(2-chlorophenyl)methyl carbonochloridate

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: To a solution of 2-chlorobenzyl alcohol (1.0 g, 7.0 mmol) in diethyl ether (15 ml) at 0° C. was added N,N-diisopropylethyl amine (2.4 ml, 14.0 mmol), and phosgene solution in toluene (7.5 ml, 14.0 mmol). The mixture was allowed to warm up to room temperature in 2 h while stirring, then it was filtered. The diethyl ether was removed by rotary evaporator, and the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction. it was filtered The diethyl ether was removed by rotary evaporator the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction

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

Procedure: To a solution of 2-chlorobenzyl alcohol (1.0 g, 7.0 mmol) in diethyl ether (15 ml) at 0° C. was added N,N-diisopropylethyl amine (2.4 ml, 14.0 mmol), and phosgene solution in toluene (7.5 ml, 14.0 mmol). The mixture was allowed to warm up to room temperature in 2 h while stirring, then it was filtered. The diethyl ether was removed by rotary evaporator, and the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction. it was filtered The diethyl ether was removed by rotary evaporator the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction

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

Procedure: To a solution of N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (24 mg, 0.24 mmol) followed by 2-chlorobenzyl carbonochloridate (49 uL, 0.24 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then to the slurry was added NaHCO3 (sat. aq., 10 mL) and ethyl acetate (10 mL). The aqueous layer was separated and the organic layer was washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford 2-Chlorobenzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidine-1-carboxylate (35 mg, 38%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.43 (m, 2H), 1.56-1.64 (m, 1H), 1.69-1.74 (b, 2H), 2.14-2.35 (m, 3H), 2.56-2.68 (m, 2H), 2.86-2.88 (m, 3H), 4.01-4.06 (m, 4H), 4.40-4.42 (m, 1H), 5.16 (s, 2H), 6.50 (d, J=7.5 Hz, 2H), 7.18-7.22 (m, 4H), 7.30-7.34 (r, 2H), 7.50 (t, J=8.1 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 8.03 (s, 1H). MS m/z: 567 (M+1). The reaction mixture was concentrated under reduced pressure to the slurry was added NaHCO3 (sat. aq., 10 mL) and ethyl acetate (10 mL) The aqueous layer was separated the organic layer was washed with brine (10 mL) The organic layer was dried over Na2SO4 filtered concentrated

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

Procedure: To a solution of N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (24 mg, 0.24 mmol) followed by 2-chlorobenzyl carbonochloridate (49 uL, 0.24 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then to the slurry was added NaHCO3 (sat. aq., 10 mL) and ethyl acetate (10 mL). The aqueous layer was separated and the organic layer was washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford 2-Chlorobenzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidine-1-carboxylate (35 mg, 38%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.43 (m, 2H), 1.56-1.64 (m, 1H), 1.69-1.74 (b, 2H), 2.14-2.35 (m, 3H), 2.56-2.68 (m, 2H), 2.86-2.88 (m, 3H), 4.01-4.06 (m, 4H), 4.40-4.42 (m, 1H), 5.16 (s, 2H), 6.50 (d, J=7.5 Hz, 2H), 7.18-7.22 (m, 4H), 7.30-7.34 (r, 2H), 7.50 (t, J=8.1 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 8.03 (s, 1H). MS m/z: 567 (M+1). The reaction mixture was concentrated under reduced pressure to the slurry was added NaHCO3 (sat. aq., 10 mL) and ethyl acetate (10 mL) The aqueous layer was separated the organic layer was washed with brine (10 mL) The organic layer was dried over Na2SO4 filtered concentrated

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

Procedure: To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.103 g, 0.27 mmol) and triethylamine (0.06 mL, 0.40 mmol) in CH2Cl2 (1 mL) was added 2-chlorobenzyl chloroformate (0.06 mL, 0.40 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. the aqueous layer was extracted with CH2Cl2 The combined organic layers were dried over Na2SO4 decanted concentrated the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes)

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

Procedure: To a solution of 2-chlorobenzyl alcohol (1.0 g, 7.0 mmol) in diethyl ether (15 ml) at 0° C. was added N,N-diisopropylethyl amine (2.4 ml, 14.0 mmol), and phosgene solution in toluene (7.5 ml, 14.0 mmol). The mixture was allowed to warm up to room temperature in 2 h while stirring, then it was filtered. The diethyl ether was removed by rotary evaporator, and the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction. it was filtered The diethyl ether was removed by rotary evaporator the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction

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

Procedure: To a solution of 2-chlorobenzyl alcohol (1.0 g, 7.0 mmol) in diethyl ether (15 ml) at 0° C. was added N,N-diisopropylethyl amine (2.4 ml, 14.0 mmol), and phosgene solution in toluene (7.5 ml, 14.0 mmol). The mixture was allowed to warm up to room temperature in 2 h while stirring, then it was filtered. The diethyl ether was removed by rotary evaporator, and the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction. it was filtered The diethyl ether was removed by rotary evaporator the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction

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

Procedure: Following general procedure D (step 2) followed by B, starting from 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-2H-[1,2,3]triazol-4-ylamine and 2-chlorobenzylchloroformate.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl]-2H-[1,2,3]triazol-4-ylamine (93 mg, 0.30 mmol) in CH2Cl2 (5.0 mL) was treated with DIPEA (0.08 mL, 0.48 mmol) followed by 2-chlorobenzylchloroformate (0.06 mL, 0.39 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and water (5.0 mL) was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (9:1 to 1:1 hept-EA) gave the title compound as an orange solid. TLC:rf (1:1 hept-EA)=0.27. LC-MS-conditions 01: tR=1.11 min; [M+H]+=478.01. The layers were separated the aq. layer extracted with CH2Cl2 (2×10 mL) extracts were dried over Na2SO4 filtered the solvent was removed under reduced pressure Purification of the residue by FC (9:1 to 1:1 hept-EA)