1-(2,6-dichlorophenyl)propan-1-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 solution of 2,6-dichlorobenzaldehyde (880 mg, 5.03 mmol) in THF (10 mL) was added EtMgCl/THF (2.0 M, 3 mL, 6.0 mmol) at 0° C. under nitrogen, the resulting mixture was allowed to warm to rt and stirred at rt overnight. The mixture was quenched with sat. aq. NH4Cl (5 mL) at 0° C., then diluted with Et2O (50 mL), the organic phase was washed with brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex:EtOAc=80:20) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.00 (t, J=7.4 Hz, 3H), 1.95-2.11 (m, 2H), 2.82 (d, J=10.4 Hz, 1H, —OH), 5.34 (m, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 2H.) The mixture was quenched with sat. aq. NH4Cl (5 mL) at 0° C. diluted with Et2O (50 mL) the organic phase was washed with brine (20 mL) dried over anhydrous sodium sulfate The residue was purified by silica gel chromatography (Hex:EtOAc=80:20)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: General procedure AA: To a mixture of 4-[4-(7-hydroxy-6-nitrofuro[3,2-c]pyridine-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.047 mmol), 1-(2,6-dichlorophenyl)propan-1-ol (28.6 mg, 0.14 mmol), triphenylphosphine (24.4 mg, 0.093 mmol) and THF (2 mL) at rt was added diisopropyl azodicarboxylate (37.7 mg, 0.186 mmol) dropwise, and the solution was flushed with nitrogen and heated to 50° C. for 4 h. The solvents were removed in vacuo, and the material was redissolved in EtOH (3 mL). Iron powder (30 mg, 0.5 mmol) and 5 drops of conc. HCl were added, and the solution was refluxed for 30 min. The solution was directly passed through a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The crude product was concentrated in vacuo, redissolved MeOH (1 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.06 (t, J=7.5 Hz, 3H), 1.93-2.05 (m, 2H), 2.09-2.17 (m, 2H), 2.33 (dt, J=13.7, 7.5 Hz, 1H), 2.48 (dd, J=14.3, 6.9 Hz, 1H), 2.78 (td, J=12.7, 2.7 Hz, 2H), 3.16-3.24 (m, 2H), 4.35 (tt, J=11.7, 4.1 Hz, 1H), 6.43 (t, J=7.5 Hz, 1H), 7.20-7.26 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.80 (s, 1H), 7.83 (s, 1H), 8.09 (s, 1H), 8.13 (s, 1H). MS (ES+): m/z 498.06/500.05 (100/72) [MH+]. HPLC: tR=2.65 min (ZQ3, polar—5 min). the solution was flushed with nitrogen The solvents were removed in vacuo the material was redissolved in EtOH (3 mL) the solution was refluxed for 30 min washed with MeOH The crude product was concentrated in vacuo redissolved MeOH (1 mL) purified via HPLC The fractions containing the pure product were concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: General procedure AA: To a mixture of 4-[4-(7-hydroxy-6-nitrofuro[3,2-c]pyridine-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.047 mmol), 1-(2,6-dichlorophenyl)propan-1-ol (28.6 mg, 0.14 mmol), triphenylphosphine (24.4 mg, 0.093 mmol) and THF (2 mL) at rt was added diisopropyl azodicarboxylate (37.7 mg, 0.186 mmol) dropwise, and the solution was flushed with nitrogen and heated to 50° C. for 4 h. The solvents were removed in vacuo, and the material was redissolved in EtOH (3 mL). Iron powder (30 mg, 0.5 mmol) and 5 drops of conc. HCl were added, and the solution was refluxed for 30 min. The solution was directly passed through a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The crude product was concentrated in vacuo, redissolved MeOH (1 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.06 (t, J=7.5 Hz, 3H), 1.93-2.05 (m, 2H), 2.09-2.17 (m, 2H), 2.33 (dt, J=13.7, 7.5 Hz, 1H), 2.48 (dd, J=14.3, 6.9 Hz, 1H), 2.78 (td, J=12.7, 2.7 Hz, 2H), 3.16-3.24 (m, 2H), 4.35 (tt, J=11.7, 4.1 Hz, 1H), 6.43 (t, J=7.5 Hz, 1H), 7.20-7.26 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.80 (s, 1H), 7.83 (s, 1H), 8.09 (s, 1H), 8.13 (s, 1H). MS (ES+): m/z 498.06/500.05 (100/72) [MH+]. HPLC: tR=2.65 min (ZQ3, polar—5 min). the solution was flushed with nitrogen The solvents were removed in vacuo the material was redissolved in EtOH (3 mL) the solution was refluxed for 30 min washed with MeOH The crude product was concentrated in vacuo redissolved MeOH (1 mL) purified via HPLC The fractions containing the pure product were concentrated in vacuo

