Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:15]=[CH:14][NH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl.C(OCC)(=O)C>[Cl:16][C:17]1[C:18]([C:19]([C:12]2[NH:13][CH:14]=[CH:15][C:11]=2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:20])=[CH:22][CH:23]=[CH:24][N:25]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: c1ccc(-c2cc[nH]c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)c1[nH]ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Aluminum chloride (1.33 g, 10 mmol) was added to a mixture of 3-phenyl-1H-pyrrole (1.35 g, 9.4 mmol, prepared as described in Journal of Organic Chemistry, 62: 2650 (1997) (incorporated herein by reference) and 2-chloronicotinoyl chloride (1.65 g, 9.4 mmol) in DCM (15 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for one hour. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 0.682 g (26%) of (2-chloro-pyridin-3-yl)-(3-phenyl-1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=[N:3]1.F[P-](F)(F)(F)(F)F.[PH4+].CCN(C(C)C)C(C)C.[NH2:36][C@@H:37]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:60])([F:59])[F:58])[CH2:38][N:39]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]1=[O:49]>C(Cl)Cl>[O:48]=[C:47]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:49])[N:39]1[CH2:38][C@@H:37]([NH:36][C:16]([C:9]1[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:18])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:59])([F:58])[F:60]
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1C(F)(F)F
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C(F)(F)F
Reaction time: 2 h
Yield: 93.6 %

Procedure:
At room temperature, a mixture of 4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylic acid (235 mg, 80% purity, 0.68 mmol), phosphoniumhexafluorophosphate (PyBrOP) (381 mg, 0.19 mmol), DIPEA (0.59 mL, 3.4 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (261 mg, 0.75 mmol) in DCM (5 mL) was stirred for 2 h. The reaction solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (386 mg, 86%) as a white solid: LC-MS (ES) 607 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[Al](Cl)(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:7]=[C:6]2[C:26](=[O:28])[CH3:27]
Reactant: COc1ccc(-n2ccc3cc(OC)ccc32)cc1
Reactant: CC(=O)Cl
Agent: CC[Al](Cl)CC
Solvent: ClCCl
Product: COc1ccc(-n2cc(C(C)=O)c3cc(OC)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared by the method of example 1C, is dissolved in 1 mL of CH2Cl2 at 0° C. Et2AlCl (300 μL, 1M in hexanes, 0.3 mmol) is then added. After stirring at 0° C. for 30 min, a solution of acetyl chloride (22 mL, 0.3 mmol) in 1 mL of CH2Cl2 is added dropwise. This is stirred at 0° C. for a further 90 min. The reaction mixture is quenched with H2O and is extracted with CH2Cl2 and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CH2Cl2 (5/95) yields the title compound as a white solid (42 mg, 71%).
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH2:26][CH2:27][CH2:28][CH3:29])[C:10]1=[O:30])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH2:26]([N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([F:25])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: [H][H]
Reactant: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 106.6 %

Procedure:
Twenty percent Pd/C (70 mg) was added to a solution of 3-benzyloxy-1-butyl-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example O-4, 0.13 g, 0.32 mmol) in 25 mL of THF, and this was shaken under 50 PSI of hydrogen for 17.5 hours. The mixture was filtered and concentrated to give 0.11 g of the title compound as a solid, mp 153-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>>[ClH:1].[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([NH:22][CH2:21][CH2:19][OH:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NCCO
Product: Cl
Product: OCCNc1cc(-c2ccc(Cl)cc2)nc2ccccc12

Procedure:
