Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][OH:18].Cl.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(OCc2ccccc2)cc1

Procedure:
4.24 g of 4-benzyloxy benzaldehyde (20 mmol) was dissolved in a 0.2M mixed solution of ethanol and water (3:1,100 ml), followed by stirring. 2.78 g of NH2OH—HCl (40 mmol) and 2.46 g of sodium acetate(30 mmol) were added thereto, and stirred at room temperature for about 30 minutes. Subsequently, the completion of the reaction was confirmed by liquid chromatography, and water and ethanol were removed by distillation under reduced pressure to obtain a pale yellow solid compound. The pale yellow solid compound was extracted three times with water and ethyl acetate, an organic solvent layer was dried under reduced pressure to obtain a crude product, and the crude product was then purified with a hexane/ethylacetate solution (10:1) to obtain a white solid compound. The obtained solid compound was subjected to subsequent reactions without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=O)[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=[S:42])[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 58.9 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.164 g, 0.362 mmol) in toluene (3 mL) and DME (3 mL) was added Lawesson's reagent (0.117 g, 0.290 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.080 g, 47%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 6.82 (d, J=10.0 Hz, 1H), 6.72 (brs, 1H), 6.47 (d, J=6.8 Hz, 1H), 4.89 (d, J=13.2 Hz, 2H), 4.16 (m, 4H), 3.85 (m, 2H), 1.64 (d, J=7.2 Hz, 3H), 1.56 (s, 3H), 1.43 (s, 9H), 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[C:23]1([NH:29][S:30](Cl)(=[O:32])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:32])=[O:31])[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)Nc1ccccc1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)Nc4ccccc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=409.1 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and phenylsulfamoyl chloride.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.FC1(CCCC2C=CC=CC=2)CCN(C[C@@H]2[C@@H](C3C=CC=C(F)C=3)CN([C@H](C(C)C)C(O)=O)C2)CC1.C(N(C(C)C)CC)(C)C.[CH2:76]([C:78]1[NH:88][C:81]2=[N:82][C:83]([CH3:87])=[CH:84][C:85]([CH3:86])=[C:80]2[N:79]=1)[CH3:77]>C(Cl)Cl.CCOCC>[CH2:76]([C:78]1[N:88]([CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:81]2=[N:82][C:83]([CH3:87])=[CH:84][C:85]([CH3:86])=[C:80]2[N:79]=1)[CH3:77]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: CC(C)[C@H](C(=O)O)N1C[C@H](CN2CCC(F)(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1nc2c(C)cc(C)nc2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 19.5 %

Procedure:
To a solution of 0.216 g of 4-hydroxymethyl-piperidine-1-carboxylic acid, tert-butyl ester (from Step B) in 6 mL of CH2Cl2 at −78° C. was added 0.202 mL of triflic anhydride. After stirring at −78° C. for 5 minutes, 0.151 mL of 2, 6-lutidine was added dropwise. The temperature was maintained below −70° C. throughout the reaction. After stirring for 15 minutes, 0.35 mL of diisopropylethylamine was added dropwise. After 15 minutes, a solution of 0.35 g 2-ethyl-5,7-dimethyl-3-H-imidazo[4,5-b]pyridine (prepared as described by Mantlo et al. U.S. Pat. No. 5, 412,097 and J. Med. Chem. 1991, 34, 2919 ) in 4 mL of CH2Cl2 was added dropwise. After warming to 0° C., the reaction was stirred at rt for 5 hr. The reaction was diluted with Et2O, then washed with H2O. The aqueous phase was extracted with 2×25 mL Et2O. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 50% EtOAc in hexane to give 73 mg of the title compound as an oil.
Reaction SMILES: FC(F)(F)C([N:5]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCC=CN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent is evaporated from the combined filtrate and washings. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:11]([NH:18][C@H:19]([C:29]([OH:31])=[O:30])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:8]1[CH2:9][CH2:10][N:5]([C:3]([CH2:2][O:31][C:29](=[O:30])[C@H:19]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:18][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[O:4])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(CCl)N1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)OCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-Benzyl-L-serine (10.0 g, 51.3 mmol), di-tert-butyl-dicarbonate (11.2 g, 51.4 mmol) and 1 N sodium hydroxide (103 mL, 103 mmol) are stirred together in 100 mL of dioxane at room temperature for 16 hours. The mixture is concentrated in vacuo, taken up in water, acidified to pH 1 with 6 N HCl and extracted with ethyl acetate. The organic layer is washed with water, then brine, and dried over anhydrous magnesium sulfate. The mixture is filtered and concentrated in vacuo to give BOC-O-benzyl-L-serine as an oil. 4-(2-Chloroacetyl)morpholine (1.22 g, 7.48 mmol) is added to a solution of BOC-O-benzyl-L-serine (2.20 g, 7.46 mmol), triethylamine (0.75 g, 7.43 mmol) and sodium iodide (0.11 g, 0.73 mmol) in 5 mL of N,N-dimethylformamide and the mixture stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate, washed with water, then with brine, and dried over anhydrous magnesium sulfate. The mixture is filtered and concentrated in vacuo to give a yellow oil. The oil is chromatographed on silica gel with hexane:ethyl acetate:methanol (35:60:5) to give BOC-O-benzyl-L-serine morpholinocarbonylmethyl ester as a colorless oil. HCl gas is bubbled through a solution of the carbamate ester (1.72 g, 4.08 mmol) in methylene chloride (50 mL) for 5 minutes and the mixture is stirred at room temperature for 3 hours. The resulting mixture is concentrated in vacuo to yield O-benzyl-L-serine morpholinocarbonylmethyl ester as a foam.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CCC=O)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCc2c(C)[nH]c3ccccc23)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-Methyl-1H-indole (0.86 g, 5.2 mmol) and 4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol) in methylene chloride (50 mL), was added TFA (1.78 g, 15.6 mmol), followed by triethylsilane (1.81 g, 15.6 mmol). The reaction mixture was stirred overnight, quenched with sat. NaHCO3 solution (50 mL), and the organic layer was washed with sat. NaHCO3 solution, water, brine, and dried (Na2SO4). Solvent was removed under reduced pressure, and the residue was purified by flash column chromatography with 10-20% EtOAc/hexanes to yield the desired 4-[3-(2-Methyl-1H-indol-3-yl)-propyl]-benzoic acid methyl ester in 88% (1.67 g) yield.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:49])[C:26]1[C:31]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][CH3:35])=[CH:30][C:29]([CH3:38])=[N:28][C:27]=1[O:39][C:40]1[C:45]([CH3:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:41]=1[CH3:48]>>[CH3:23][O:24][C:25](=[O:49])[C:26]1[C:31]([NH:32][CH:33]([CH:36]=[O:37])[CH2:34][CH3:35])=[CH:30][C:29]([CH3:38])=[N:28][C:27]=1[O:39][C:40]1[C:41]([CH3:48])=[CH:42][C:43]([Cl:47])=[CH:44][C:45]=1[CH3:46]
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC