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

Procedure: 1,3-Dichloro-2-[1-(4-nitrophenoxy)propyl]benzene was prepared according to the method described in Example 20f but from 0.236 g of sodium hydride (at 60% in the oil), 1.1 g of 1-(2,6-dichlorophenyl)propan-1-ol and 0.832 g of 1-fluoro-4-nitrobenzene. We thus obtain 1.18 g of 1,3-dichloro-2-[1-(4-nitrophenoxy)propyl]benzene in the form of a colorless oil which crystallizes, having the following characteristics: We thus obtain 1.18 g of 1,3-dichloro-2-[1-(4-nitrophenoxy)propyl]benzene in the form of a colorless oil which crystallizes

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

Procedure: To a solution of 2,6-dichlorobenzaldehyde (880 mg, 5.03 mmol) in THF (10 mL) was added EtMgCl/THF (2.0 M, 3 mL, 6.0 mmol) at 0° C. under nitrogen, the resulting mixture was allowed to warm to rt and stirred at rt overnight. The mixture was quenched with sat. aq. NH4Cl (5 mL) at 0° C., then diluted with Et2O (50 mL), the organic phase was washed with brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex:EtOAc=80:20) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.00 (t, J=7.4 Hz, 3H), 1.95-2.11 (m, 2H), 2.82 (d, J=10.4 Hz, 1H, —OH), 5.34 (m, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 2H.) The mixture was quenched with sat. aq. NH4Cl (5 mL) at 0° C. diluted with Et2O (50 mL) the organic phase was washed with brine (20 mL) dried over anhydrous sodium sulfate The residue was purified by silica gel chromatography (Hex:EtOAc=80:20)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: General procedure AA: To a mixture of 4-[4-(7-hydroxy-6-nitrofuro[3,2-c]pyridine-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.047 mmol), 1-(2,6-dichlorophenyl)propan-1-ol (28.6 mg, 0.14 mmol), triphenylphosphine (24.4 mg, 0.093 mmol) and THF (2 mL) at rt was added diisopropyl azodicarboxylate (37.7 mg, 0.186 mmol) dropwise, and the solution was flushed with nitrogen and heated to 50° C. for 4 h. The solvents were removed in vacuo, and the material was redissolved in EtOH (3 mL). Iron powder (30 mg, 0.5 mmol) and 5 drops of conc. HCl were added, and the solution was refluxed for 30 min. The solution was directly passed through a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The crude product was concentrated in vacuo, redissolved MeOH (1 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.06 (t, J=7.5 Hz, 3H), 1.93-2.05 (m, 2H), 2.09-2.17 (m, 2H), 2.33 (dt, J=13.7, 7.5 Hz, 1H), 2.48 (dd, J=14.3, 6.9 Hz, 1H), 2.78 (td, J=12.7, 2.7 Hz, 2H), 3.16-3.24 (m, 2H), 4.35 (tt, J=11.7, 4.1 Hz, 1H), 6.43 (t, J=7.5 Hz, 1H), 7.20-7.26 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.80 (s, 1H), 7.83 (s, 1H), 8.09 (s, 1H), 8.13 (s, 1H). MS (ES+): m/z 498.06/500.05 (100/72) [MH+]. HPLC: tR=2.65 min (ZQ3, polar—5 min). the solution was flushed with nitrogen The solvents were removed in vacuo the material was redissolved in EtOH (3 mL) the solution was refluxed for 30 min washed with MeOH The crude product was concentrated in vacuo redissolved MeOH (1 mL) purified via HPLC The fractions containing the pure product were concentrated in vacuo