The title compound, m.p. 262-264° C., and MS: m/e=299.2 (M+H+), was prepared from 4-chloro-2-(4-chloro-phenyl)-quinoline and ethanolamine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:11][C:3]1[C:2]([CH3:1])=[CH:8][C:6]([OH:7])=[C:5]([CH3:9])[C:4]=1[CH3:10])=[O:23]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(O)c(C)c(C)c1OC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask is equipped with a stirring bar and charged with 15.2 g (100 mmol) of trimethylhydroquinone and 23.7 g (3×100 mmol) of pyridine in 100 mL dichloromethane. The solution is stirred at ambient temperature and a solution of 20.8 g (100 mmol) of pivaloyl chloride in 100 mL of dichloromethane is added over 15 minutes. The final solution is stirred at ambient temperature for 48 hours, then washed with 1×100 mL of 3N hydrochloric acid solution, 1×50 mL of 3N hydrochloric acid solution, water, dried (magnesium sulfate) and evaporated leaving 26.6 g (>100%) of a pale yellow solid, mp 88°-112° C. (after drying 24.1 g). Recrystallization from hexane in the presence of charcoal affords the title compound as colorless cubes; mp 119°-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A flame dried flask was charged with methyl 3-amino-2-thiophenecarboxylate (5.0 g, 35.0 mmol), pyridine (2.82 mL, 35.0 mmol), and dry methylene chloride (160 mL). The solution was cooled to 0° C. and 4-tert-butylbenzoyl chloride (6.21 mL, 31.8 mmol) was added. After 1 h, the solvent was removed in vacuo and the remaining material was dissolved in ethyl acetate. The organic phase was washed four times with water and once with brine. The organic phase was then dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel using an eluent of 2% ethyl acetate in hexane and 5% ethyl acetate in hexane to afford the product (9.67 g, 96% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.N([O-])=O.[Na+].[CH3:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24].[NH3:31]>O>[C:1]([NH:4][C:5]1[CH:11]=[CH:10][C:8]([C:19]2[C:18]([CH3:17])=[C:30]([N:31]=[N:4][C:5]3[CH:11]=[CH:10][CH:8]=[CH:7][CH:6]=3)[CH:29]=[CH:28][C:20]=2[N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1cccc(N(CCO)CCO)c1
Reactant: N
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(-c2c(N(CCO)CCO)ccc(N=Nc3ccccc3)c2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.2 mol (30 g) of p-acetamidoaniline, followed by 34 ml of concentrated hydrochloric acid, are added to 100 ml of water containing 300 g of crushed ice. A solution of 15.2 g of sodium nitrite in 30 ml of water is added to the suspension. The solution obtained in this way is added, after being filtered, to an ice-cold solution of 0.2 mol (39 g) of 3-methyl-N,N-bis(β-hydroxyethyl)aniline in 160 g of water containing 34 ml of concentrated hydrochloric acid. After 30 minutes stirring and making alkaline with a 20% ammonia solution, the product is obtained in the form of crystals.
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.Cl.[NH2:30][C@@H:31]([C:33]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])=[O:34])[CH3:32]>CN(C=O)C.C(Cl)CCl>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])=[O:38])=[O:34])[CH3:32])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of Boc-Gly-Ala prepared as in Example 33B (10.2 g, 41.5 mmol) in anhydrous DMF (300 ml), was added HOBT.circle-solid.H2O (6.21 g, 46.0 mmol), EDC.circle-solid.HCl (8.81 g, 46.0 mmol) and DAla-Gly-Gly-OBzl.circle-solid.HCl (13.7 g, 41.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (40 ml). The resulting solution Was extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (100 ml), saturated sodium bicarbonate (100 ml) and brine (100ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and concentrated to half volume. The product crystallized out upon standing at RT for 30 min. Collection of the crystals by filtration and drying at high vacuum afforded 17.4 g (80% yield) of the pure product: 1H NMR (DMSO-d6) δ 1.21 (d, J=7.4 Hz, 3H), 1.23 (d, J=7.3 Hz, 3H), 1.38 (s, 9H), 3.56 (d, J=6.3 Hz, 2H), 3.75 (d, J=5.7 Hz, 2H), 3.93 (d, J=6.0 Hz, 2H), 4.24-4.34 (m, 2H), 5.14 (s, 2H), 6.98 (t, J=5.7 Hz, 1H), 7.34-7.40 (m, 5H), 7.93 (d, J=7.2 Hz, 1H), 8.17-8.24 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]