Procedure:
The title compound was prepared by Dess-Martin oxidation of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester. The title compound was obtained after column chromatography. 1H MNR (CDCl3) 9.54(d, 1H), 8.56(d, 1H), 7.01(s, 2H), 5.93(s, 1H), 3.92(m, 1H), 3.89(s, 3H), 2.08(s, 3H), 2.05(s, 6H), 1.05(t, 3H) ppm.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A mixture of 3β-acetoxyandrost-5-ene-7,17-dione (7.97 g) and 10% Pd/C (0.80 g) in EtOH (0.5 L) was stirred under H2 at atm pressure for 2 h. The mixture was filtered through Celite and the filtrate evaporated to dryness. The crude product was crystallized from Et2O to give 3β-acetoxyandrostane-7,17-dione (4.75 g, 60%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.57 (m, 1H), 2.66-0.96 (m, 20H), 1.96 (s, 3H), 1.05 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]CC)=[O:26])[CH:19]=2)[NH:14]1)=[O:5].O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=2)[NH:14]1)=[O:5]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NC(=O)c1ccccc1F)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2NC(=O)c2ccccc2F)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(2-fluorobenzamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(2-fluoro-benzoylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 419.30.
Reaction SMILES: CC(=O)CCC(=O)C.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.N1CCCC1.CC(OC[C:24]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](COC(C)=O)=[C:30]2C=1C=C[CH:28]=[CH:29]2)=O>CO>[C:10]1(=[C:34]([CH2:35][CH2:36][C:37](=[C:32]2[CH:28]=[CH:29][CH:30]=[CH:31]2)[CH3:24])[CH3:33])[CH:9]=[CH:13][CH:12]=[CH:11]1
Reactant: C1=CCC=C1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)CCC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(CCC(C)=C1C=CC=C1)=C1C=CC=C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a modified reaction procedure [a], 11.0 g (96.3 mmol) of 2,5-hexanedione and 12.7 g (193 mol) of freshly cracked cyclopentadiene are dissolved in 60 ml of methanol, the solution is cooled to 0° C., and 8.60 g (121 mmol) of pyrrolidine are added. The reaction solution is stirred at 0° C. for 90 minutes, hydrolyzed using 5 ml of glacial acetic aaid and 50 ml of water, and extracted twice with 70 ml of diethyl ether in each case, and the combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, giving, after removal of the solvent in vacuo, 18.0 g (89%) of the difulvene as an orange-red, oily residue.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13]2)=[CH:6][CH:5]=1.CO.O.O[Li].O>C1COCC1>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[C:15](=[O:17])[CH2:16][CH:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][CH:6]=3)[CH2:13]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(F)cc3)C2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCC2CC(=O)N(c3ccc(F)cc3)C2)cc1
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a stirred solution of 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester obtained in step 1 (0.14 g, 0.408 mmol) in THF:MeOH:H2O (6 mL, 2:1:3), LiOH.H2O was added at 20-25° C. The reaction mixture was stirred for 16 hours at that temperature. The solvents were removed under reduced pressure and the residue was diluted with water (10 ml). The aqueous layer was washed with DCM, acidified with 2% HCl. The acidified mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4. The organic layer was evaporated under reduced pressure to obtain 4-[1-(4-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid (0.130 g, quantitative) as a white solid.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].O=C1CCC(=O)N1[O:45][C:46](=O)[CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]>CN(C=O)C>[C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH:19][C:46](=[O:45])[CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=C(CCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Solvent: CN(C)C=O
Product: O=C(CCCCC(=O)OCc1ccccc1)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-aminoethyl α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranoside (1.23 g, 2.247 mmol, WO 2010/088294 A1) in DMF (20 mL) at 0° C. was added benzyl 6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexanoate (1.02 g, 3.06 mmol) and TEA (0.5 mL, 3.59 mmol). After stirring at 0° C. for 1 hour, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse silica gel column (275 g), eluting with 0-40% AcCN in H2O to give the title compound. UPLC Method B: calculated for C33H51NO19 765.31, observed m/e=766.26 [M+1]; Rt=4.04 min. 1H NMR (D2O) δ 7.43-7.37 (5H, m), 5.14 (2H, s), 5.07-5.06 (1H, m), 4.82-4.81 (1H, m), 4.77-4.76 (1H, m), 4.06-4.01 (2H, m), 3.96-3.92 (2H, m), 3.87-3.81 (5H, m), 3.79-3.77 (1H, m), 3.74-3.67 (5H, m), 3.65-3.60 (4H, m), 3.53-3.49 (1H, m), 3.37-3.35 (2H, m), 2.43-2.40 (2H, m), 2.22-2.19 (2H, m), 1.62-1.52 (4H, m).
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1.[O:15]=[C:16]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[NH:19][CH2:18][CH:17]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C)C=O>[O:15]=[C:16]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]([CH:7]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:18][CH:17]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: BrC1C=CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCCCC2)c2ccccc2NC1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Sodium bicarbonate (606 mg) and 3-bromocyclooctene (1.36 g) were added to a solution of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) in N,N-dimethylformamide (20 ml), the mixture was stirred overnight at 80° C. After the reaction mixture was allowed to cool, ice-water was added thereto, extracted with ethyl acetate, the organic layer was washed with saturated brine. The resultant mixture was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for crystallization, and collected by filtration, to thereby obtain 615 mg of the title compound as the mixture of diastereomer compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])N1C(OCC)=O.C(N(CC)CC)C.O>CN(C=O)C>[O:11]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([N:1]3[C:17](=[O:16])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:26])=[CH:3][C:4]=2[C:12]([F:15])([F:13])[F:14])[NH:8]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: Nc1cc2c(c(C(F)(F)F)c1)CC(=O)N2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cc2c(cc(N3C(=O)c4ccccc4C3=O)cc2C(F)(F)F)N1

