benzyl (2S)-2-amino-3-phenylpropanoate;hydrochloride

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp 170-171° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp 170-171° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: A solution of L-PHENYLALANINE BENZYL ESTER HYDROCHLORIDE (2 g, 6.85 mmol), Z-Phe-OH (2.257 g, 7.54 mmol), DIPEA (2.99 mL, 17.14 mmol) and DCM (100 mL) was treated with 1-HYDROXY-7-AZABENZOTRIAZOLE (1.120 g, 8.23 mmol) and EDC (1.577 g, 8.23 mmol) and stirred at rt for 15 h. The mixture was washed with saturated NaHCO3 (2×100 mL), 1 M HCl (2×50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-benzyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-3-phenylpropanoate (3.2 g, 5.96 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.42-7.11 (m, 21H), 4.96 (d, J=2.0 Hz, 4H), 4.63-4.45 (m, 1H), 4.06-3.91 (m, 2H), 3.34-2.96 (m, 3H), 2.85 (br. s., 4H) The mixture was washed with saturated NaHCO3 (2×100 mL), 1 M HCl (2×50 mL) and brine (50 mL) dried over sodium sulfate concentrated under reduced pressure

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171 ° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. the product was purified by recrystallization from MeOH

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

Procedure: Benzyl (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoate (12.8 g, 36 mmol) was stirred in HCl, 2 M in diethyl ether (90 mL) and HCl, 4 M in dioxane (18 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with hexanes (100 mL) and filtered to collect the title compound (7.98 g, 76%) as a fine white powder. 1H NMR (CD3OD, 400 MHz): δ (ppm) 7.40-7.15 (m, 10H), 5.23 (s, 2H), 4.36-4.31 (m, 1H), 3.26-3.12 (m, 2H). filtered to collect the title compound (7.98 g, 76%) as a fine white powder

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

Procedure: To a solution of acid 124 (319 mg, 0.648 mmol) in DMF (5 mL) at 0° C. was added DIEA (226 μL, 130 mmol) and HBTU (246 mg, 0.648 mmol). After stirring for 15 min at 0° C., L-Phenylalanine benzyl ester hydrochloride (189 mg, 0.648 mmol) was added and stirring was continued while warming to room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with H2O and saturated aqueous NaCl then dried over Na2SO4. The crude product was purified by silica gel chromatography (gradient of 0 to 20% methanol in ethyl acetate) using a Biotage Horizons™ system. Compound 125 was obtained as a colourless liquid (150 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 1.20 (t, J=7.0, 3H), 1.21 (t, J=7.0, 3H), 1.25-1.32 (m, 18H), 1.44 (s, 3H), 1.45 (s, 3H), 1.47 (s, 3H), 1.48 (s, 3H), 2.47-2.67 (m, 12H), 2.87 (bd, J=6.2, 4H), 3.89-4.18 (m, 12H), 5.03 (AB q, J=12.3, 2H), 5.05 (AB q, J=12.3, 2H), 5.88 (bt, J=8.8, 2H), 6.91-6.95 (m, 4H), 7.01 (ddd, J=3.5, 5.2, 8.7, 2H), 7.17-7.23 (m, 10H), 7.31-7.32 (m, 6H), 7.71 (ddd, J=1.8, 8.1, 11.6, 1H), 7.75 (ddd, J=1.8, 8.1, 11.6, 1H), 7.86 (t, J=14.0, 1H), 7.87 (t, J=14.0, 1H): 31P (162 MHz, CDCl3) δ 20.31 (d, J=4.9, 1 P), 20.37 (d, J=4.9, 1 P), 33.93 (bd, J=9.5, 2P). stirring while warming to room temperature overnight washed with H2O and saturated aqueous NaCl then dried over Na2SO4 The crude product was purified by silica gel chromatography (gradient of 0 to 20% methanol in ethyl acetate)

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

Procedure: Benzyl (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoate (12.8 g, 36 mmol) was stirred in HCl, 2 M in diethyl ether (90 mL) and HCl, 4 M in dioxane (18 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with hexanes (100 mL) and filtered to collect the title compound (7.98 g, 76%) as a fine white powder. 1H NMR (CD3OD, 400 MHz): δ (ppm) 7.40-7.15 (m, 10H), 5.23 (s, 2H), 4.36-4.31 (m, 1H), 3.26-3.12 (m, 2H). filtered to collect the title compound (7.98 g, 76%) as a fine white powder