Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1I.[CH3:16][Si:17]([CH3:34])([CH3:33])/[CH:18]=[CH:19]/[Sn](CCCC)(CCCC)CCCC>ClC(Cl)C.C(OCC)(=O)C.O.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1/[CH:19]=[CH:18]/[Si:17]([CH3:34])([CH3:33])[CH3:16]
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Reactant: CCc1nc(C(=O)OC)c(I)c(N)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc(C(=O)OC)c(/C=C/[Si](C)(C)C)c(N)c1F
Temperature: 120 °C
Yield: 57.9 %

Procedure:
Methyl 4-amino-6-ethyl-5-fluoro-3-iodopicolinate (270 mg, 0.833 mmol) and bis(triphenylphosphine)palladium(II) dichloride (58.5 mg, 0.083 mmol) were combined in a microwave reactor vessel. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (649 mg, 1.666 mmol) dissolved in dichloroethane (0.8 mL) was added and the reaction mixture was heated at 120° C. for 30 min a microwave reactor. The cooled reaction mixture was diluted with ethyl acetate and water. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated on to silica. The product was purifed by flash chromatography (SiO2, 0-30% EtOAc:Hex gradient) to provide the title compound as an off-white solid (143 mg, 0.482 mmol, 57.9% yield): 1H NMR (400 MHz, DMSO-d6) δ 0.14 (s, 9H), 1.16 (t, J=7.6 Hz, 3H), 2.65 (qd, J=7.6, 2.6 Hz, 2H), 3.71 (s, 3H), 5.99 (d, J=19.3 Hz, 1H), 6.25 (s, 2H), 6.84 (d, J=19.2 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −148.85; ESIMS m/z 297 ([M+H]+), 295 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.CN(C)C=O.[CH2:15]([Li])CCC.[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24]C>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:15])[CH:7]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CNc1ccc(Br)cc1
Reactant: CCCCCC
Reactant: [Li]CCCC
Solvent: CN(C)C=O
Product: CN(c1ccc(Br)cc1)C1CCCCC1
Temperature: 0 °C

Procedure:
26 g 4-bromo-N-methylaniline (XXI) and 100 ml anhydrous N,N-dimethyl formamide (HCONEt2) were plced into a four-necked flask and cooled down to 0° C. under nitrogen. 40 ml of 2.5 M n-butyl lithium (n-BuLi) solution in n-hexane was dropped with stirring and stirred for 2 hours while maintaining at 0° C. N-hexane and n-butane were evaporated and 16.2 g bromo-cyclohexane was added and stirred under reflux for 8 hours. After cooling, lithium bromide was filtered off and N,N-dimethyl formamide recovered. The residue was recrystallized twice from 95% ethanol to yield 16 g 4bromo-N-methyl-N-cyclohexyl aniline (II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]([C:16](OCC)=[O:17])[C:6]2=[O:21].[NH3:22]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]([C:16]([NH2:22])=[O:17])[C:6]2=[O:21]
Reactant: N
Reactant: CCOC(=O)c1cn(C)c2cc(OC)c(OC)cc2c1=O
Solvent: CCO
Product: COc1cc2c(=O)c(C(N)=O)cn(C)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of ethyl 6,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (4.0 g) and ethanol saturated with ammonia (200 ml) was heated at 100° in a stainless steel pressure vessel for 20 hours, then cooled to ambient temperature. The mixture was evaporated and the residue purified by high pressure liquid chromatography on silica using dichloromethane IMS 96.5:3.5 as the eluent. The resulting product was recrystallised from IMS to give the novel compound 6,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, m.p. 323°-325° (dec).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([NH2:13])=[O:12].[CH2:16]([N:23]=[C:24]=[S:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[CH2:27][CH2:28]Br>CN(C)C=O.O.C(OCC)(=O)C>[CH2:16]([N:23]1[CH2:28][CH2:27][S:25][C:24]1=[N:13][C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[C:4]([F:3])([F:14])[F:15])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C=NCc1ccccc1
Reactant: NC(=O)c1cnccc1C(F)(F)F
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N=C1SCCN1Cc1ccccc1)c1cnccc1C(F)(F)F
Reaction time: 1 h

