(2S)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid

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

Procedure: Following a procedure analogous to that for the synthesis of Compound D, (S)-2-((S)-2-amino-3,3-dimethylbutanoyl)-7-nitro-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2.17 g, 4.67 mmol) and (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Advanced ChemTech, 0.95 g, 4.67 mmol) were converted to the title compound (2.93 g, 97%). MS (ESI+) m/z 650.5 (M+H)+.

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

Procedure: To a solution of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Chem-Impex, 2.49 g, 12.3 mmol) in DMF (20 mL) at 0° C. were added EDC (2.94 g, 15.3 mmol), HOAt (2.09 g, 15.3 mmol) and NMM (2.81 mL, 25.6 mmol). The reaction mixture was stirred at ice bath temperature for 20 min, and then treated with a solution of (9H-fluoren-9-yl)methyl ((3S,5S)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)carbamate (6.45 g, 10.2 mmol) in DMF (5 mL). The reaction mixture was stirred at rt for 2 h and then cold water (200 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2Cl2 (200 mL). The organic solution was washed with sat. aq. NaHCO3 solution, 5% aq. citric acid solution and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash column chromatography (gradient elution from 10 to 40% EtOAc in CH2Cl2) provided the title compound (6.14 g, 77%) as a light tan solid. MS (ESI+) m/z 780.5 (M+H)+. The reaction mixture was stirred at rt for 2 h The solid that formed was collected by filtration washed with cold water (100 mL) The solid was dissolved in CH2Cl2 (200 mL) The organic solution was washed with sat. aq. NaHCO3 solution, 5% aq. citric acid solution and brine dried over MgSO4 filtered The filtrate was concentrated in vacuo The residue was dissolved in CH2Cl2 purified by flash column chromatography (gradient elution from 10 to 40% EtOAc in CH2Cl2)

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

Procedure: To a 0° C. solution of (S)-methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (966 mg, 2.02 mmol) and (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Advanced ChemTech, 411 mg, 2.02 mmol) in DMF (20 mL) was added EDC (465 mg, 2.43 mmol), followed by HOAt (330 mg, 2.43 mmol). NMM (667 μl, 6.07 mmol) was then added, and the resulting reaction mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 4 h. The reaction mixture was then poured into a separatory funnel containing EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with 1N HCl (2×) and 10% LiCl, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (1.34 g, 2.02 mmol, 100%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 663.3 (M+H)+. the resulting reaction mixture warmed to room temperature stirred for 4 h The reaction mixture was then poured into a separatory funnel The aqueous layer was extracted with EtOAc (3×) The combined organic extracts were washed with 1N HCl (2×) and 10% LiCl dried over MgSO4 filtered concentrated in vacuo

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

Procedure: The title compound of Example 1 was treated with trifluoroacetic acid using the general procedure A to deprotect the BOC group. The resulting trifluoroacetic acid salt was coupled to Boc-N-Me-Ala-OH using the general procedure D to prepare the title compound of Example 2. 1H NMR (CDCl3): consistent with proposed structure.

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

Procedure: In a similar manner to that described for Example 36 Step 1 except 4 equivalents of DIEA were used, (2S,3S)-3-amino-2-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (58 mg, 0.155 mmol) and (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (31.5 mg, 155 μmol) were converted to a material which was purified by silica gel chromatography to afford methyl-[(S)-1-((6S,7S)-6-methyl-8-oxo-2-trifluoromethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (52 mg, 75%) was purified by silica gel chromatography

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

Procedure: A mixture of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (1.60 g, 5.23 mmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.06 g, 5.23 mmol, Eq: 1.00), HOBT (801 mg, 5.23 mmol, Eq: 1.00), HBTU (1.98 g, 5.23 mmol, Eq: 1.00) at 0° C. and DIEA (2.03 g, 2.73 mL, 15.7 mmol, Eq: 3.00) in DMF (50 mL) was stirred at 0° C. for 1 h, diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to afford methyl-[(S)-1-((S)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.04 g) which was used without purification. washed with water, brine dried over Na2SO4 filtered concentrated The residue was purified by silica gel chromatography

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

Procedure: 3-Amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride (1.0 g, 5.15 mmol, Eq: 1.00), BOC—N-Me-Ala-OH (1.26 g, 1.62 mmol, Eq: 1.2) and TEA (2.2 mL, 15.45 mmol, Eq: 3.00) were dissolved in DMF (30 mL) and HOBT.H2O (697 mg, 5.14 mmol, Eq: 1.20) and HBTU (2.34 g, 6.18 mmol, Eq: 1.20) were added. After 1 h 20 min. the mixture was diluted with 1 N HCl and extracted with EtOAc. The organic extracts were washed with 1 N NaOH, brine, dried over Na2SO4 and concentrated to afford the title compound (1.66 g, 85% yield) which was used without purification. extracted with EtOAc The organic extracts were washed with 1 N NaOH, brine dried over Na2SO4 concentrated

