(2R)-6-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid

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

Procedure: A solution of N-α-Boc-D-lysine 12 (1.00 g, 4.06 mmol) in CH2Cl2 (20 mL) and MeOH (5.0 mL) was charged with TMS-diazomethane [(CH3)3SiCHN2 0.6 M solution in hexane, 13.5 mL, 8.12 mmol] at 0° C. and stirred at the same temperature for 1 h and at room temperature for another 1 h. The solvent was removed under reduced pressure to afford crude product 14 (1.04 g, crude) as a yellow oil, which was directly used for the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 4.12-4.05 (m, 1H), 3.70 (s, 3H), 2.62 (t, J=7.0 Hz, 2H), 1.82-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.54-1.32 (m, 4H), 1.43 (s, 9H). The solvent was removed under reduced pressure

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

Procedure: A solution of N-α-Boc-D-lysine 12 (10.0 g, 40.6 mmol) in CH2Cl2 (200 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (11.3 g, 36.6 mmol) and triethylamine (11.0 mL, 81.3 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (300 mL), 1 N HCl was added to adjust the pH to 5-6, and the mixture was extracted with CH2Cl2 (500 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 8 (18.5 g, 94%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.13-4.03 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.91-1.77 (m, 1H), 1.74-1.55 (m, 3H), 1.52 (s, 9H), 1.51-1.38 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H). The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) the solvent was removed under reduced pressure The residue was dissolved in 1 N NaOH (300 mL) 1 N HCl was added the mixture was extracted with CH2Cl2 (500 ml) The CH2Cl2 layer was separated the aqueous layer was extracted with CH2Cl2 (2×250 mL) The combined organic layers were dried over Na2SO4 filtered concentrated

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

Procedure: A solution of N-α-Boc-D-lysine 12 (10.0 g, 40.6 mmol) in CH2Cl2 (200 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (11.3 g, 36.6 mmol) and triethylamine (11.0 mL, 81.3 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (300 mL), 1 N HCl was added to adjust the pH to 5-6, and the mixture was extracted with CH2Cl2 (500 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 8 (18.5 g, 94%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.13-4.03 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.91-1.77 (m, 1H), 1.74-1.55 (m, 3H), 1.52 (s, 9H), 1.51-1.38 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H). The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) the solvent was removed under reduced pressure The residue was dissolved in 1 N NaOH (300 mL) 1 N HCl was added the mixture was extracted with CH2Cl2 (500 ml) The CH2Cl2 layer was separated the aqueous layer was extracted with CH2Cl2 (2×250 mL) The combined organic layers were dried over Na2SO4 filtered concentrated

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

Procedure: The pyrazole acid, prepared by coupling methyl ester 85 (Procedure 26) with 2-chlorobenzoyl chloride (21) followed by hydrolysis and bromination as shown in Procedure 8, was coupled to (R)-3-tert-butoxycarbonylaminoazepane-1-carboxylic acid benzyl ester (prepared as described in Procedure 23 using Boc-D-Lys-OH (Bachem, A-2705) followed by Cbz protection of the piperidine amine using the method of Procedure 30) using Procedure 3. Removal of the Cbz group using the method of Procedure 20 afforded the title compound. followed by hydrolysis and bromination prepared Removal of the Cbz group

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

Procedure: A solution of N-α-Boc-D-lysine 12 (1.00 g, 4.06 mmol) in CH2Cl2 (20 mL) and MeOH (5.0 mL) was charged with TMS-diazomethane [(CH3)3SiCHN2 0.6 M solution in hexane, 13.5 mL, 8.12 mmol] at 0° C. and stirred at the same temperature for 1 h and at room temperature for another 1 h. The solvent was removed under reduced pressure to afford crude product 14 (1.04 g, crude) as a yellow oil, which was directly used for the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 4.12-4.05 (m, 1H), 3.70 (s, 3H), 2.62 (t, J=7.0 Hz, 2H), 1.82-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.54-1.32 (m, 4H), 1.43 (s, 9H). The solvent was removed under reduced pressure

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

Procedure: A solution of N-α-Boc-D-lysine 12 (10.0 g, 40.6 mmol) in CH2Cl2 (200 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (11.3 g, 36.6 mmol) and triethylamine (11.0 mL, 81.3 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (300 mL), 1 N HCl was added to adjust the pH to 5-6, and the mixture was extracted with CH2Cl2 (500 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 8 (18.5 g, 94%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.13-4.03 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.91-1.77 (m, 1H), 1.74-1.55 (m, 3H), 1.52 (s, 9H), 1.51-1.38 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H). The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) the solvent was removed under reduced pressure The residue was dissolved in 1 N NaOH (300 mL) 1 N HCl was added the mixture was extracted with CH2Cl2 (500 ml) The CH2Cl2 layer was separated the aqueous layer was extracted with CH2Cl2 (2×250 mL) The combined organic layers were dried over Na2SO4 filtered concentrated