(2S)-N,N-dimethylpyrrolidine-2-carboxamide;hydrochloride

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

Procedure: To the subtitle product of step i) (5.0 g) was added hydrochloric acid (20 ml, 4M). The mixture was stirred at room temperature for 3 h before the solvent was evaporated to afford the subtitle compound as a colourless solid. Yield: 3.50 g was evaporated

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

Procedure: To a solution of the subtitle product of step ii) (3.70 g) in dioxane (50 ml) was added triethylamine (2.02 g) and sulfamide (9.96 g). The mixture was heated at reflux for 3 days before the reaction mixture was cooled, filtered and washed with methanol (50 ml). The solvent was evaporated and the residue purified by column chromatography (2% methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.70 g. The mixture was heated at reflux for 3 days before the reaction mixture was cooled filtered washed with methanol (50 ml) The solvent was evaporated the residue purified by column chromatography (2% methanol/EtOAc)

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

Procedure: To a solution of the subtitle product of step ii) (3.70 g) in dioxane (50 ml) was added triethylamine (2.02 g) and sulfamide (9.96 g). The mixture was heated at reflux for 3 days before the reaction mixture was cooled, filtered and washed with methanol (50 ml). The solvent was evaporated and the residue purified by column chromatography (2% methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.70 g. The mixture was heated at reflux for 3 days before the reaction mixture was cooled filtered washed with methanol (50 ml) The solvent was evaporated the residue purified by column chromatography (2% methanol/EtOAc)

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

Procedure: To the subtitle product of step i) (5.0 g) was added hydrochloric acid (20 ml, 4M). The mixture was stirred at room temperature for 3 h before the solvent was evaporated to afford the subtitle compound as a colourless solid. Yield: 3.50 g was evaporated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the compound obtained in Step 2 (200 mg) in dichloromethane (6 mL) were added (2S)-2-(N,N-dimethylaminocarbonyl)pyrrolidine hydrochloride and diisopropylethylamine (0.27 ml) at 5° C. The mixture was stirred at 5° C. for 10 min. Then sodium triacetoxyborohydride (327 mg) was added, and the mixture was stirred for 3 hrs. aq. NH4Cl was added, and the mixture was extracted with dichloromethane. The organic layer was dried over MgSO4. The layer was concentrated under reduced pressure. The resulting crude mixture was purified by silica gel column chlomatography with mixed solvent (dichloromethane/methanol=15/1) as an eluent to give tert-butyl(4-{2-[2-(acetylamino)-5-({(2S)-2-[(N,N-dimethylamino)carbonyl]-1-pyrrolidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate as a pale yellow amorphous substance. the mixture was stirred for 3 hrs the mixture was extracted with dichloromethane The organic layer was dried over MgSO4 The layer was concentrated under reduced pressure The resulting crude mixture was purified by silica gel column chlomatography with mixed solvent (dichloromethane/methanol=15/1) as an eluent

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

Procedure: To a solution of the crude product containing N,N-dimethyl-L-prolinamide hydrochloride obtained in B) (10.5 g) and triethylamine (13.6 g) in ethanol (100 mL) was added 4-thioxothiazolidin-2-one (6.0 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.3 g). the solvent was evaporated under reduced pressure the suspension was filtered through celite pad and silica gel pad The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (NH, ethyl acetate)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the compound obtained in Step 2 (200 mg) in dichloromethane (6 mL) were added (2S)-2-(N,N-dimethylaminocarbonyl)pyrrolidine hydrochloride and diisopropylethylamine (0.27 ml) at 5° C. The mixture was stirred at 5° C. for 10 min. Then sodium triacetoxyborohydride (327 mg) was added, and the mixture was stirred for 3 hrs. aq. NH4Cl was added, and the mixuture was extracted with dichloromethane. The organic layer was dried over MgSO4. The layer was concentrated under reduced pressure. The resulting crude mixture was purified by silica gel column chlomatography with mixed solvent (dichloromethane/methanol=15/1) as an eluent to give tert-butyl (4-{2-[2-(acetylamino)-5-({(2S)-2-[(N,N-dimethylamino)carbonyl]-1-pyrrolidinyl}methyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate as a pale yellow amorphous substance. the mixture was stirred for 3 hrs the mixuture was extracted with dichloromethane The organic layer was dried over MgSO4 The layer was concentrated under reduced pressure The resulting crude mixture was purified by silica gel column chlomatography with mixed solvent (dichloromethane/methanol=15/1) as an eluent

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

Procedure: To a solution of the subtitle product of step ii) (3.70 g) in dioxane (50 ml) was added triethylamine (2.02 g) and sulfamide (9.96 g). The mixture was heated at reflux for 3 days before the reaction mixture was cooled, filtered and washed with methanol (50 ml). The solvent was evaporated and the residue purified by column chromatography (2% methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.70 g. The mixture was heated at reflux for 3 days before the reaction mixture was cooled filtered washed with methanol (50 ml) The solvent was evaporated the residue purified by column chromatography (2% methanol/EtOAc)

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

Procedure: To the subtitle product of step i) (5.0 g) was added hydrochloric acid (20 ml, 4M). The mixture was stirred at room temperature for 3 h before the solvent was evaporated to afford the subtitle compound as a colourless solid. Yield: 3.50 g was evaporated