4-[(4-fluorophenyl)methyl]piperidin-4-ol

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

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

Procedure: The title compound MS: m/e=448.6 (M+H+) was prepared from 4-(4-fluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.

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

Procedure: The title compound MS: m/e=448.6 (M+H+) was prepared from 4-(4-fluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.

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

Procedure: The title compound MS: m/e=448.6 (M+H+) was prepared from 4-(4-fluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.

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

Procedure: The title compound, MS: m/e=436.5 (M+H+), was prepared from 1-(2-bromoethoxy)-4-(benzyloxy)-benzene and 4-(4-fluoro-benzyl)-piperidin-4-ol.

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

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

Procedure: To a 20 mL vial equipped with a magnetic stirring bar was added 78 mg of 4-(4-Fluoro-benzyl)-piperidin-4-ol (0.37 mmol, 1.0 equiv.), 100 mg of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.41 mmol, 1.1 equiv), and 207 mg of (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.40 mmol, 1.1 equiv.). The reagents were dissolved in 3 mL of DMA and to the resultant solution was added 0.26 mL of DIPEA (1.5 mmol, 4.1 equiv). The reaction solution was stirred for 5 h and then poured into 50 mL of EtOAc. The organic phase was washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL). The organic phase was then dried over MgSO4 and concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC to afford 129 mg of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (80% yield): MS (ES) M+H expected=414.2, found 414.2. 1H NMR (CDCl3, 400 MHz, 23° C.) δ 7.10-7.14 (m, 2H), 6.99-7.03 (m, 2H), 5.00 (d, J=15.6 Hz, 1H), 4.86 (d, J=15.6 Hz, 1H), 4.32-4.35 (m, 1H), 3.64-6.68 (m, 1H), 3.42-3.50 (m, 1H), 2.96-3.03 (m, 1H), 2.74 (s, 2H), 2.26 (s, 3H), 1.55-1.61 (m, 4H), 1.23 (s, 1H). To a 20 mL vial equipped with a magnetic stirring bar The organic phase was washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL) The organic phase was then dried over MgSO4 concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC

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

Procedure: To a 20 mL vial equipped with a magnetic stirring bar was added 63 mg of 4-(4-Fluoro-benzyl)-piperidin-4-ol (0.3 mmol, 1.2 equiv.), 62 mg of (4-Chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-acetic acid (0.26 mmol, 1.0 equiv), and 138 mg of benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.27 mmol, 1.0 equiv). The reagents were dissolved in 0.6 mL of DMA and to the resultant solution was added 0.18 mL of DIPEA (1.0 mmol, 3.8 equiv.). The reaction solution was stirred for 14 h and then poured into 50 mL of EtOAc. The organic extracts were washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL). The organic extracts were dried over MgSO4 and concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC to afford 34 mg of 2-(4-Chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (30% yield): MS (ES) M+H expected=413.2, found 413.2. 1H NMR (CDCl3, 400 MHz, 23° C.) δ 7.69 (s, 1H), 7.27 (s, 1H), 7.11-7.14 (m, 2H), 6.98-7.03 (m, 2H), 5.06 (d, J=16.0 Hz, 1H), 4.93 (d, J=16.0 Hz, 1H), 4.32-4.35 (m, 1H), 3.66-3.69 (m, 1H), 3.43-3.50 (m, 1H), 2.96-3.03 (m, 1H), 2.74 (s, 2H), 2.30 (s, 3H), 1.55-1.63 (m, 4H). To a 20 mL vial equipped with a magnetic stirring bar The organic extracts were washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL) The organic extracts were dried over MgSO4 concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC

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

Procedure: A mixture of 1-benzyl-4-(4-fluorobenzyl)-4-hydroxypiperidine (520 mg, 1.7 mmol), 5% Pd/C (150 mg) and EtOH (15 mL) was shaken under H2 (30 psi) for 14 h and filtered. The filtrate was evaporated to give 350 mg (98%) of the title compound as a yellowish oil. 1H NMR (CDCl3), 1.45-1.64 (m, 6H), 2.792 (s, 2H), 2.63-2.96 (m, 4H), 6.97-7.02 (m, 2H), 7.14-7.19 (m, 2H). filtered The filtrate was evaporated

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

Procedure: 2-Chloro-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone was prepared from 4-(4-fluorobenzyl)piperidin-4-ol according to the procedure described for Compound 76 in Example 40.

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

Procedure: The title compound, MS: m/e=450.5 (M+H+), was prepared from 1-(3-bromopropoxy)-4-(benzyloxy)-benzene and 4-(4-fluor-benzyl)-piperidin-4-ol.

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

Procedure: The title compound MS: m/e=448.6 (M+H+) was prepared from 4-(4-fluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.