol, prepared as in Example 2, Step 1-2) was added dioxane (50.0 mL) and water (25.0 mL). The mixture was heated to 140° C. for 10 min. The reaction mixture was allowed to cool to RT, filtered and then partitioned between EtOAc and water. The organic layer was washed with water and brine, and concentrated. The residue was diluted with EtOAc and then filtered. The solid was dried in air to afford 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzonitrile as a light brown solid. to cool to RT filtered partitioned between EtOAc and water The organic layer was washed with water and brine concentrated The residue was diluted with EtOAc filtered The solid was dried in air

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

Procedure: A solution of 2-bromo-3-methylbenzonitrile (0.40 g, 2.04 mmol) in THF (2.04 mL) under inert atmosphere was cooled to 0° C. in an ice-water bath. A solution of o-tolylmagnesium bromide, ˜2M in Et2O (1.22 mL, 2.45 mmol) was added dropwise via syringe. On completion of addition reaction mixture was allowed to warm to ambient temperature and then heated to 50° C. for 3 h. 2 mL of 2N aq. HCl was added carefully, the heating element was turned off and the reaction mixture allowed to be cooled to ambient temperature and stirred overnight. Then the reaction mixture was diluted with water (75 mL) and extracted with EtOAc (1×75 mL). The organic extract was washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL), and brine (75 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude material was purified by column chromatography eluting with a gradient of 5-50% Et2O in hexane, to provide (2-bromo-3-methylphenyl)(o-tolyl)methanone as a white solid. On completion of addition reaction mixture heated to 50° C. for 3 h to be cooled to ambient temperature extracted with EtOAc (1×75 mL) The organic extract was washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL), and brine (75 mL) dried over MgSO4 The solution was filtered concentrated in vacuo to give the crude material as a light-yellow oil The crude material was purified by column chromatography eluting with a gradient of 5-50% Et2O in hexane

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N-[2-(4-cyano-phenoxy)-ethyl]-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl)-ethyl]-methanesulfonamide (0.079 g, 0.20 mmol), 2-bromo-methyl-benzonitrile (0.041 g, 0.21 mmol) and anhydrous potassium carbonate (0.042 g, 0.30 mmol) was added dry acetonitrile (4 mL). The mixture was heated by microwave irradiation (15 minutes, 160° C.) and was then filtered. The filtrate was loaded onto a cation exchange column (SCX-2, Isolute™, 2 g). The column was washed with dichloromethane, acetonitrile and dichloromethane/methanol 80:20 before eluting the crude product with 20% methanol saturated with ammonia in dichloromethane. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 57 mg (55.9%) of the title compound. was then filtered The column was washed with dichloromethane, acetonitrile and dichloromethane/methanol 80:20 before eluting the crude product with 20% methanol saturated with ammonia in dichloromethane The filtrate was concentrated in vacuo the crude product was purified by chromatography on silica gel

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N-[2-(4-cyano-phenoxy)-ethyl]-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl)-ethyl]-methanesulfonamide (0.079 g, 0.20 mmol), 2-bromo-methyl-benzonitrile (0.041 g, 0.21 mmol) and anhydrous potassium carbonate (0.042 g, 0.30 mmol) was added dry acetonitrile (4 mL). The mixture was heated by microwave irradiation (15 minutes, 160° C.) and was then filtered. The filtrate was loaded onto a cation exchange column (SCX-2, Isolute™, 2 g). The column was washed with dichloromethane, acetonitrile and dichloromethane/methanol 80:20 before eluting the crude product with 20% methanol saturated with ammonia in dichloromethane. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 57 mg (55.9%) of the title compound. was then filtered The column was washed with dichloromethane, acetonitrile and dichloromethane/methanol 80:20 before eluting the crude product with 20% methanol saturated with ammonia in dichloromethane The filtrate was concentrated in vacuo the crude product was purified by chromatography on silica gel

