tert-butyl N-carbamothioylcarbamate

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

Procedure: N-tert-butoxycarbonyl-thiourea (0.600 g, 3.40 mmole) was suspended in ethanol (5 mL) and the mixture was cooled in an ice-water bath. To this mixture was added a solution of bromo-thioacetic acid S-ethyl ester (0.880 g [75% pure]; 3.61 mmole) in ethanol (5 mL). Following completion of the addition, the mixture was warmed to room temperature and stirred overnight. After 20 hours, the reaction was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was washed with water and brine. The aqueous phases were then backwashed with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes, to give (4-ethylsulfanyl-thiazol-2yl)-carbamic acid tert-butyl ester (0.514 g, 58%). the mixture was cooled in an ice-water bath completion of the addition After 20 hours the reaction was concentrated The residue was partitioned between methylene chloride and water The organic phase was washed with water and brine dried over sodium sulfate concentrated The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes

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

Procedure: N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, prepared according to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth. Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled in an ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582 mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.; Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol (7.0 mL) was added dropwise over 3 minutes. The suspension turned homogeneous at the end of the addition, the bath was removed, and the reaction was stirred at room temperature. The solvent was removed, and the crude material was partitioned between dichloromethane and water. The organics were washed with water and brine. The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to an orange glass (stench). The crude material was adsorbed onto ca. 5 g silica gel with ethyl acetate, and flushed through a plug of silica gel with hexanes (discarded) followed by 9:1 hexanes:ethyl acetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%) as a colorless solid. cooled in an ice bath The suspension turned homogeneous at the end of the addition the bath was removed The solvent was removed the crude material was partitioned between dichloromethane and water The organics were washed with water and brine The combined aqueous layers were back-extracted with dichloromethane the combined organics were dried with anhydrous MgSO4 filtered concentrated in vacuo to an orange glass (stench) flushed through a plug of silica gel with hexanes (discarded) The eluent was evaporated in vacuo

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

Procedure: To a solution of Intermediate VII (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with NaHCO3 (3 g) and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptane, 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid. stirred for 15 min The solids were removed by filtration the filtrate was concentrated in vacuo

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

Procedure: To a solution of Intermediate VII (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with NaHCO3 (3 g) and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptane, 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid. stirred for 15 min The solids were removed by filtration the filtrate was concentrated in vacuo

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

Procedure: N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, prepared according to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth. Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled in an ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582 mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.; Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol (7.0 mL) was added dropwise over 3 minutes. The suspension turned homogeneous at the end of the addition, the bath was removed, and the reaction was stirred at room temperature. The solvent was removed, and the crude material was partitioned between dichloromethane and water. The organics were washed with water and brine. The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to an orange glass (stench). The crude material was adsorbed onto ca. 5 g silica gel with ethyl acetate, and flushed through a plug of silica gel with hexanes (discarded) followed by 9:1 hexanes:ethyl acetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%) as a colorless solid. cooled in an ice bath The suspension turned homogeneous at the end of the addition the bath was removed The solvent was removed the crude material was partitioned between dichloromethane and water The organics were washed with water and brine The combined aqueous layers were back-extracted with dichloromethane the combined organics were dried with anhydrous MgSO4 filtered concentrated in vacuo to an orange glass (stench) flushed through a plug of silica gel with hexanes (discarded) The eluent was evaporated in vacuo

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

Procedure: N-tert-butoxycarbonyl-thiourea (0.600 g, 3.40 mmole) was suspended in ethanol (5 mL) and the mixture was cooled in an ice-water bath. To this mixture was added a solution of bromo-thioacetic acid S-ethyl ester (0.880 g [75% pure]; 3.61 mmole) in ethanol (5 mL). Following completion of the addition, the mixture was warmed to room temperature and stirred overnight. After 20 hours, the reaction was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was washed with water and brine. The aqueous phases were then backwashed with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes, to give (4-ethylsulfanyl-thiazol-2yl)-carbamic acid tert-butyl ester (0.514 g, 58%). the mixture was cooled in an ice-water bath completion of the addition After 20 hours the reaction was concentrated The residue was partitioned between methylene chloride and water The organic phase was washed with water and brine dried over sodium sulfate concentrated The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes

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

Procedure: N-tert-butoxycarbonyl-thiourea (0.600 g, 3.40 mmole) was suspended in ethanol (5 mL) and the mixture was cooled in an ice-water bath. To this mixture was added a solution of bromo-thioacetic acid S-ethyl ester (0.880 g [75% pure]; 3.61 mmole) in ethanol (5 mL). Following completion of the addition, the mixture was warmed to room temperature and stirred overnight. After 20 hours, the reaction was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was washed with water and brine. The aqueous phases were then backwashed with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes, to give (4-ethylsulfanyl-thiazol-2yl)-carbamic acid tert-butyl ester (0.514 g, 58%). the mixture was cooled in an ice-water bath completion of the addition After 20 hours the reaction was concentrated The residue was partitioned between methylene chloride and water The organic phase was washed with water and brine dried over sodium sulfate concentrated The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes

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

Procedure: To a solution of N-Boc-thiourea (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with 3 g of NaHCO3 and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptanes 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid. stirred for 15 min The solids were removed by filtration the filtrate was concentrated in vacuo

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

Procedure: N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, prepared according to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth. Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled in an ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582 mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.; Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol (7.0 mL) was added dropwise over 3 minutes. The suspension turned homogeneous at the end of the addition, the bath was removed, and the reaction was stirred at room temperature. The solvent was removed, and the crude material was partitioned between dichloromethane and water. The organics were washed with water and brine. The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to an orange glass (stench). The crude material was adsorbed onto ca. 5 g silica gel with ethyl acetate, and flushed through a plug of silica gel with hexanes (discarded) followed by 9:1 hexanes:ethyl acetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%) as a colorless solid. cooled in an ice bath The suspension turned homogeneous at the end of the addition the bath was removed The solvent was removed the crude material was partitioned between dichloromethane and water The organics were washed with water and brine The combined aqueous layers were back-extracted with dichloromethane the combined organics were dried with anhydrous MgSO4 filtered concentrated in vacuo to an orange glass (stench) flushed through a plug of silica gel with hexanes (discarded) The eluent was evaporated in vacuo

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

Procedure: N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, prepared according to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth. Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled in an ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582 mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.; Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol (7.0 mL) was added dropwise over 3 minutes. The suspension turned homogeneous at the end of the addition, the bath was removed, and the reaction was stirred at room temperature. The solvent was removed, and the crude material was partitioned between dichloromethane and water. The organics were washed with water and brine. The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to an orange glass (stench). The crude material was adsorbed onto ca. 5 g silica gel with ethyl acetate, and flushed through a plug of silica gel with hexanes (discarded) followed by 9:1 hexanes:ethyl acetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%) as a colorless solid. cooled in an ice bath The suspension turned homogeneous at the end of the addition the bath was removed The solvent was removed the crude material was partitioned between dichloromethane and water The organics were washed with water and brine The combined aqueous layers were back-extracted with dichloromethane the combined organics were dried with anhydrous MgSO4 filtered concentrated in vacuo to an orange glass (stench) flushed through a plug of silica gel with hexanes (discarded) The eluent was evaporated in vacuo

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

Procedure: To a solution of Intermediate VII (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with NaHCO3 (3 g) and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptane, 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid. stirred for 15 min The solids were removed by filtration the filtrate was concentrated in vacuo

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

Procedure: N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, prepared according to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth. Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled in an ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582 mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.; Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol (7.0 mL) was added dropwise over 3 minutes. The suspension turned homogeneous at the end of the addition, the bath was removed, and the reaction was stirred at room temperature. The solvent was removed, and the crude material was partitioned between dichloromethane and water. The organics were washed with water and brine. The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to an orange glass (stench). The crude material was adsorbed onto ca. 5 g silica gel with ethyl acetate, and flushed through a plug of silica gel with hexanes (discarded) followed by 9:1 hexanes:ethyl acetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%) as a colorless solid. cooled in an ice bath The suspension turned homogeneous at the end of the addition the bath was removed The solvent was removed the crude material was partitioned between dichloromethane and water The organics were washed with water and brine The combined aqueous layers were back-extracted with dichloromethane the combined organics were dried with anhydrous MgSO4 filtered concentrated in vacuo to an orange glass (stench) flushed through a plug of silica gel with hexanes (discarded) The eluent was evaporated in vacuo