1-(3-chloropropyl)piperidin-4-ol

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:0.00; pressure:0.00; stir:

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

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

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (533 mg, 2.62 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (750 mg, 4.22 mmol), DMF (10 ml) and K2CO3 (1.44 g, 10.42 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (550 mg, 61%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.13-4.04 (m, 2H), 4.02 (t, 2H), 3.89 (td, 2H), 3.70 (m, 1H), 2.87-2.71 (m, 2H), 2.50 (t, 2H), 2.23-1.84 (m, 10H), 1.68-1.49 (m, 3H). Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2)

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

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (533 mg, 2.62 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (750 mg, 4.22 mmol), DMF (10 ml) and K2CO3 (1.44 g, 10.42 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (550 mg, 61%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.13-4.04 (m, 2H), 4.02 (t, 2H), 3.89 (td, 2H), 3.70 (m, 1H), 2.87-2.71 (m, 2H), 2.50 (t, 2H), 2.23-1.84 (m, 10H), 1.68-1.49 (m, 3H). Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2)

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

Procedure: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (378 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was dissolved in EtOAc (30 ml), washed with NaOH (2M, 2×20 ml) and water (25 ml), dried over MgSO4 filtered and concentrated in vacuo at 35° C. to give the title compound (411 mg, 51%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.80-3.65 (m, 3H), 3.55 (td, 2H), 2.85-2.73 (m, 2H), 2.52 (t, 2H), 2.40 (s, 2H), 2.22-1.82 (m, 10H), 1.97 (s, 6H), 1.66-1.54 (m, 2H), 1.52 (br s, 1H). washed with NaOH (2M, 2×20 ml) and water (25 ml) dried over MgSO4 filtered concentrated in vacuo at 35° C.

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

Procedure: 4-Hydroxypiperidine (3 g, 30 mmol), acetone (60 ml, 20 vol), 5M NaOH solution (7.2 ml) and 1-bromo-3-chloropropane (14.2 g, 90 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.5 g, 28%) as a pale yellow oil.

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

Procedure: 4-Hydroxypiperidine (3 g, 30 mmol), acetone (60 ml, 20 vol), 5M NaOH solution (7.2 ml) and 1-bromo-3-chloropropane (14.2 g, 90 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.5 g, 28%) as a pale yellow oil.

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

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (533 mg, 2.62 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (750 mg, 4.22 mmol), DMF (10 ml) and K2CO3 (1.44 g, 10.42 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (550 mg, 61%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.13-4.04 (m, 2H), 4.02 (t, 2H), 3.89 (td, 2H), 3.70 (m, 1H), 2.87-2.71 (m, 2H), 2.50 (t, 2H), 2.23-1.84 (m, 10H), 1.68-1.49 (m, 3H). Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2)

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

Procedure: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (378 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was dissolved in EtOAc (30 ml), washed with NaOH (2M, 2×20 ml) and water (25 ml), dried over MgSO4 filtered and concentrated in vacuo at 35° C. to give the title compound (411 mg, 51%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.80-3.65 (m, 3H), 3.55 (td, 2H), 2.85-2.73 (m, 2H), 2.52 (t, 2H), 2.40 (s, 2H), 2.22-1.82 (m, 10H), 1.97 (s, 6H), 1.66-1.54 (m, 2H), 1.52 (br s, 1H). washed with NaOH (2M, 2×20 ml) and water (25 ml) dried over MgSO4 filtered concentrated in vacuo at 35° C.