Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl-]>ClCCl>[CH3:12][C:10]1([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16][B:8]([C:4]2[CH:3]=[C:2]([NH:1][C:10](=[O:9])[C:13]([CH3:15])=[CH2:14])[CH:7]=[CH:6][CH:5]=2)[O:9]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-aminophenylboronic acid pinacol ester (5.04 g, 23.0 mmol) in dichloromethane (100 mL) was added TEA (6.41 mL, 46.0 mmol). The resulting solution was cooled to 0° C., then methacrolyl chloride (2.70 mL, 27.6 mmol) was added. The cooling bath was removed, and the reaction was allowed to warm to room temperature and stir for approximately 2 hours. The reaction mixture was washed with 7.5% aqueous ammonium chloride (100 mL) and the layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a solid. The solid was triturated with hexanes (50 mL) and isolated by filtration to afford N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide. LRMS (ESI) calcd for C16H22BNO3 [M+H]+: 288, found 288.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([C:13]#[N:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9](=[O:15])[NH:10][C@H:11]([CH3:12])/[C:13](/[NH2:14])=[N:17]/[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C#N)NC(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](NC(=O)OCc1ccccc1)/C(N)=N/O
Temperature: 75 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of benzyl[(1R)-1-cyanoethyl]carbamate (2.52 g, 12.3 mmol) in ethanol (30 ml) was added hydroxylamine hydrochloride salt (0.90 g, 13.0 mmol) and triethylamine (3.43 ml, 24.6 mmol) and the mixture heated to 75° C. After 16 h, the solution was concentrated and the residue was dissolved in 200 mL of dichloromethane. The mixture was washed with 100 mL of saturated aqueous sodium bicarbonate (2×) and brine (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give benzyl[(1R,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (2.9 g). MS 238.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:3]=1[CH2:18]O.[CH:20]1([N:23]2[C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[NH:25][C:24]2=[O:32])[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:3]=1[CH2:18][N:25]1[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[N:23]([CH:20]2[CH2:21][CH2:22]2)[C:24]1=[O:32]
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Reactant: CS(=O)(=O)CCCn1c(CO)c(Br)c2cnccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(Br)c2cnccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol 12 (200 mg, 0.576 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (101 mg, 0.576 mmol) and triphenylphosphine (151 mg, 0.576 mmol) in dry THF (4 ml) was placed under N2 atmosphere. Then diisopropylazodicarboxylate (DIAD) (113 μl, 0.576 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight. The formed solid was filtered off and washed with diethyl ether to give 83 mg of the desired product P17 as a white powder (0.165 mmol, 27.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89-0.98 (m, 2H) 1.03-1.12 (m, 2H) 1.74-1.88 (m, 2H) 2.92 (s, 3H) 3.00 (tt, J=6.84, 3.45 Hz, 1H) 3.07 (t, J=7.30 Hz, 2H) 4.39 (t, J=7.65 Hz, 2H) 5.35 (s, 2H) 7.28 (d, J=5.27 Hz, 1H) 7.62 (d, J=5.77 Hz, 1H) 8.23 (s, 1H) 8.24 (d, J=5.27 Hz, 1H) 8.36 (d, J=6.02 Hz, 1H) 8.75 (s, 1H); m/z=504 (M+H)+, Br pattern.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=O)=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH3:42]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:42])=[O:27])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyloxycarbonyl-isoleucyl-prolyl-proline (4.5 g) is dissolved in a mixture of tetrahydrofuran (30 ml) and triethylamine (1.4 ml). The solution is chilled in a -5° cooling bath and isobutyl chloroformate (1.6 ml) is added. The solution is allowed to warm to room temperature (10 minutes) and concentrated aqueous ammonia (10 ml) is added. After four hours stirring at room temperature, the reaction is concentrated in vacuo, diluted with ethyl acetate and washed sequentially with saturated sodium bicarbonate, water, 0.1 N hydrochloric acid and water. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:24])=[O:26])=[CH:21][CH:22]=3)=[N:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C2=NN(S(=O)(=O)c3ccc(I)cc3)CCC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C2=NN(S(=O)(=O)c3ccc(I)cc3)CCC2)cc1

Procedure:
A solution of 1-(4Iodobenzenesulfonyl)-3-(4-methylthiophenyl)-1,4,5,6-tetrahydropyridazine (1.27 g, 2.69 mmol) in methanol (450 mL) was added to a solution of sodium periodate (0.61 g, 2.82 mmol) in water (6 mL) and stirred at a low heat for 16 hours. The resulting mixture was filtered, concentrated arylphosphonyl dihalide and purified by column chromatography on silica gel using ether/methylene chloride as an eluent to give the title compound as a solid: mp 191°-193° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CS(C)=O>[Cl:15][C:16]1[CH:23]=[C:22]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 75 °C
Reaction time: 39 h
Yield: 100 %

