Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]2)[C:3]1=[O:13].[CH3:15][Li]>>[CH3:15][C:3]1([OH:13])[C:4]2([CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]2)[CH2:5][CH2:6][CH2:7][C:2]1([CH3:14])[CH3:1]
Reactant: CC1(C)CCCC2(CC=CCC2)C1=O
Reactant: [Li]C
Product: CC1(C)CCCC2(CC=CCC2)C1(C)O
Yield: 98 %

Procedure:
2,2-Dimethylspiro[5,5]undec-8-en-1-one was treated with methyllithium according to the general procedure (example 2, procedure 5) to give 1,2,2-trimethylspiro[5,5]undec-8-en-1-ol in 98% yield. The crude product was purified by bulb-to-bulb distillation (B.p.=140-150° C./0.032 mbar).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].ClCCC1C=C[C:38]([C:41](=[O:43])C)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:41]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1)(=[O:43])[CH3:38]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CC(=O)c1ccc(CCCl)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)c1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-[4-(2-chloro-ethyl)-phenyl]-ethanone and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [Si]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:28])[C:14]2[C:19]([C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][CH:9]([C:11]1[O:12][C:13](=[O:28])[C:14]2[C:19]([C:20]=1[CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1CN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1oc(=O)c2ccccc2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (Intermediate B59.3, 0.203 g, 0.503 mmol) was dissolved in THF (7 mL); TBAF (1.0 M solution in THF, 0.33 ml, 0.33 mmol) was added drop-wise and the resulting mixture was stirred at room temperature for 2 hrs. Water (10 ml) was added and the mixture was extracted twice with DCM; the combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude was purified by reverse phase flash chromatography on C18 Biotage cartridge ((H2O:CH3CN=95:5 to 80:20, with 0.1% HCOOH) to afford the title compound (0.145 g). The product was used in the next step without further purifications.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:5]([Br:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:13](=[O:14])[C:6]=2[C:5]([Br:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Br)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nc(Br)c2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of 1 ml of ethanol and 2 ml of hydrazine monohydrate was dissolved 90 mg of 3-amino-6-bromo-4,5-diethoxycarbonyl-2-phenylpyridine, and the mixture was stirred for 2 hours at room temperature. After the solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, the resulting crystals were collected by filtration. The crystals were dissolved in a small volume of methanol. After mixing the methanol solution with silica gel, purification by silica gel column chromatography (eluent:ethyl acetate→ethylacetate/methanol 1:1) was conducted, followed by collection by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][C:3]=1[F:13].[OH-:14].[Na+].OO.Cl>>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=1[C:6]([OH:12])=[O:14]
Reactant: [OH-]
Reactant: O=C1Nc2cc(Br)c(F)cc2C1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1cc(Br)c(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a 100 mL round bottom flask, 6-bromo-5-fluoro-1H-indole-2,3-dione (3 g, 0.0121 mol) and 2N NaOH (15 mL) were added and cooled the reaction vessel to 0° C. To this reaction mixture 30% hydrogen peroxide (10.5 mL) was slowly added. The reaction mixture was stirred at 0° C. for 3 h. Subsequently, the reaction mixture was acidified with 2 N HCl at 0° C. [pH-5] to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound (700 mg, 25%). 1H NMR (300 MHz, DMSO-d6): δ 7.52 (d, J=9.6 Hz, 1H), 7.09 (d, J=6.0 Hz, 1H); LC-MS (ESI): Calculated mass: 232.9; Observed mass: 231.9 [M−H]+ (RT: 0.23 min).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:31]=[CH:30][C:11]3[N:12]([CH2:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]4)[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.C[Si]([N:36]=[C:37]=[O:38])(C)C>>[C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][N:12]2[C:11]3[CH:30]=[CH:31][C:8]([S:5]([CH:3]4[CH2:4][N:1]([C:37]([NH2:36])=[O:38])[CH2:2]4)(=[O:7])=[O:6])=[CH:9][C:10]=3[N:14]=[C:13]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:22][CH2:23]1)(=[O:29])[CH3:28]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CNC4)ccc32)CC1
Product: CC(=O)N1CCC(Cn2c(CC(C)(C)C)nc3cc(S(=O)(=O)C4CN(C(N)=O)C4)ccc32)CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using 1-(4-((5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)ethanone (STEP D) and trimethylsilyl isocyanate instead of methanesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][S:9][CH:10]=1)[CH3:2].[OH2:12]>ClCCCl>[CH2:1]([O:3][C:4](=[O:11])[C:5]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)Cc1cscn1
Reactant: O
Solvent: ClCCCl
Product: CCOC(=O)C(=O)c1cscn1