Procedure:
Sodium hydride (0.09 g, 60% dispersion in mineral oil) was added portionwise to a solution of 4-trifluoromethyl-3-pyridinecarboxamide (0.40 g) in N,N-dimethylformamide at 20° C., and stirred for 1 hour. Benzyl isothiocyanate (0.31 ml) was added and stirred at 20° C. for 1 hour, then 1,2-dibromoethane (0.30 ml) added and stirred at 20° C. for 1 hour. Sodium hydride (0.09 g, 60% dispersion in mineral oil) was added in portions to the solution then stirred for 5 hours. Ethyl acetate and water were added, the organic phase dried (magnesium sulfate), evaporated and the residue purified by silica gel column chromatography eluting with n-hexane/ethyl acetate (3:1) to give 3-benzyl-2-(4-trifluoromethyl-3-pyridylcarbonyl)iminothiazolidine (0.50 g, Compound D-40).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][OH:22].[OH-].[Na+].C(O)C>O>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:19][CH2:20][CH2:21][OH:22])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCl
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Yield: 65.4 %

Procedure:
12.02 g (50 mmoles) of 5-benzyl-benzimidazoline-2-thione, 4.72 ml of 3-chloro-1-propanol, 2.0 g (50 mmoles) of sodium hydroxide dissolved in water and ethanol are reacted as described in the above Example. The recovering of the product is carried out similarly. 9.76 g (65.4%) of title product are obtained. M.p.: 103°-105° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:12]1([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:12]1([C:18]2[CH2:23][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH2:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (2.71 ml), 1,2,3,6-tetrahydro-4-phenylpyridine hydrochloride (5 g) and potassium carbonate (8.83 g) in dimethylsulfoxide (50 ml) was stirred for 1 hour at 100° C. The reaction mixture was pulverized with water. The precipitate was collected by filtration, and dried under reduced pressure to give 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]=[C:38]=[S:39])([CH3:29])[CH3:28].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[NH:37][C:38]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:39])([CH3:29])[CH3:28]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N=C=S)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)C)c(NC(=S)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (0.160 g, 0.442 mmol) in a 25 mL vial equipped with a stir bar was added 1-isopropyl-2-isothiocyanato-4-methylbenzene (65% in dichloromethane, 0.156 g, 0.530 mmol) in dichloromethane (6.31 ml) followed by triethylamine (0.062 ml, 0.442 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and adsorbed onto Celite®. Purification by flash column chromatography using 2.5-40% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent provided a white solid. The solid was dried overnight at 50° C. at about 25 in. Hg providing the title compound as a white solid (0.172 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>>[ClH:1].[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH:48][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37])[CH3:44]
Reactant: CCN(CC)CCN
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with N,N-diethylethane-1,2-diamine to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-diethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide hydrochloride. MS (ES+) m/z calcd. for C37H44Cl2F2N5O3: [(M+H)+]: 714. found: 714.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](=[S:13])=[S:12].I[CH3:15]>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[S:13])[S:12][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: S=C=S
Reactant: NCCCc1ccccc1
Product: CSC(=S)NCCCc1ccccc1
Yield: 94.1 %

Procedure:
3-Phenyl-1-propylamine (0.074 mol) was reacted with carbon disulfide (0.074 mol) and iodomethane (0.074 mol) substantially as described in Example 1B above to obtain 15.7 g (94%) of a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].O.C(OCC)(=O)C>CO>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:5])[CH3:17]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
In 25 ml of methanol was dissolved 5.44 g of methyl 4-[(diethylamino)carbonyl]-benzoate. After adding 25 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, and the aqueous layer was separated. The aqueous layer was mixed with ethyl acetate, pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the deposited crystal was collected by filtration to obtain 2.94 g of 4-[(diethylamino)carbonyl]-benzoic acid as a colorless crystalline product.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])[CH2:5][CH2:4][O:3]1.[CH3:14][CH2:15][Mg+].[Br-].[NH4+].[Cl-].O>C(OCC)C>[CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH:9]([OH:10])[CH2:14][CH3:15])[CH3:11])[CH2:5][CH2:4][O:3]1
Reactant: CC[Mg+]
Reactant: CC1(C)OCCC(C(C)(C)C=O)O1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCC(O)C(C)(C)C1CCOC(C)(C)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 268 mg (1.44 mmol) of aldehyde 45 in 4 ml of diethyl ether is mixed at 0° C. with 528 μl (1.58 mmol, 1.1 equivalents) of a 3 M solution of EtMgBr in ether. It is allowed to stir for 2 hours at 0° C., heated to room temperature and allowed to stir for another hour. For working-up, it is mixed with saturated aqueous NH4Cl solution, and then water is added steadily until the precipitate goes into solution. The aqueous phase is extracted with ether, the combined organic phases are dried on MgSO4 and concentrated by evaporation. The residue is purified by column chromatography with pentane:ether=1:1. 251 mg (1.16 mmol) of alcohol 46, corresponding to a yield of 80%, is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34].C[OH:37]>>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:31][CH2:32][C:33]([CH3:35])([OH:37])[CH3:34])=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CO
Reactant: CC(C)CNO
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C