Procedure:
To a suspension of D-allo-threonine (5.08 g, 42.7 mmol) and K2CO3 (10.32 g, 74.7 mmol) in DMSO (50 mL) was added 2-chloro-4-fluorobenzonitrile (5.53 g, 35.5 mmol) at room temperature. The reaction mixture was heated to 75° C. and stirred for 39 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (400 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a brown solid (9.04 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.51 (d, J=8.8 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.83 (dd, J=2.4, 8.8 Hz, 1H), 6.31 (br d, J=7.6 Hz, 1H), 4.28-4.20 (m, 2H), 1.31 (d, J=6.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[O:13]([CH3:15])[Na]>CO>[Cl:12][C:4]1[N:3]=[C:2]([O:13][CH3:15])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: CO[Na]
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CO
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A 5-L, four neck round bottom flask equipped with overhead stirrer, positive pressure nitrogen inlet, 500-mL addition funnel with nitrogen outlet and a thermocouple was charged with 2,6-dichloro-3-nitropyridin-4-amine (150.0 g, 0.72 mol) and MeOH (1.50 L) and the resulting brown suspension was stirred at room temperature. NaOCH3 (25% solution in MeOH, 260 mL, 1.155 mol) was charged to the addition funnel and added over 30 min (the temperature did not exceed 32° C.). The resulting red suspension was stirred for 1 h, then transferred to a 3-L round bottom flask (with MeOH) and evaporated to near dryness on a rotary evaporator. The resulting red sludge was diluted with aqueous ammonium chloride (1.75 L) and extracted with EtOAc (2×900 mL). The combined organics were washed with water (150 mL), the water layer was diluted with brine (100 mL) and back-extracted with EtOAc (100 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure at 60° C. to yield 6-chloro-2-methoxy-3-nitropyridin-4-amine as a yellow solid. 1H NMR (CHLOROFORM-d) δ: 6.36 (s, 1H), 6.14 (br. s., 2H), 4.04 (s, 3H)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([CH3:24])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:16][C:17]1[N:18]=[C:19]([CH3:24])[N:20]=[C:21]([O:1][CH2:2][C@H:3]2[CH2:5][C@@H:4]2[C:6]2[N:11]=[CH:10][C:9]([C:12]([OH:15])([CH3:13])[CH3:14])=[CH:8][CH:7]=2)[CH:22]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(O)c1ccc([C@H]2C[C@@H]2CO)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC[C@H]2C[C@@H]2c2ccc(C(C)(C)O)cn2)n1
Yield: 27.7 %

Procedure:
A solution of compound 8-2 (135 mg, 0.652 mmol) and 4,6-dichloro-2-methylpyrimidine (106.3 mg, 0.65 mmol) in THF (3.0 mL) was treated with Cs2CO3 (281 mg, 0.86 mmol) and heated to reflux for 12 h. The reaction mixture was filtrated and the filtrate was concentrated and purified directly by gradient elution on silica gel (Petroleum ether:ethyl acetate=2:1-1:1) to afford the title compound as a colorless oil (60 mg, 28%). LRMS (ES) calculated M+H for C17H20ClN3O2: 334.12. Found: 334.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(C(O)Cc2ccccc2)ccc1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1cc(C(=O)Cc2ccccc2)ccc1F
Reaction time: 8 h
Yield: 151.3 %

Procedure:
To a solution of 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanol (23.7 g, 40.6 mmol) in acetone (240 mL) was added Jones reagent (64 mL) at rt. The reaction mixture was stirred overnight, quenched by the addition of isopropanol and diluted with EtOAc. The organic portion was washed with 1 N HCl (2×), dried over Na2SO4, filtered and concentrated under reduced pressure to yield the 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanone (15 g, 66% yield). LCMS: RT=3.250 min [M+H] 245.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ ppm 7.62 (dd, J=8, 1 Hz, 1H), 7.60-7.55 (m, 1H), 7.35-7.29 (m, 2H), 7.26-7.23 (m, 3H), 7.10 (dd, J=10, 8 Hz, 1H), 4.24 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[Br:12][CH2:13][C:14](O)=[O:15].O>C1(C)C=CC=CC=1>[Br:12][CH2:13][C:14]([O:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1)=[O:15]
Reactant: O=C(O)CBr
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)CBr)C1