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

Procedure: A solution of 35 g (0.18 mole) of cyanobromotoluene and 16.18 g (0.19 mole) of piperidine in 300 mL of anhydrous DMF was treated with 73 g (0.5 mole) of K2CO3 at 50° C. for 2 hr. The reaction mixture was filtered through a plug of Celite, washed with 400 mL of ethyl acetate, and the filtrate was partitioned between ethyl acetate and ½ saturated brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo, yielding 36 g (0.18 mole) 100% of 2-Piperidin-1-ylmethyl-benzonitrile. 1H NMR (300 MHz, CDCl3) 7.6 (m, 3H), 7.24 (m, 1H), 3.6 (s, 2H), 2.4 (m, 4H), 1.5 (m, 6H). The reaction mixture was filtered through a plug of Celite washed with 400 mL of ethyl acetate the filtrate was partitioned between ethyl acetate and ½ saturated brine The organic layer was dried over anhydrous Na2SO4 concentrated in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-3-methylbenzonitrile (0.744 g, 3.79 mmol), N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.60 g, 1.265 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.121 g, 0.253 mmol), potassium phosphate, anhydrous (0.524 mL, 6.32 mmol), and Pd2(dba)3 (0.116 g, 0.126 mmol) was purged with N2 followed by the addition of degassed dioxane (2 mL) and degassed water (1.0 mL). The resulting mixture was heated in microwave at 140° C. for 12 min. The reaction went to completion and it was filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a yellow solid as (2-(2-(4-methoxybenzylamino)-3-(tetrahydro-2H-pyran-4-yl) quinolin-6-yl)-3-methylbenzonitrile. was purged with N2 followed by the addition of degassed dioxane (2 mL) degassed water (1.0 mL) was filtered concentrated chromatographed on silica gel using gradient 2:1 hexanes/EtOAc

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of potassium phosphate (5.98 g, 28.2 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.54 g, 1.13 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), 2-bromo-3-methylbenzonitrile (2.21 g, 11.26 mmol) and 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (2.00 g, 5.63 mmol, prepared as in Example 2, Step 1-2) was added dioxane (50.0 mL) and water (25.0 mL). The mixture was heated to 140° C. for 10 min. The reaction mixture was allowed to cool to RT, filtered and then partitioned between EtOAc and water. The organic layer was washed with water and brine, and concentrated. The residue was diluted with EtOAc and then filtered. The solid was dried in air to afford 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzonitrile as a light brown solid. to cool to RT filtered partitioned between EtOAc and water The organic layer was washed with water and brine concentrated The residue was diluted with EtOAc filtered The solid was dried in air

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

Procedure: A solution of 2-bromo-3-methylbenzonitrile (0.40 g, 2.04 mmol) in THF (2.04 mL) under inert atmosphere was cooled to 0° C. in an ice-water bath. A solution of o-tolylmagnesium bromide, ˜2M in Et2O (1.22 mL, 2.45 mmol) was added dropwise via syringe. On completion of addition reaction mixture was allowed to warm to ambient temperature and then heated to 50° C. for 3 h. 2 mL of 2N aq. HCl was added carefully, the heating element was turned off and the reaction mixture allowed to be cooled to ambient temperature and stirred overnight. Then the reaction mixture was diluted with water (75 mL) and extracted with EtOAc (1×75 mL). The organic extract was washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL), and brine (75 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude material was purified by column chromatography eluting with a gradient of 5-50% Et2O in hexane, to provide (2-bromo-3-methylphenyl)(o-tolyl)methanone as a white solid. On completion of addition reaction mixture heated to 50° C. for 3 h to be cooled to ambient temperature extracted with EtOAc (1×75 mL) The organic extract was washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL), and brine (75 mL) dried over MgSO4 The solution was filtered concentrated in vacuo to give the crude material as a light-yellow oil The crude material was purified by column chromatography eluting with a gradient of 5-50% Et2O in hexane

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N-[2-(4-cyano-phenoxy)-ethyl]-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl)-ethyl]-methanesulfonamide (0.079 g, 0.20 mmol), 2-bromo-methyl-benzonitrile (0.041 g, 0.21 mmol) and anhydrous potassium carbonate (0.042 g, 0.30 mmol) was added dry acetonitrile (4 mL). The mixture was heated by microwave irradiation (15 minutes, 160° C.) and was then filtered. The filtrate was loaded onto a cation exchange column (SCX-2, Isolute™, 2 g). The column was washed with dichloromethane, acetonitrile and dichloromethane/methanol 80:20 before eluting the crude product with 20% methanol saturated with ammonia in dichloromethane. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 57 mg (55.9%) of the title compound. was then filtered The column was washed with dichloromethane, acetonitrile and dichloromethane/methanol 80:20 before eluting the crude product with 20% methanol saturated with ammonia in dichloromethane The filtrate was concentrated in vacuo the crude product was purified by chromatography on silica gel