Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CC1C=CC(S(O)(=O)=O)=CC=1.CN1CCOCC1.[NH:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:36]([C:40](O)=[O:41])[CH:37]([CH3:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:35]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[C@@H:36]([C:40]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:41])[CH:37]([CH3:38])[CH3:39]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Leu-OBzl.TsOH(70g) in dichloromethane(600 ml) was added successively N-methylmorpholine (19.5 ml), Boc-DVal(39 g), HOBT.H2O(27 g) and EDCI.HCl(36 g) under ice cooling. The reaction mixture was stirred under ice cooling for lh and at room temperature for 2 h, diluted with dichloromethane, washed successively with saturated NaHCO3, 10% citric acid, water and saturated NaCl, dried over MgSO4, and filtered. Solvents were rmmoved under reduced pressure to give Boc-DVal-Leu-OBzl (80 g) as a colorless oil. A solution of the oil(80 g) in methanol(400 ml) was added to a suspension of 10% Pd/C (2 g) in methanol(400 ml). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen(under atmospheric pressure) for 12 h. The catalysts were filtered and the filtrate was concentrated under reduced pressure to give Boc-DVal-Leu(63 g) as a colorless oil. To a solution of Boc-nVal-Leu(62 g) in methanol(400 ml) was added water(120 ml) and cesium carbonate(31 g) at room temperature. The resulting mixture was concentrated in vacuo to give cesium salt, which was suspended in DMF(600 ml). To the suspension was added bromoacetophenone(38 g) at room temperature. The mixture was stirred for 1 h and the resulting white precipitate was filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed successively with water, 4% NaHCO3 and water, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude yellow powder. The powder was recrystallized from hexane/EtOAc to give Boc-DVal-Leu-OPac(65 g) as colorless crystals. The crystals(11.3 g) were dissolved in TFA(70 ml) under ice cooling. The solution was stirred under ice cooling for 1 h and concentrated under reduced pressure. The residue was dissolved in dichloromethane(120 ml). To the solution was added successively N-methylmorpholine (7.8 ml), Boc-Pro(5.95 g), HOBT.H2O(4.34 g) and EDCI.HCl (6.00 g) under ice cooling. The reaction mixture was stirred under ice cooling for 1 h and at room temperature for 2 h, diluted with dichloromethane, washed successively with saturated NaHCO3, 10% citric acid, water and saturated NaCl, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give Boc-Pro-DVal-Leu-OPac(11.2 g) as a pale yellow, amorphous solid. The tripeptide(11.2 g) was dissolved in TFA (70 ml) under ice cooling. The solution was stirred under ice cooling for 30 min and concentrated under reduced pressure. The residue was dissolved in dichloromethane. N-Methylmorpholine(7.2 ml), Boc-DAsp(OBzl)(6.92 g), HOBT.H2O(3.14 g) and EDCI.HCl (4.31 g) was added to the dichloromethane solution under ice cooling and the resulting mixture was stirred under ice cooling for 1 h and at room temperature for 2 h, saturated NaHCO3, 10% citric acid, water and saturated NaCl, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give Boc-DAsp(OBzl)-Pro-DVal-Leu-OPac(13.8 g) as a yellow oil. The oil(13.8 g) was dissolved in TFA(60 ml) under ice cooling. The solution was stirred under ice cooling for 30 min and concentrated under reduced pressure. The residue was dissolved in dichloromethane(100 ml). To the solution was added N-methylmorpholine(6.8 ml), Boc-DTrp(8.86 g), HOBT.H2O(2.95 g) and EDCI.HCl(3.87 g) under ice cooling. The reaction mixtue was stirred under ice cooling for 1 h and at room temperature for 5 h, diluted with dichloromethane, washed successively with saturated NaHCO3, 10% citric acid, water and saturated NaCl, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel(WAKOGEL C-200) with chloroform/methanol(30/1) for elution to give Boc-DTrp-nAsp(OBzl)-Pro-DVal-Leu-OPac(16.1 g) as a colorless, amorphous solid. To a solution of the solid (16.1 g) in 90% acetic acid(400 ml) was added by portions zinc powder(30 g) under ice cooling and the mixture was stirred under ice cooling for 50 min and at room temperature for 30 min. The supernatant of the reaction mixture was separated from zinc dust by decantation and concentrated under reduced pressure. The residue was partitioned between 10% citric acid and EtOAc and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residual oil, which was triturated with petroleum ether. The resulting amorphous solid was dried in vacuo and dissolved in formic acid(200 ml) at room temperature. The reaction mixture was stirred at room temperture for 1.5 h and concentrated under reduced pressure. The residue was partitioned between water and chloroform. The aqueous phase was extracted with chloroform. The combined chloroform layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ether to give DTrp-DAsp(OBzl)-Pro-DVal-Leu(13.6 g) as a pale yellow powder. A solution of the pentapeptide(13.3 g) in DMF (400 ml) was added dropwise over a period of 7 h to a solution of HOBT H2O(4.13 g) and EDCI HCl(5.17 g) in DMF (800 ml) at room temperature. The reaction mixture was stirred at room temperature for 10.5 h, and concentrated in vacuo. The residue was purified by column chromatography on silica gel(WAKOGEL C-300) with dichloromethane/methanol(50/1→30/1) for elution to give cyclo(-DTrp-DAsp(OBzl)-Pro-DVal-Leu-)(7.20 g) as a pale yellow powder. A solution of the powder(5.89 g) in methanol(20 ml) was added to a suspension of 10% Pd/C (1.2 g) in methanol(100 ml). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen(under atmospheric pressure) for 20 h. The catalysts were filtered off and the filtrate was concentrated under reduced pressure. The residual powder was purified by reverse-phase column chromatography (NACALAI TESQUE, COSMOSIL 75 C18 -OPN) with methanol/water(1/1→2/1) for elution to give cyclo (-DTrp-DAsp-Pro-Val-Leu-)(4.30 g) as a colorless powder. To a solution of the powder(5.01 g) in methanol(10 ml) was added dropwise an aqueous solution of NaHCO3 (689 mg) at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methanol to give the title compound (4.4 g) as colorless crystals.