(2R)-3-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid

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

Procedure: (R)-tert-Butyl3-cyclohexyl-1-(3,5-dibromopyrazin-2-ylamino)-1-oxopropan-2-ylcarbamate. (R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropanoic acid (1.00 g, 3.69 mmol), 1,1′-carbonyldiimidazole (896 mg, 5.53 mmol), dichloromethane (3 mL), and DMF (1 mL) were combined in a scintillation vial and stirred 3.75 h at room temperature under nitrogen. 3,5-Dibromopyrazin-2-amine (1.86 g, 7.37 mmol) was added and the resulting mixture sealed and heated 21 h at 40° C., then 22.5 h at 50° C. Diisopropylethylamine (1.3 mL, 7.37 mmol) was added and the resulting mixture sealed and heated at 45° C. with stirring overnight. The dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The resulting suspension was filtered through Celite and the filter cake washed thoroughly with ethyl acetate. Brine was added to the filtrate and the resulting two layers separated in a separatory funnel. The organics were washed with water, then brine, and concentrated on a rotary evaporator. The residue was dissolved in methanol, filtered, and purified using reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Vials containing product were combined and neutralized with saturated aqueous sodium bicarbonate. Acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under vacuum to give the desired product (616 mg, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (s, 1H), 7.14 (d, J=8.20, 1H), 4.26 (q, J=7.81, 1H), 1.77 (d, J=12.49, 1H), 1.58-1.72 (m, 5H), 1.51-1.57 (m, 2H), 1.38 (s, 9H), 1.07-1.25 (m, 3H), 0.80-0.98 (m, 2H); MS (ESI) m/z 507 [M+1]+. the resulting mixture sealed heated 21 h at 40° C. 22.5 h at 50° C the resulting mixture sealed heated at 45° C. with stirring overnight The dichloromethane was removed on a rotary evaporator The resulting mixture was diluted with ethyl acetate and water shaken in a separatory funnel The resulting suspension was filtered through Celite the filter cake washed thoroughly with ethyl acetate Brine was added to the filtrate the resulting two layers separated in a separatory funnel The organics were washed with water brine, and concentrated on a rotary evaporator The residue was dissolved in methanol filtered purified reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Vials containing product Acetonitrile was removed on a rotary evaporator the resulting aqueous mixture extracted with ethyl acetate The organics were washed with brine dried over magnesium sulfate filtered concentrated on a rotary evaporator dried under vacuum

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

Procedure: A solution of Boc-D-Cha-OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L-Pro-OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combined filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder. After stirring an additional 3 h between 0° C. and 10° C. the mixture was filtered over diatomaceous earth The filter cake was rinsed with dichloromethane (100 mL) then the combined filtrates were concentrated in vacuo The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL) The layers were separated the organic phase was washed with 0.625M aq. NaHCO3 (80 mL) The combined bicarbonate extracts were then washed with ethyl acetate (100 mL) The aqueous phase was then stirred with ethyl acetate (300 mL) The layers were separated the acidic aqueous phase was extracted with ethyl acetate (100 mL) The combined ethyl acetate extracts were concentrated in vacuo filtered washed again with ethyl acetate dried