Reactant: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-tert-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.075 g, 0.13 mol) in dichloromethane (1.5 mL) and the mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (15 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-30% methanol in dichloromethane) to give the title compound as a white solid (0.022, 0.037 mol, 30%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.8 Hz, 1 H), 7.41 (dd, J=0.8, 0.8 Hz, 1 H), 7.15-7.14 (m, 2 H), 7.02 (dd, J=2.4, 9.2 Hz, 1 H), 6.53 (s, 1 H), 6.23 (q, J=7.2 Hz, 1 H), 4.90-4.84 (m, 1 H), 4.58-4.54 (m, 1 H), 4.32-4.28 (m, 1 H), 3.97-3.74 (m, 3 H), 3.56-3.44 (m, 3 H), 3.20-3.16 (m, 1 H), 2.97-2.94 (m, 1 H), 2.85-2.80 (m, 1 H), 2.14 (d, J=6.8 Hz, 3 H), 1.82-1.71 (m, 3 H), 1.47-1.25 (m, 2 H); MS: (ES) m/z calculated for C24H29Cl2N6O [M+H]+ 487.2 found 487.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([NH2:24])=[C:22](I)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:26]([OH:31])[CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:24][C:23]1[C:22]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][OH:31])=[N:21][CH:20]=[N:19][C:18]=1[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: C#CCCCO
Reactant: Nc1c(I)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(C#CCCCO)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
To a solution of N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine (300 mg) and 4-pentyn-1-ol (65 mg) in acetonitrile-triethylamine (6.0 mL-4.5 mL) were added bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and copper(I) iodide (7.3 mg) at room temperature, and the mixture was stirred at room temperature under an argon atmosphere for 24 hrs. 4-Pentyn-1-ol (65 mg), bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and copper(I) iodide (7.3 mg) were added to the reaction system and the mixture was stirred at 60° C. for 2 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate→methanol:ethyl acetate=1:19) to give the title compound (157.2 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[NH:17][C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34].O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[N:17]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[CH2:32][CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)c(NC(=O)CCCCCNC(=O)OCc2ccccc2)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(=O)CCCCCNC(=O)OCc1ccccc1)c1cc(C#N)ccc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound (961 mg) obtained in Example 48-1 was dissolved in DMF (20 ml). After having been cooled to 0° C., the solution was added with 60% sodium hydride (72.9 mg) and warmed back to room temperature and the whole was stirred for 30 minutes. 1-Iodopropane (0.30 ml) was dropped to the solution and the whole was stirred for additional 3 hours. After having been cooled to 0° C., the solution was added with water to stop the reaction and concentrated. The residue was subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (317 mg) as a yellow oily substance.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20]CC2C=CC=CC=2)[C@H:10]1[O:28]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl>C(Cl)Cl>[OH:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][OH:20])[C@H:10]1[OH:28]
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)C[C@@H]2O1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)hexahydrobenzo[d]oxazol-2(3H)-one (7.35 g, 15.5 mmol) in DCM (80 mL) at −78° C. was added a solution of BCl3 in DCM (1.0 M, 53 mL, 53 mmol). The mixture was slowly warmed up to 0° C. and stirred at this temperature for 4 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (50 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 5%-15% MeOH in DCM to give (3aR,4R,5R,6R,7aS)-4,5-dihydroxy-6-(hydroxymethyl)-hexahydrobenzo[d]oxazol-2(3H)-one (2.99 g, 95%) as a white solid. 1H NMR (400 MHz, MeOD) δ 4.68-4.71 (m, 1H), 3.72 (dd, J=10.8 Hz, 3.4 Hz, 1H), 3.64 (dd, J=10.8 Hz, 5.2 Hz, 1H), 3.46 (t, J=7.2 Hz, 1H), 3.32 (t, J=8.7 Hz, 1H), 3.19 (t, J=9.4 Hz, 1H), 2.17-2.25 (m, 1H), 1.64-1.75 (m, 2H).