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

Procedure: A solution of HBTU (43.2 g, 114 mmol, Eq: 1.2) and HOBT.H2O (17.4 g, 114 mmol, Eq: 1.2) in DMF (300 mL) was added to a mixture of 3-amino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one hydrochloride (27 g, 94.8 mmol, Eq: 1.00), BOC-N-Me-Ala-OH (23.1 g, 114 mmol, Eq: 1.2) and TEA (38.4 g, 52.9 mL, 379 mmol, Eq: 4) in DMF (300 mL). After 18 h the mixture was poured into brine (750 mL) and the mixture extracted with EtOAc. The combined extracts were washed with 1:1 sat NaHCO3/brine, brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to afford a mixture of diastereomers (36.2 g) as a light yellow solid. The diastereomers were separated by supercritical fluid chromatography (SFC) using a Daicel AD column (5×25 cm) eluted with 15% MeOH/CO2 at 200 mL/min and 220 nM detection at 100 bar backpressure and 35° C. oven. The first diastereomer eluted from the column afforded the title compound (15.29 g, 37%) as an off-white foam. MS m/z 434.1 (MH+). the mixture extracted with EtOAc The combined extracts were washed with 1:1 dried over Na2SO4 concentrated The residue was purified by flash chromatography to afford a mixture of diastereomers (36.2 g) as a light yellow solid The diastereomers were separated by supercritical fluid chromatography (SFC) eluted with 15% MeOH/CO2 at 200 mL/min and 220 nM detection at 100 bar backpressure and 35° C. oven The first diastereomer eluted from the column

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

Procedure: DIEA (712 mg, 972 μl, 5.51 mmol, Eq: 5.00) was added to a mixture of (S)-methyl 3-amino-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate trifluoroacetate (660 mg, 1.1 mmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (224 mg, 1.1 mmol, Eq: 1.0), HBTU (418 mg, 1.1 mmol, Eq: 1.0) and HOBT.H2O (149 mg, 1.1 mmol, Eq: 1.0) in DMF (12.5 mL) at 0° C. The mixture was warmed to RT, stirred for 1 h, diluted with EtOAc, washed with H2O, brine and dried over Na2SO4. The mixture was filtered and concentrated to afford the title compound (725 mg, 98%) as an off-white foam which was used without purification. at 0° C washed with H2O, brine dried over Na2SO4 The mixture was filtered concentrated

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

Procedure: DIEA (712 mg, 972 μl, 5.51 mmol, Eq: 5.00) was added to a mixture of (S)-methyl 3-amino-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate trifluoroacetate (660 mg, 1.1 mmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (224 mg, 1.1 mmol, Eq: 1.0), HBTU (418 mg, 1.1 mmol, Eq: 1.0) and HOBT.H2O (149 mg, 1.1 mmol, Eq: 1.0) in DMF (12.5 mL) at 0° C. The mixture was warmed to RT, stirred for 1 h, diluted with EtOAc, washed with H2O, brine and dried over Na2SO4. The mixture was filtered and concentrated to afford the title compound (725 mg, 98%) as an off-white foam which was used without purification. at 0° C washed with H2O, brine dried over Na2SO4 The mixture was filtered concentrated

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

Procedure: To a mixture of (S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (500 mg, 1.71 mmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (348 mg, 1.71 mmol, Eq: 1.00), O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (HBTU, 682 mg, 1.8 mmol, Eq: 1.05) and 1-hydroxybenzotriazole hydrate (HOBT120, 243 mg, 1.8 mmol, Eq: 1.05) in DMF (5 mL) was added N,N-diisopropylethylamine (DIEA, 553 mg, 4.28 mmol, Eq: 2.50). The mixture was stirred for 45 min., diluted with 50 mL EtOAc and washed H2O, 2% KHSO4, 5% NaHCO3 and 5% brine. The organic solution was dried over Na2SO4, filtered and concentrated to give the title compound (525 mg, 84%) as a tan foam which was used without purification. washed H2O, 2% KHSO4, 5% NaHCO3 and 5% brine The organic solution was dried over Na2SO4 filtered concentrated

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

Procedure: To a mixture of (S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (500 mg, 1.71 mmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (348 mg, 1.71 mmol, Eq: 1.00), O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (HBTU, 682 mg, 1.8 mmol, Eq: 1.05) and 1-hydroxybenzotriazole hydrate (HOBT120, 243 mg, 1.8 mmol, Eq: 1.05) in DMF (5 mL) was added N,N-diisopropylethylamine (DIEA, 553 mg, 4.28 mmol, Eq: 2.50). The mixture was stirred for 45 min., diluted with 50 mL EtOAc and washed H2O, 2% KHSO4, 5% NaHCO3 and 5% brine. The organic solution was dried over Na2SO4, filtered and concentrated to give the title compound (525 mg, 84%) as a tan foam which was used without purification. washed H2O, 2% KHSO4, 5% NaHCO3 and 5% brine The organic solution was dried over Na2SO4 filtered concentrated