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

Procedure: (R)-tert-Butyl 3-cyclohexyl-1-(3,5-dibromopyrazin-2-ylamino)-1-oxopropan-2-ylcarbamate. (R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropanoic acid (1.00 g, 3.69 mmol), 1,1′-carbonyldiimidazole (896 mg, 5.53 mmol), dichloromethane (3 mL), and DMF (1 mL) were combined in a scintillation vial and stirred 3.75 h at room temperature under nitrogen. 3,5-Dibromopyrazin-2-amine (1.86 g, 7.37 mmol) was added and the resulting mixture sealed and heated 21 h at 40° C., then 22.5 h at 50° C. Diisopropylethylamine (1.3 mL, 7.37 mmol) was added and the resulting mixture sealed and heated at 45° C. with stirring overnight. The dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The resulting suspension was filtered through Celite and the filter cake washed thoroughly with ethyl acetate. Brine was added to the filtrate and the resulting two layers separated in a separatory funnel. The organics were washed with water, then brine, and concentrated on a rotary evaporator. The residue was dissolved in methanol, filtered, and purified using reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Vials containing product were combined and neutralized with saturated aqueous sodium bicarbonate. Acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under vacuum to give the desired product (616 mg, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (s, 1H), 7.14 (d, J=8.20, 1H), 4.26 (q, J=7.81, 1H), 1.77 (d, J=12.49, 1H), 1.58-1.72 (m, 5H), 1.51-1.57 (m, 2H), 1.38 (s, 9H), 1.07-1.25 (m, 3H), 0.80-0.98 (m, 2H); MS (ESI) m/z 507 [M+1]+. the resulting mixture sealed heated 21 h at 40° C. 22.5 h at 50° C the resulting mixture sealed heated at 45° C. with stirring overnight The dichloromethane was removed on a rotary evaporator The resulting mixture was diluted with ethyl acetate and water shaken in a separatory funnel The resulting suspension was filtered through Celite the filter cake washed thoroughly with ethyl acetate Brine was added to the filtrate the resulting two layers separated in a separatory funnel The organics were washed with water brine, and concentrated on a rotary evaporator The residue was dissolved in methanol filtered purified reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Vials containing product Acetonitrile was removed on a rotary evaporator the resulting aqueous mixture extracted with ethyl acetate The organics were washed with brine dried over magnesium sulfate filtered concentrated on a rotary evaporator dried under vacuum

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

Procedure: (R)-tert-Butyl 3-cyclohexyl-1-(3,5-dibromopyrazin-2-ylamino)-1-oxopropan-2-ylcarbamate. (R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropanoic acid (1.00 g, 3.69 mmol), 1,1′-carbonyldiimidazole (896 mg, 5.53 mmol), dichloromethane (3 mL), and DMF (1 mL) were combined in a scintillation vial and stirred 3.75 h at room temperature under nitrogen. 3,5-Dibromopyrazin-2-amine (1.86 g, 7.37 mmol) was added and the resulting mixture sealed and heated 21 h at 40° C., then 22.5 h at 50° C. Diisopropylethylamine (1.3 mL, 7.37 mmol) was added and the resulting mixture sealed and heated at 45° C. with stirring overnight. The dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The resulting suspension was filtered through Celite and the filter cake washed thoroughly with ethyl acetate. Brine was added to the filtrate and the resulting two layers separated in a separatory funnel. The organics were washed with water, then brine, and concentrated on a rotary evaporator. The residue was dissolved in methanol, filtered, and purified using reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Vials containing product were combined and neutralized with saturated aqueous sodium bicarbonate. Acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under vacuum to give the desired product (616 mg, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (s, 1H), 7.14 (d, J=8.20, 1H), 4.26 (q, J=7.81, 1H), 1.77 (d, J=12.49, 1H), 1.58-1.72 (m, 5H), 1.51-1.57 (m, 2H), 1.38 (s, 9H), 1.07-1.25 (m, 3H), 0.80-0.98 (m, 2H); MS (ESI) m/z 507 [M+1]+. the resulting mixture sealed heated 21 h at 40° C. 22.5 h at 50° C the resulting mixture sealed heated at 45° C. with stirring overnight The dichloromethane was removed on a rotary evaporator The resulting mixture was diluted with ethyl acetate and water shaken in a separatory funnel The resulting suspension was filtered through Celite the filter cake washed thoroughly with ethyl acetate Brine was added to the filtrate the resulting two layers separated in a separatory funnel The organics were washed with water brine, and concentrated on a rotary evaporator The residue was dissolved in methanol filtered purified reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Vials containing product Acetonitrile was removed on a rotary evaporator the resulting aqueous mixture extracted with ethyl acetate The organics were washed with brine dried over magnesium sulfate filtered concentrated on a rotary evaporator dried under vacuum

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

Procedure: A solution of Boc-D-Cha-OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L-Pro-OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combine filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder. After stirring an additional 3 h between 0° C. and 10° C. the mixture was filtered over diatomaceous earth The filter cake was rinsed with dichloromethane (100 mL) then the combine filtrates were concentrated in vacuo The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL) The layers were separated the organic phase was washed with 0.625M aq. NaHCO3 (80 mL) The combined bicarbonate extracts were then washed with ethyl acetate (100 mL) The aqueous phase was then stirred with ethyl acetate (300 mL) The layers were separated the acidic aqueous phase was extracted with ethyl acetate (100 mL) The combined ethyl acetate extracts were concentrated in vacuo filtered washed again with ethyl acetate dried

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

Procedure: A solution of Boc-D-Cha-OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L-Pro-OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combine filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder. After stirring an additional 3 h between 0° C. and 10° C. the mixture was filtered over diatomaceous earth The filter cake was rinsed with dichloromethane (100 mL) then the combine filtrates were concentrated in vacuo The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL) The layers were separated the organic phase was washed with 0.625M aq. NaHCO3 (80 mL) The combined bicarbonate extracts were then washed with ethyl acetate (100 mL) The aqueous phase was then stirred with ethyl acetate (300 mL) The layers were separated the acidic aqueous phase was extracted with ethyl acetate (100 mL) The combined ethyl acetate extracts were concentrated in vacuo filtered washed again with ethyl acetate dried

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

Procedure: (R)-tert-Butyl3-cyclohexyl-1-(3,5-dibromopyrazin-2-ylamino)-1-oxopropan-2-ylcarbamate. (R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropanoic acid (1.00 g, 3.69 mmol), 1,1′-carbonyldiimidazole (896 mg, 5.53 mmol), dichloromethane (3 mL), and DMF (1 mL) were combined in a scintillation vial and stirred 3.75 h at room temperature under nitrogen. 3,5-Dibromopyrazin-2-amine (1.86 g, 7.37 mmol) was added and the resulting mixture sealed and heated 21 h at 40° C., then 22.5 h at 50° C. Diisopropylethylamine (1.3 mL, 7.37 mmol) was added and the resulting mixture sealed and heated at 45° C. with stirring overnight. The dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The resulting suspension was filtered through Celite and the filter cake washed thoroughly with ethyl acetate. Brine was added to the filtrate and the resulting two layers separated in a separatory funnel. The organics were washed with water, then brine, and concentrated on a rotary evaporator. The residue was dissolved in methanol, filtered, and purified using reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Vials containing product were combined and neutralized with saturated aqueous sodium bicarbonate. Acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under vacuum to give the desired product (616 mg, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (s, 1H), 7.14 (d, J=8.20, 1H), 4.26 (q, J=7.81, 1H), 1.77 (d, J=12.49, 1H), 1.58-1.72 (m, 5H), 1.51-1.57 (m, 2H), 1.38 (s, 9H), 1.07-1.25 (m, 3H), 0.80-0.98 (m, 2H); MS (ESI) m/z 507 [M+1]+. the resulting mixture sealed heated 21 h at 40° C. 22.5 h at 50° C the resulting mixture sealed heated at 45° C. with stirring overnight The dichloromethane was removed on a rotary evaporator The resulting mixture was diluted with ethyl acetate and water shaken in a separatory funnel The resulting suspension was filtered through Celite the filter cake washed thoroughly with ethyl acetate Brine was added to the filtrate the resulting two layers separated in a separatory funnel The organics were washed with water brine, and concentrated on a rotary evaporator The residue was dissolved in methanol filtered purified reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Vials containing product Acetonitrile was removed on a rotary evaporator the resulting aqueous mixture extracted with ethyl acetate The organics were washed with brine dried over magnesium sulfate filtered concentrated on a rotary evaporator dried under vacuum

