Methyl (S)-2-(Boc-aMino)-4-broMobutyrate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure

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

Procedure: (S)-4-Bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (0.10 g, 0.34 mmol) (prepared as in Example 120, Steps A-D) and piperidine (1 mL) were heated to 50° C. for 16 hours and then cooled to room temperature and concentrated under reduced pressure. The residue was azeotroped with toluene (3×10 mL) and then chromatographed eluting with MeOH/dichloromethane (1:9) to provide 93 mg of colorless oil (97% yield). concentrated under reduced pressure The residue was azeotroped with toluene (3×10 mL) chromatographed eluting with MeOH/dichloromethane (1:9)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester (27.5 g, 93 mmol) in THF (100 mL) in a pressure reaction vessel was added triethylamine (26 mL) and dimethylamine (93 mL of 2.0 M in THF). The reaction vessel was sealed and heated to 60° C. for 16 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in dichloromethane (500 mL). The solution was washed with water (3×200 mL) and brine (200 mL), dried over MgSO4, filtered through Celite and concentrated under reduced pressure. The residue was dried under high vacuum to afford 23.4 g of yellow oil (97% yield). The reaction vessel was sealed cooled to room temperature The reaction mixture was concentrated under reduced pressure dissolved in dichloromethane (500 mL) The solution was washed with water (3×200 mL) and brine (200 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The residue was dried under high vacuum

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

Procedure: To a cooled (0° C.) solution of (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester (28.7 g, 123 mmol) in dichloromethane (500 mL) was added CBr4 (51.0 g, 154 mmol). The mixture was stirred for 5 minutes before the portion-wise addition of triphenylphosphine (48.41 g, 185 mmol). The mixture continued to stir at 0° C. for 1 hour and was then allowed to warm to room temperature. The solvent was removed under reduced pressure and was then diluted with ether (500 mL) and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed eluting with ether/hexanes (1:2) to afford 27.5 g of white solid (76% yield). to warm to room temperature The solvent was removed under reduced pressure was then diluted with ether (500 mL) stirred for 30 minutes The mixture was filtered the filtrate was concentrated under reduced pressure The residue was chromatographed eluting with ether/hexanes (1:2)

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

Procedure: (S)-4-Bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (0.10 g, 0.34 mmol) (prepared as in Example 120, Steps A-D) and piperidine (1 mL) were heated to 50° C. for 16 hours and then cooled to room temperature and concentrated under reduced pressure. The residue was azeotroped with toluene (3×10 mL) and then chromatographed eluting with MeOH/dichloromethane (1:9) to provide 93 mg of colorless oil (97% yield). concentrated under reduced pressure The residue was azeotroped with toluene (3×10 mL) chromatographed eluting with MeOH/dichloromethane (1:9)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (27.5 g, 93 mmol) in THF (100 mL) in a pressure reaction vessel was added triethylamine (26 mL) and dimethylamine (93 mL of 2.0 M in THF). The reaction vessel was sealed and heated to 60° C. for 16 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in dichloromethane (500 mL). The solution was washed with water (3×200 mL) and brine (200 mL), dried over MgSO4, filtered through Celite and concentrated under reduced pressure. The residue was dried under high vacuum to afford 23.4 g of yellow oil (97% yield). The reaction vessel was sealed cooled to room temperature The reaction mixture was concentrated under reduced pressure dissolved in dichloromethane (500 mL) The solution was washed with water (3×200 mL) and brine (200 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The residue was dried under high vacuum

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure

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

Procedure: (S)-4-Bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (0.10 g, 0.34 mmol) (prepared as in Example 120, Steps A-D) and piperidine (1 mL) were heated to 50° C. for 16 hours and then cooled to room temperature and concentrated under reduced pressure. The residue was azeotroped with toluene (3×10 mL) and then chromatographed eluting with MeOH/dichloromethane (1:9) to provide 93 mg of colorless oil (97% yield). concentrated under reduced pressure The residue was azeotroped with toluene (3×10 mL) chromatographed eluting with MeOH/dichloromethane (1:9)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester (27.5 g, 93 mmol) in THF (100 mL) in a pressure reaction vessel was added triethylamine (26 mL) and dimethylamine (93 mL of 2.0 M in THF). The reaction vessel was sealed and heated to 60° C. for 16 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in dichloromethane (500 mL). The solution was washed with water (3×200 mL) and brine (200 mL), dried over MgSO4, filtered through Celite and concentrated under reduced pressure. The residue was dried under high vacuum to afford 23.4 g of yellow oil (97% yield). The reaction vessel was sealed cooled to room temperature The reaction mixture was concentrated under reduced pressure dissolved in dichloromethane (500 mL) The solution was washed with water (3×200 mL) and brine (200 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The residue was dried under high vacuum

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

Procedure: To a cooled (0° C.) solution of (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester (28.7 g, 123 mmol) in dichloromethane (500 mL) was added CBr4 (51.0 g, 154 mmol). The mixture was stirred for 5 minutes before the portion-wise addition of triphenylphosphine (48.41 g, 185 mmol). The mixture continued to stir at 0° C. for 1 hour and was then allowed to warm to room temperature. The solvent was removed under reduced pressure and was then diluted with ether (500 mL) and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed eluting with ether/hexanes (1:2) to afford 27.5 g of white solid (76% yield). to warm to room temperature The solvent was removed under reduced pressure was then diluted with ether (500 mL) stirred for 30 minutes The mixture was filtered the filtrate was concentrated under reduced pressure The residue was chromatographed eluting with ether/hexanes (1:2)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure