1-(3-Chloropropyl)piperidine hydrochloride

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

Procedure: A mixture of 63.6 g (0.30 mole) of 2,7-dihydroxy-fluoren-9-one, 188 g (0.95 mole) of 1-(3-chloropropyl) piperidine hydrochloride, 132 g (2.0 mole) of 85% potassium hydroxide in 900 ml of toluene and 300 ml of water is refluxed with vigorous stirring for 20 hours. The layers are separated upon cooling and the organic layer is washed 3 times with water, once with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent removed in vacuo. The residue is taken up in isopropyl alcohol and acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from a mixture of 3 parts isopropyl alcohol to 1 part methanol, and the 2,7-bis(3-piperidinopropoxy)fluoren-9-one dihydrochloride so prepared is dried at 100° C. for 24 hours under vacuum, m.p. 279.5°-80.5° C., λmaxH2O 270, and E1cm1% 1370. is refluxed The layers are separated upon cooling the organic layer is washed 3 times with water once with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate The mixture is filtered the solvent removed in vacuo The solid which precipitates is filtered recrystallized from a mixture of 3 parts isopropyl alcohol to 1 part methanol the 2,7-bis(3-piperidinopropoxy)fluoren-9-one dihydrochloride so prepared is dried at 100° C. for 24 hours under vacuum, m.p. 279.5°-80.5° C., λmaxH2O 270, and E1cm1% 1370

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-{3-[2-(4-Fluoro-phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-7-yl}-phenol (Ex. 1.102) (1 eq, 0.131 mmol, 50 mg), 1-(3-chloropropyl)piperidine monohydrochloride (2.0 eq, 0.262 mmol, 53.7 mg) and potassium carbonate (3.0 eq, 0.394 mmol, 54.4 mg) are dissolved in DMF (4 ml) and heated at 60° C. for 16 h. The reaction mixture is diluted with CH2Cl2 and washed with NaHCO3 and brine. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 7/3 to yield 3-[2-(4-fluoro-phenyl)-pyridin-4-yl]-7-[3-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=507 washed with NaHCO3 and brine The organic phase is dried over MgSO4 filtered evaporated to dryness The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 7/3

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

Procedure: A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.41). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p.178-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190-192° C. was heated at reflux for 16 hours The mixture was washed with brine the layers were separated The organic solution was concentrated The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.41) The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol The solid was collected Recrystallization from ethanol

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

Procedure: A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.41). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p.178°-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190°-192° C. was heated at reflux for 16 hours The mixture was washed with brine the layers were separated The organic solution was concentrated The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.41) The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol The solid was collected Recrystallization from ethanol

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

Procedure: A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.41). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p.178°-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190°-192° C. was heated at reflux for 16 hours The mixture was washed with brine the layers were separated The organic solution was concentrated The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.41) The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol The solid was collected Recrystallization from ethanol

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-{3-[7-(6-Oxo-1,6-dihydro-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (0.12 g, 0.63 mmol) in DMF (1.5 ml) was added N-(3-chloropropyl)piperidine hydrochloride (0.125 g, 0.63 mmol), Cs2CO3 (0.32 g, 0.98 mmol) and NaI (0.095 g, 0.63 mmol). The reaction was heated at 80° C. for 48 hours then partitioned between EtOAc and water, the organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (16 mg) MS: [M+H]+553 then partitioned between EtOAc and water the organic layer was washed with brine dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by preparative HPLC

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

Procedure: 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (200 mg, 0.704 mmol), 3-chloropropylpiperidine hydrochloride (152 mg, 0.775 mmol) and potassium carbonate (204 mg, 1.48 mmol) were stirred in DMF (1 ml) at 45° C. for 24 hours until complete. The reaction was then partitioned between ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give a solid. The solid was purified by preparative HPLC to give the title compound (220 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44-1.55 (m, 2H), 1.64-1.78 (m, 4H), 1.85-2.00 (m, 2H), 2.08-2.18 (m, 4H), 2.52-2.70 (m, 6H), 3.48 (d, 2H), 3.52-3.62 (m, 2H), 3.78-3.85 (m, 2H), 4.02 (t, 2H), 6.21 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.24 (d, 2H), 7.34 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 410 [MH]+. The reaction was then partitioned between ethyl acetate (40 ml) and water (40 ml) The organic layer was separated dried over sodium sulphate concentrated in vacuo to give a solid The solid was purified by preparative HPLC

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

Procedure: 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (200 mg, 0.704 mmol), 3-chloropropylpiperidine hydrochloride (152 mg, 0.775 mmol) and potassium carbonate (204 mg, 1.48 mmol) were stirred in DMF (1 ml) at 45° C. for 24 hours until complete. The reaction was then partitioned between ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give a solid. The solid was purified by preparative HPLC to give the title compound (220 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44-1.55 (m, 2H), 1.64-1.78 (m, 4H), 1.85-2.00 (m, 2H), 2.08-2.18 (m, 4H), 2.52-2.70 (m, 6H), 3.48 (d, 2H), 3.52-3.62 (m, 2H), 3.78-3.85 (m, 2H), 4.02 (t, 2H), 6.21 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.24 (d, 2H), 7.34 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 410 [MH]+. The reaction was then partitioned between ethyl acetate (40 ml) and water (40 ml) The organic layer was separated dried over sodium sulphate concentrated in vacuo to give a solid The solid was purified by preparative HPLC

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

Procedure: A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p.178°-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190°-192° C. was heated at reflux for 16 hours The mixture was washed with brine the layers were separated The organic solution was concentrated The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l) The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol The solid was collected Recrystallization from ethanol

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

Procedure: A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p.178°-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190°-192° C. was heated at reflux for 16 hours The mixture was washed with brine the layers were separated The organic solution was concentrated The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l) The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol The solid was collected Recrystallization from ethanol

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

Procedure: A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p. 178°-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190°-192° C. was heated at reflux for 16 hours The mixture was washed with brine the layers were separated The organic solution was concentrated The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l) The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol The solid was collected Recrystallization from ethanol

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

Procedure: A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K2CO3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p. 178°-181° C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p.=190°-192° C. was heated at reflux for 16 hours The mixture was washed with brine the layers were separated The organic solution was concentrated The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH3OH:0.5% DEA in DCM, 1.4 l) The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol The solid was collected Recrystallization from ethanol