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

Procedure: (R)-tert-Butyl3-cyclohexyl-1-(3,5-dibromopyrazin-2-ylamino)-1-oxopropan-2-ylcarbamate. (R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropanoic acid (1.00 g, 3.69 mmol), 1,1′-carbonyldiimidazole (896 mg, 5.53 mmol), dichloromethane (3 mL), and DMF (1 mL) were combined in a scintillation vial and stirred 3.75 h at room temperature under nitrogen. 3,5-Dibromopyrazin-2-amine (1.86 g, 7.37 mmol) was added and the resulting mixture sealed and heated 21 h at 40° C., then 22.5 h at 50° C. Diisopropylethylamine (1.3 mL, 7.37 mmol) was added and the resulting mixture sealed and heated at 45° C. with stirring overnight. The dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The resulting suspension was filtered through Celite and the filter cake washed thoroughly with ethyl acetate. Brine was added to the filtrate and the resulting two layers separated in a separatory funnel. The organics were washed with water, then brine, and concentrated on a rotary evaporator. The residue was dissolved in methanol, filtered, and purified using reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Vials containing product were combined and neutralized with saturated aqueous sodium bicarbonate. Acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under vacuum to give the desired product (616 mg, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (s, 1H), 7.14 (d, J=8.20, 1H), 4.26 (q, J=7.81, 1H), 1.77 (d, J=12.49, 1H), 1.58-1.72 (m, 5H), 1.51-1.57 (m, 2H), 1.38 (s, 9H), 1.07-1.25 (m, 3H), 0.80-0.98 (m, 2H); MS (ESI) m/z 507 [M+1]+. the resulting mixture sealed heated 21 h at 40° C. 22.5 h at 50° C the resulting mixture sealed heated at 45° C. with stirring overnight The dichloromethane was removed on a rotary evaporator The resulting mixture was diluted with ethyl acetate and water shaken in a separatory funnel The resulting suspension was filtered through Celite the filter cake washed thoroughly with ethyl acetate Brine was added to the filtrate the resulting two layers separated in a separatory funnel The organics were washed with water brine, and concentrated on a rotary evaporator The residue was dissolved in methanol filtered purified reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Vials containing product Acetonitrile was removed on a rotary evaporator the resulting aqueous mixture extracted with ethyl acetate The organics were washed with brine dried over magnesium sulfate filtered concentrated on a rotary evaporator dried under vacuum

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

Procedure: A solution of Boc-D-Cha-OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L-Pro-OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combined filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder. After stirring an additional 3 h between 0° C. and 10° C. the mixture was filtered over diatomaceous earth The filter cake was rinsed with dichloromethane (100 mL) then the combined filtrates were concentrated in vacuo The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL) The layers were separated the organic phase was washed with 0.625M aq. NaHCO3 (80 mL) The combined bicarbonate extracts were then washed with ethyl acetate (100 mL) The aqueous phase was then stirred with ethyl acetate (300 mL) The layers were separated the acidic aqueous phase was extracted with ethyl acetate (100 mL) The combined ethyl acetate extracts were concentrated in vacuo filtered washed again with ethyl acetate dried

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

Procedure: A solution of Boc-D-Cha-OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L-Pro-OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combined filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder. After stirring an additional 3 h between 0° C. and 10° C. the mixture was filtered over diatomaceous earth The filter cake was rinsed with dichloromethane (100 mL) then the combined filtrates were concentrated in vacuo The residual oil was partitioned between ethyl acetate (100 mL) and 0.625M aqueous NaHCO3 (320 mL) The layers were separated the organic phase was washed with 0.625M aq. NaHCO3 (80 mL) The combined bicarbonate extracts were then washed with ethyl acetate (100 mL) The aqueous phase was then stirred with ethyl acetate (300 mL) The layers were separated the acidic aqueous phase was extracted with ethyl acetate (100 mL) The combined ethyl acetate extracts were concentrated in vacuo filtered washed again with ethyl acetate dried

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

Procedure: Boc-D-Cha-Pro-OBzl was prepared according a similar manner as described in example 1 using Boc-D-Cha and Pro-OBzl.

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

Procedure: To a solution of N-Boc-β-cyclohexyl-D-alanine (1.00 g, 3.69 mmol) and HOBt hydrate (0.678 g, 4.43 mmol) in DMF (10 mL), EDC (0.850 g, 4.43 mmol) was added. The mixture was stirred for 60 min. Then conc. NH4OH (1.00 mL, ˜14.0 mmol) was added. It was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-3-cyclohexyl-1-oxopropan-2-ylcarbamate as a white solid (0.917 g). It was stirred for 18 h The organic phase was separated washed with 5% NaHCO3 dried over Na2SO4 concentrated in vacuo