Procedure:
In DMF, 6-amino-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one and ethyl 1,3-dioxo-1,3-dihydro-2H-isoindol-2-carboxylate were allowed to undergo the reaction at 60° C. for 18 hours in the presence of triethylamine. Water was added to the reaction liquid and the resulting precipitate was collected by filtration to obtain 2-[2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-indol-6-yl]-1H-isoindol-1,3-(2H)-dione.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=1.[SH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].C(OCC)(=O)C>CN(C)C=O>[C:20]([O:19][C:17]([NH:16][C:12]1[CH:11]=[C:10]([CH2:9][S:24][C:25]2[C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=[CH:32][N:33]=2)[CH:15]=[CH:14][N:13]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Reactant: O=C(O)c1cccnc1S
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CSc2ncccc2C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
A solution of triethylamine (0.75 mL, 5.4 mmol) in N,N-dimethylformamide (2.0 mL) was added to a solution of 4-bromomethyl-2-tert-butoxycarbonylaminopyridine (Reference compound No. 8-1, 500 mg, 1.7 mmol) and 2-mercaptonicotinic acid (270 mg, 1.7 mmol) in N,N-dimethylformamide (3.0 mL) under ice-cooling, and the mixture was stirred for 12 hours at room temperature. Ethyl acetate (20 mL) was added to the reaction mixture, and the whole was extracted with 0.1N aqueous sodium hydroxide solution (50 mL). 1N Hydrochloric acid was added to the aqueous layer to adjust to pH 5, and the precipitated crystal was filtered off. The crystal was dried under reduced pressure at 60° C. to give 560 mg of the title reference compound as a colorless crystal. (Yield 88%)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:28])=[N:14][C:15]=2[NH:17][C@H:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19]O)[N:10]=[C:9]1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][N:14]3[C:13]([Cl:28])=[N:12][C:11]=2[N:10]=[C:9]1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](Cc1ccccc1)Nc1nc(Cl)nc2nc(C3CCCC3)n(Cc3ccccc3)c12
Solvent: O=S(Cl)Cl
Product: ClC1=Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 60 °C
Yield: 104 %

Procedure:
To Compound C2 (1.87 g, 4.05 mmol) obtained in Reference Example 37 was added thionyl chloride (15.0 mL, 207 mmol, 51 equivalents) and the mixture was stirred with heating at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the solvent was azeotroped with toluene, to the residue were carefully added chloroform and saturated sodium hydrogen carbonate, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with chloroform, then the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=90:10) to obtain the title compound (1.87 g, 99%).