Procedure:
For the first stage, a solution of (−)-menthol (1.56 g, 10 mmol), 2-bromoacetic acid (1.39 g, 10 mmol) and monohydrated p-toluenesulphonic acid (0.5 g, 2.6 mmol) was brought to reflux for 3 h in 100 ml toluene. The water given off during the reaction is separated by azeotropic distillation. 100 ml toluene is added, and the mixture is washed 3 times with 10 ml of a 5% NaOH solution, then twice with 100 ml of brine, the organic solvent is dried on Na2SO4 and the solvent evaporated under vacuum. The menthyl 2-bromoacetate obtained (2.45 g, 89%) is used in the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1[CH2:51]N>>[CH3:37][C@H:36]([NH:35][CH2:34][C:32]1[CH:33]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[CH:29]=[C:30]([F:42])[CH:31]=1)[CH:47]([CH3:51])[CH3:48]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@@H](C)C(C)C)c4)cc23)CC1
Yield: 42 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2S)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.3 mg of the title compound (42%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:15]([O:17]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:16].Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([C:15](=[O:17])[CH3:16])=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8][CH2:7]1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) (1.78 g, 7 mmol), 1-ethoxyvinyltributyltin (EVTB) (3.3 g, 9.12 mmol), bis(triphenylphosphine)paliadium(II)chloride (260 mg, 0.23 mmol) in THF (25 mL) was refluxed for 24 h under argon atmosphere. To the reaction, additional EVTB (1.5 g, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (200 mg, 0.2 mmol) were added and the mixture was and refluxed for an additional 24 h. The reaction mixture was cooled to room temeperature and 10% hydrochloric acid (10 ml) was added. After 10 min, the mixture was extracted with ether (3×50 mL), the combined organic layer was washed with water (10 mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried with magnesium sulfate. Solvent was removed under reduced pressure, and after purification by flash chromatography the title compound was obtained as a white solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccc(F)cc1
Yield: 90.6 %

Procedure:
A mixture of Z-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.73 g, 2.61 mmol) and 10% palladium/carbon (340 mg) in methanol (50 ml) was stirred at room temperature in a hydrogen atmosphere for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=100:10:1) to give Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.25 g, 91%). EI-MS:528 (M+)
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.O>CN(C)C=O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]([CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:10]=1
Reactant: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of N-(3-methylbutyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (500 mg, 1.59 mmol) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (63.6 mg, 1.59 mmol) and the mixture was stirred for 30 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (462 mg, 1.45 mmol) was added and the obtained mixture was stirred at room temperature for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (490 mg, yield 57%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O[CH:40]2[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:40]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[C:16]4[N:10]([CH2:11][CH2:12][O:13][C:14]=3[CH:20]=2)[C:9]2[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:8]=2[C:7]=4[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:41]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(O)ccc1-3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(C(=O)OC(C)(C)C)C2)ccc1-3
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.80 g, 2.04 mmol) in N,N-dimethylformamide (8 ml) were successively added tert-butyl 3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (1.09 g, 3.07 mmol) and potassium carbonate (0.57 g, 4.08 mmol) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to give methyl 3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.68 g). The obtained compound was used for Step 3 without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([NH:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:49][CH2:50][CH3:51])[O:52][CH2:53][CH3:54])[CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:16])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 79 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:50][C:51]1([C:57]2[S:58][CH:59]=[CH:60][C:61]=2[O:62][CH3:63])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N:54]1[CH2:55][CH2:56][C:51]([OH:50])([C:57]2[S:58][CH:59]=[CH:60][C:61]=2[O:62][CH3:63])[CH2:52][CH2:53]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccsc1C1(O)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccsc1C1(O)CCN(C[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
2.513 g (10 mmol) of (S)-(-)-2-(t-Butoxycarbonylamino)-3-phenyl-1-propanol was added at once to a magnetically stirred solution of 2.885 g (11 mmol) triphenylphosphine in tetrahydrofuran (100 mL) at 0° C. Thereafter 1.9 mL (12 mmol) diethyl azodicarboxylate was added dropwise over 3 minutes while the temperature was maintained between 0 and 5° C. This was immediately followed by adding a solution of 2.14 g (10 mmol) of 4-hydroxy-4-(3-methoxy-thiophen-2-yl)-piperidine in 100 mL tetrahydrofuran. The reaction mixture was stirred at ambient temperature overnight, evaporated in vacuo to dryness and the residue flash chromatographed on 300 g silica gel using chloroform as eluant yielding 2.6 g of the title compound as a faintly yellow dense oil.