1-chloro-2-(isocyanatomethyl)benzene

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

Procedure: To a solution of crude (2S,4R)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1-carboxylate in MeOH was added HCl (4 N in dioxane). The reaction was stirred at rt for 1 h and concentrated. The residue was dissolved in THF (10 mL). To this solution were added DIEA (469 μL, 2.7 mmol) and 2-chlorobenzylisocyanate. The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in 10 ml of 20% piperidine in DCM. The reaction mixture was stirred at rt for 15 min, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (210 mg, 53% for 4 steps). LRMS (M+H+) m/z 431.1. concentrated The residue was dissolved in THF (10 mL) The mixture was stirred at rt for 1 h concentrated The residue was dissolved in 10 ml of 20% piperidine in DCM The reaction mixture was stirred at rt for 15 min concentrated purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 2,2′-azanediyldiethanol (1.58 g, 15 mmol) in DMF (5 mL) was added 2-chlorobenzylisocyanate (1.26 g, 7.5 mmol). The reaction mixture was stirred at rt for 30 min. The mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (1.3 g, 65%). LRMS (M+H+) m/z 272.1. The mixture was purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 2,2′-azanediyldiethanol (1.58 g, 15 mmol) in DMF (5 mL) was added 2-chlorobenzylisocyanate (1.26 g, 7.5 mmol). The reaction mixture was stirred at rt for 30 min. The mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (1.3 g, 65%). LRMS (M+H+) m/z 272.1. The mixture was purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 2-(methylamino)ethanol (600 mg, 7.99 mmol) in THF (5.0 mL) was added 2-chlorobenzylisocyanate (0.75 mL, 6.66 mmol). The reaction was stirred at rt for 30 min. The mixture was concentrated, re-dissolved in MeOH, filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (950 mg, 49%). LRMS (M+H+) m/z 243.0. The mixture was concentrated re-dissolved in MeOH filtered purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of (S)-pyrrolidin-2-ylmethanol (110 mg, 1.1 mmol) in THF (2.0 mL) was added 2-chlorobenzyl-isocyanate (167 mg, 1.0 mmol). The reaction mixture was stirred for 1 h and concentrated under reduced pressure to give (S)—N-(2-chlorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide as an oil (277 mg), which was used without further purification. LRMS (M+H+) m/z 269.0. concentrated under reduced pressure

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

Procedure: To a solution of (S)-pyrrolidin-2-ylmethanol (110 mg, 1.1 mmol) in THF (2.0 mL) was added 2-chlorobenzyl-isocyanate (167 mg, 1.0 mmol). The reaction mixture was stirred for 1 h and concentrated under reduced pressure to give (S)—N-(2-chlorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide as an oil (277 mg), which was used without further purification. LRMS (M+H+) m/z 269.0. concentrated under reduced pressure

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

Procedure: To a solution of 2-chlorobenzylisocyanate (125.6 mg, 0.75 mmol) in DMF (1.0 ml), 2-hydroxy-4-cyanoaniline (100 mg, 0.75 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel (50% Ethyl acetate/Hexane) gave desired product (80 mg, 58.8%). EI-MS m/z 302.8 (M+).

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

Procedure: To a solution of 2-chlorobenzylamine (1.0 g, 7.06 mmol) in a mixture of CH2Cl2 and H2O (10 mL/10 mL), triphosgene (838 mg, 2.82 mmol) and NaHCO3 (1.78 g, 21.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was partitioned between CH2Cl2 and water. The combined organic layers are dried over MgSO4 and filtered. The solvent was evaporated to give the desired product (1.1 g, 93%). EI-MS m/z 168.7 (M+). were added Then the reaction mixture was partitioned between CH2Cl2 and water The combined organic layers are dried over MgSO4 filtered The solvent was evaporated

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

Procedure: To a solution of 2-chlorobenzylamine (1.0 g, 7.06 mmol) in a mixture of CH2Cl2 and H2O (10 mL/10 mL), triphosgene (838 mg, 2.82 mmol) and NaHCO3 (1.78 g, 21.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was partitioned between CH2Cl2 and water. The combined organic layers are dried over MgSO4 and filtered. The solvent was evaporated to give the desired product (1.1 g, 93%). EI-MS m/z 168.7 (M+). were added Then the reaction mixture was partitioned between CH2Cl2 and water The combined organic layers are dried over MgSO4 filtered The solvent was evaporated

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

Procedure: To a solution of crude (2S,4R)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1-carboxylate in MeOH was added HCl (4 N in dioxane). The reaction was stirred at rt for 1 h and concentrated. The residue was dissolved in THF (10 mL). To this solution were added DIEA (469 μL, 2.7 mmol) and 2-chlorobenzylisocyanate. The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in 10 ml of 20% piperidine in DCM. The reaction mixture was stirred at rt for 15 min, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (210 mg, 53% for 4 steps). LRMS (M+H+) m/z 431.1. concentrated The residue was dissolved in THF (10 mL) The mixture was stirred at rt for 1 h concentrated The residue was dissolved in 10 ml of 20% piperidine in DCM The reaction mixture was stirred at rt for 15 min concentrated purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 2,2′-azanediyldiethanol (1.58 g, 15 mmol) in DMF (5 mL) was added 2-chlorobenzylisocyanate (1.26 g, 7.5 mmol). The reaction mixture was stirred at rt for 30 min. The mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (1.3 g, 65%). LRMS (M+H+) m/z 272.1. The mixture was purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 2-(methylamino)ethanol (600 mg, 7.99 mmol) in THF (5.0 mL) was added 2-chlorobenzylisocyanate (0.75 mL, 6.66 mmol). The reaction was stirred at rt for 30 min. The mixture was concentrated, re-dissolved in MeOH, filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (950 mg, 49%). LRMS (M+H+) m/z 243.0. The mixture was concentrated re-dissolved in MeOH filtered purified on RP-HPLC a mixture of acetonitrile and H2O