Procedure:
Alternatively, the 1,3-thiazol-4-yl-glyoxyl ester is obtained by heating 17.1 g of 1,3-thiazol-4-yl-acetic acid ethyl ester in 50 ml of 1,2-dichloroethane together with 10.5 g of SeO2 with reflux on a water separator. When the separation of water is complete, the mixture is filtered with suction, the residue is washed with 1,2-dichloroethane, the combined dichloroethane phases are concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[N:3]=1.Cl[CH2:15][CH:16]=O>C(O)C>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][C:4]1[N:3]2[CH:15]=[CH:16][N:1]=[C:2]2[CH:7]=[CH:6][N:5]=1
Reactant: O=CCCl
Reactant: Nc1ccnc(SCCCCO)n1
Solvent: CCO
Product: OCCCCSc1nccc2nccn12

Procedure:
To a solution of 4.98 g (25 mmol) of 4-amino-2-(4-hydroxybutylthio)pyrimidine in 70 ml of ethanol, 30 ml of a 40% chloroacetaldehyde solution was added, followed by refluxing for 4 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/1→1/4→ethyl acetate) to yield 3.15 g (56.4%, white crystal) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(C)n2)c1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)Nc3ccccc3)sc2-c2ccnc(C)n2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of [5-(2-methyl-4-pyrimidinyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) in N,N-dimethylacetamide (10 mL) was added phenylisocyanate (0.29 mL, 2.7 mmol), and the mixture was stirred at 80° C. for 2 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The resulting crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.55 g, yield 78%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37]>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[CH:12]([C:10]([N:9]([CH2:8][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=1)=[O:11])[CH2:13][CH2:14][CH2:15]2
Reactant: CN(C)CCCl
Reactant: CCn1cc(CN(C(=O)C2CCCc3cc(O)ccc32)c2ccc(C(C)C)cc2)cn1
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3cc(OCCN(C)C)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 38.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 6-[2-(dimethylamino)ethoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g) was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([N:17]([CH3:26])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])[CH:13]=2)=[C:6]([C:31]2[CH:36]=[C:35]([C:37](=[O:50])[NH:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=3)[CH:34]=[CH:33][N:32]=2)[CH:5]=1)C.[CH3:53]NCCC>>[CH3:26][N:17]([CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:15](=[O:16])[C:14]1[CH:27]=[CH:28][CH:29]=[C:12]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH3:1])[CH2:51][CH2:52][CH3:53])=[CH:5][C:6]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:50])[NH:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:47])[F:48])[CH:41]=3)[CH:34]=[CH:33][N:32]=2)=[O:30])[CH:13]=1
Reactant: CCCNC
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CCCN(C)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N1-(4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide 25, using N-methylpropan-1-amine in place of diethylamine. MS (ES, m/z): 717.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)c1cc(Br)cs1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cs1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a dry flask under N2 with a stirbar was added 6 g (29.1 mmol) of 4-bromothiophene-2-carboxylic acid (as prepared in the previous step) and dry methanol (100 mL). The solution was cooled in an ice-salt bath for 15 min and 2.55 mL (34.9 mmol) of thionyl chloride was added over 15 min, keeping the temperature <−5° C. The reaction mixture was stirred on the ice-salt bath for an additional 15 min, then for 1 h at rt, and finally refluxed for 8 h under N2. The resulting solution was cooled and concentrated to 6.7 g of pale amber oil. This oil was passed through 150 g of silica with ˜600 mL CH2Cl2 (discarded the first 120 mL which contained minor impurities and no ester). The solvent was removed in vacuo to afford 6.11 g (95% yield) of the title compound as a colorless solid, which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:19])([CH3:18])[CH:13]=[C:14]([F:17])[CH2:15][OH:16])=[CH:8][CH:7]=1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:16][CH2:15][C:14]([F:17])=[CH:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(C)(C=C(F)CO)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC(C)(C)c1ccc(Cl)cc1
Yield: 87 %