Reaction SMILES: C(OC(=O)C[C@@H](N1C=CC(C2C=CC=CC=2)=C1)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([NH:69][C:70](OC(C)(C)C)=O)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])=[O:48])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CO[CH:80]1[CH:84]([C:85]2[CH:90]=[CH:89][C:88]([C:91]3[CH:96]=[CH:95][N:94]=[CH:93][CH:92]=3)=[CH:87][CH:86]=2)[CH2:83]C(OC)O1.CO.C(Cl)Cl>ClCCCl>[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([N:69]1[CH:70]=[CH:83][C:84]([C:85]2[CH:90]=[CH:89][C:88]([C:91]3[CH:96]=[CH:95][N:94]=[CH:93][CH:92]=3)=[CH:87][CH:86]=2)=[CH:80]1)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:54])=[O:48])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1
Reactant: COC1CC(c2ccc(-c3ccncc3)cc2)C(OC)O1
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: O=C(C[C@H](C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Yield: 56 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, N-(2-benzyloxycarbonyloxy-1(S)-phenyl-ethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester and 2,5-dimethoxy-3-(4-pyridin4-yl-phenyl)-tetrahydrofuran (prepared as described in Example 5(a)) were condensed in wet 1,2-dichloroethane at 80-90° C. after 18 hours. Flash column chromatagraphy with 4% MeOH/CH2Cl2 as eluant gave 140 mg (56%) of N-(2-benzyloxycarbonyloxy-1(S)-phenylethyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a yellow solid, mp 138-40° C. 1H NMR (CDCl3): δ 8.66 (bs, 2H), 7.60 (s, 5H), 7.50 (d, 3H, J=5.3 Hz), 7.34-7.22 (m, 10H), 7.19 (d, 1H, J=2.2 Hz), 7.17 (d, 1H, J=1.9 Hz), 7.09 (t, 1H, J=1.9 Hz), 6.77 (dd, 1H, J=2.5, 2.8 Hz), 6.57 (bt, 1H, J=1.9, 2.5 Hz), 6.24 (d, 1H, J=7.8 Hz), 5.26 (m, 1H), 4.25 (dd, 1H, J=7.2, 11.5 Hz), 3.44 (dd, 1H, J=7.2, 16.8 Hz), 3.00 (dd, 1H, 8.7, 16.8 Hz). IR (KBr): 2985, 1738, 1657, 1598, 1560, 1495, 1202, 815, 697 cm-1. HRFABMS: Calculated for C42H37N3O6Cs (M+Cs+): 812.1737. Found: 812.1712. Anal. Calculated for C42H37N3O6.0.25 CHCl3 : C, 71.51; H, 5.29. Found: C, 71.72; H, 5.60.
Reaction SMILES: [NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:12])=[O:10])[NH2:8].[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:1][C:2](=[N:21][N+:22]([O-:24])=[O:23])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([N:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH3:12])=[O:10])[NH:8][C:32](=[O:33])[CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CN(Cc1ccc(O)cc1)C(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-]
Product: CN(Cc1ccc(O)cc1)C(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
Prepared analogously to Example 69c) from (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-N-methyl-ornithinamide and diphenylacetylchloride in a yield of 85% of theory.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([C:11]1[CH:38]=[CH:37][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][CH2:22][C@H:23]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:24]([OH:26])=[O:25])=[O:20])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].[CH2:39]([O:46][C:47](ON1C(=O)CCC1=O)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C=O)C>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:31]1([S:28]([NH:27][C@@H:23]([CH2:22][NH:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:37]=[CH:38][C:11]([C:8](=[NH:9])[NH:10][C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])=[CH:12][CH:13]=2)[C:24]([OH:26])=[O:25])(=[O:30])=[O:29])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N=C(N)c1ccc(OCCCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (51 mg) obtained in the above (1) in DMF (2 ml) are added N-(benzyloxycarbonyloxy)succinimide (25 mg) and triethylamine (14 μl), and the mixture is allowed to stand at room temperature for one day. The reaction mixture is concentrated under reduced pressure, and the residue is purified by HPLC, and the fractions containing the title compound are concentrated under reduced pressure. To the residue is added a mixture of 1N hydrochloric acid (2 ml) and acetic acid (2 ml), and the mixture is stirred at 50° C. for 13 hours. The reaction mixture is concentrated under reduced pressure, and the resultant is purified by HPLC to give the title compound (3 mg) as a white powder.