Procedure:
The method of Example 11 was repeated using acetyl chloride (0.76 ml), 4-(4-chlorophenyl)-2-fluoro4-methylpent-2-enol (Example 8) (0.34 g), benzene (20 ml) and pyridine (0.15 ml) to yield the title compound (0.35 g, 87%).
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].[ClH:16]>C(O)C>[ClH:16].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNCCO
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1CCO
Temperature: 77.5 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a flask having an inner volume of 100 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 8.43 g (55 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.0% by weight synthesized in the same manner as in Example 1, 4.01 g (50 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 50 ml of ethanol and 7.60 g (75 mmol) of conc. hydrochloric acid, and the mixture was reacted under reflux (76 to 79° C.) for one hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 20 ml of toluene and 20 ml of isopropyl alcohol were added to the concentrate, and the mixture was stirred at room temperature for one hour. Then, the solution was filtered and the filtrate was dried at 40° C. under reduced pressure to obtain 6.85 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrochloride (Isolation yield: 67.4%) as yellow solid with a purity of 94.8% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:24]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate (Parish Chemical Company, 1.0 g, 3.23 mmol) and benzyl bromide (0.60 g, 3.5 mmol) in THF (50 mL) was treated with Cs2CO3 (3.26 g, 10 mmol) and heated to a gentle reflux for 16 h. After cooling to room temperature the reaction was quenched by addition of water and then partitioned between water and EtOAc. The organic phase was dried over MgSO4, and concentrated to yield ethyl 1-benzyl-5-nitro-3-phenyl-1H-indole-2-carboxylate as a yellowish solid (1.20 g, 93%): 1H NMR (DMSO-d6) δ 0.93 (t, J=7.0 Hz, 3 H), 4.11 (q, J=7.0 Hz, 2 H), 5.91 (s, 2 H), 7.12 (d, J=8.3 Hz, 2 H), 7.30-7.32 (m, 3 H), 7.50-7.55 (m, 5 H), 7.92 (d, J=9.2 Hz, 1 H), 8.22 (dd, J=9.2, 2.0 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H); MS (EI) m/z 400.1 (MH+); Anal. calcd for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00. Found: C, 71.77; H, 5.14; N, 6.71.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O[CH2:21][C@@H:22]([CH3:54])[C@H:23]([NH:34][C:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:24]([O:26]CC1C=CC=CC=1)=[O:25]>C1COCC1>[CH3:21][C@@H:22]1[CH2:54][O:26][C:24](=[O:25])[C@H:23]1[NH:34][C:35]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:46]2[C:47]1=[CH:42][CH:43]=[CH:44][CH:45]=2
Reactant: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1COC(=O)[C@H]1NC1(c2ccccc2)c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
The relative stereochemical assignments of the DIBAL-reduction products were made based on NOE studies conducted on lactone derivatives prepared from each isomer by employing the following protocol: LiHMDS (50 μL of 1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL) solution of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg, 0.135 mmol), and the reaction mixture was stirred at similar temperature for ˜2 hr. The volatile component was removed in vacuo and the residue was partitioned between CH2Cl2 (30 mL), water (20 mL) and saturated aqueous NH4Cl solution (1 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo, and the resulting crude material was submitted to a Biotage purification (40 g silica gel; 10-15% EtOAc/hexanes) to afford (3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one as a colorless film of solid (28.1 mg). (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was elaborated similarly to (3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one. (3S,4S)-lactone isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.83 (d, J=7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J=8.3, 1H), 3.60 (d, J=5.8, NH), 3.45 (app t, J=9.2, 1H), ˜2.47 (m, 1H, partially overlapped with solvent signal), 2.16 (m, 1H), 0.27 (d, J=6.6, 3H). LC (Cond. 1): RT=1.98 min; LC/MS: Anal. Calcd. for [M+Na]+ C24H21NNaO2: 378.15; found 378.42. (3S,4R)-lactone isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.89 (d, J=7.6, 1H), 7.85 (d, J=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd, J=9.1, 4.8, 1H), 3.76 (d, J=8.8, 1H), 2.96 (d, J=3.0, NH), 2.92 (dd, J=6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0, 3H). LC (Cond. 1): RT=2.03 min; LC/MS: Anal. Calcd. for [M+Na]+ C24H21NNaO2: 378.15; found 378.49.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]12[O:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2>C1(C)C=CC=CC=1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[OH:29])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: C1CCC2OC2C1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1NC1CCCCC1O
Temperature: 80 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A 100-mL pressure vessel was charged with (E)-ethyl 3-(2-amino-5-(benzylthio) phenyl)acrylate (3 g, 9.57 mmol), toluene (31.9 ml), cyclohexene oxide (2.91 ml, 28.7 mmol), and activated Al2O3 (24 g, 9.57 mmol) (dried at 150° C. for 16 h). The reaction vessel was sealed with a Teflon cap and the yellow reaction mixture was warmed to 80° C. After 16 h, additional cyclohexene oxide (2.91 ml, 28.7 mmol) and activated Al2O3(10 g, 3.98 mmol) was added and the reaction vessel was sealed with a Teflon cap and warmed to 80° C. After 48 h, the reaction mixture was allowed to cool to RT then filtered through a fritted funnel and the pad of Al2O3 was eluted with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure to furnish a yellow residue which was purified by flash column chromatography (100-g Biotage column, eluent: gradient, 0 to 50% EtOAc in heptane) to afford (±)-(E)-ethyl 3-(5-(benzylthio)-2-((2-hydroxycyclohexyl)amino) phenyl)acrylate (3.5 g, 8.50 mmol, 89% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ=7.84 (d, J=15.7 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.31-7.18 (m, 6H), 7.14 (dd, J=2.2, 8.7 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 6.27 (d, J=15.5 Hz, 1H), 5.48 (d, J=6.8 Hz, 1H), 4.75 (d, J=5.0 Hz, 1H), 4.03 (s, 1H), 3.52-3.39 (m, 1H), 3.20-3.11 (m, 1H), 3.07 (d, J=8.9 Hz, 1H), 1.90 (d, J=9.7 Hz, 1H), 1.80 (d, J=2.5 Hz, 1H), 1.70-1.50 (m, 2H), 1.21-1.05 (m, 2H). m/z (ESI) 412.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>C(Cl)(Cl)Cl>[CH3:9][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:19][C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:18]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)C(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccccc2nc1-c1ccccc1
Yield: 98 %

Procedure:
3.23 g of 1-phenyl-1,2-propanedione and 2.48 g of 1,2-phenylendiamine were refluxed in a chloroform solvent in nitrogen atmosphere for 4 hours. An organic layer was washed with 1 mol/L hydrochloric acid, and washed with a saturated salt solution, then, dried. The solvent was distilled off to give a ligand, 2-methyl-3-phenylquinoxaline (abbreviated as Hmpq) (pale orange powder, yields of 98%). A synthesis scheme of the step 1 (b-1) is represented as follows:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:14]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:7]=[CH:6]2)#[N:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:27][C:24]1[CH:25]=[CH:26][C:14]([O:13][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:9]=2)=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc2cc(C#N)ccc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(N)ccc1Oc1ccc2cc(C#N)ccc2c1

Procedure:
The compound (t-butyl 2-(6-cyano-2-naphthyloxy)-5-nitrobenzoate) (760 mg) obtained in a previous production example, iron powder (718 mg) and ammonium chloride (73 mg) were heated to reflux in ethanol:water (3:1, 30 ml) and reacted for 30 minutes. The insoluble portion was immediately filtered using celite, and the filtrate was concentrated. A saturated sodium bicarbonate solution was added to the obtained residue, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline and then dried over magnesium sulfate, and the solvent was distilled off to obtain 736 mg of t-butyl 5-amino-2-(6-cyano-2-naphthyloxy)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([NH2:10])=[O:9].Br[C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])N=1>>[CH3:19][C:15]1[S:14][C:13]2=[N:11][C:6]3[C:7]([C:8](=[O:9])[N:10]2[C:16]=1[CH3:18])=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=3
Reactant: Cc1cccc(N)c1C(N)=O
Reactant: Cc1nc(Br)sc1C
Product: Cc1sc2nc3cccc(C)c3c(=O)n2c1C
Yield: 76.2 %

Procedure:
9.6 g of 6-methylanthranilamide and 12.6 g of 2-bromo-4,5-dimethylthiazole were stirred for 12 hours at 150° C. After working up in the conventional manner there was obtained 11.9 g (81%) of the above compound; m.p. 278°-280° C.