Procedure:
Triethylamine (81.3 g, 0.803 mol) was added to a solution of 230.0 g (0.731 mol) of 7-benzyloxy-4-chloro-3-nitroquinoline (230.0 g, 0.731 mmol), prepared in Parts A-D of Example 1, in methanol (1.84 L). Hydroxyisobutylamine (71.6 g, 0.803 mol) was then added over a period of five minutes; the temperature rose from 30° C. to 39° C. during the addition. The reaction mixture was heated at reflux for four hours and then allowed to cool to room temperature. The solid product was isolated by filtration, washed with ethanol (1 L), and dried under vacuum at 55° C. to provide 261.2 g of 1-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:18]=[CH:17]4)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH2:46][O:47][C:48](=[O:50])[CH3:49].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:18]=[CH:17]4)[N:11]2[CH2:49][C:48]([O:47][CH3:46])=[O:50])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc4nc(-c5cc(OC)ccc5-c5ccc(Cl)cc5)ccc4c3)[nH]c2c1
Reactant: CC(=O)OCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
To a mixture of intermediate 15-2 (1.024 g, 1.7 mmol) and bromomethylacetate (388 mg, 1.5 eq) in dry DMF (30 mL) was added NaH (60% dispersion in mineral oil, 122 mg, 1.8 eq) at 0° C. After stirring for 20 min at this temperature, the reaction mixture was warmed up to room temperature. After 24 h, the reaction mixture was poured into 300 mL of ice-cold water. The formed yellow solid was filtered off, washed with petroleum ether and purified by column chromatography (CH2Cl2) to give 450 mg (39%) of 2-[2-(4′-Chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-3-cyclohexyl-1-methoxycarbonylmethyl-1H-indole-6-carboxylic acid methyl ester 15-3; m/z=674 (M+H+).
Reaction SMILES: [C:1]12(CS(O)(=O)=O)[C:8]([CH3:10])(C)[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C1(C)C=CC=CC=1>[CH:16]1[CH:10]=[CH:8][C:1]2[C:7](=[CH:6][CH:5]=[CH:4][C:2]=2[OH:3])[CH:17]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cccc2ccccc12
Temperature: 25 °C

Procedure:
The compound of the above formula (30) and 221.1 mg (0.9 mmol) of (±)-10-camphorsulfonic acid were dissolved in 150 ml of toluene and refluxed for 30 minutes. The resulting solution was left to be cooled to room temperature, added to 100 ml of a toluene solution of 4.5 g (27.3 mmol) of p-toluenesulfonic acid heated at 90° C. and refluxed for 4 hours. After the reaction, the reaction solution was washed in water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a naphthol compound represented by the following formula (31) as 3.7 g (8.2 mmol, yield rate of 45%) of a yellow solid.
Reaction SMILES: [C:1]([O:6][CH:7]([CH:30]=[CH2:31])[C@H:8]1[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])([O:3][CH2:4][CH3:5])=[O:2].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:6][CH:7]([CH:30]=[CH2:31])[C@H:8]1[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[N:16]([C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:14]2=[O:15])[CH2:10][C@@H:9]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(OC(=O)OCC)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(OC(=O)OCC)[C@H]1O[C@@H](n2cc(C)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 15 h

Procedure:
To a solution of 5'-O-carbethoxy-5'-vinyl-3'-O-t-butyldimethylsilyl thymidine (1.7 g) in 20 ml of pyridine was added benzoyl chloride (2.5 eq.) and diisopropyl-ethylamine (95.0 eq.) and the resulting mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate followed by brine, and the organic layer was then dried over sodium sulfate. The title compound was purified by flash chromatography using 20% ethyl acetate/hexane.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:15]2[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>O1CCCC1>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:1][N:2]=[C:3]2[C:4]3[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
3.8 g (0.015 mol) of 9-hydroxyimino-3,6-dimethoxyfluorene and 2.3 g (0.0225 mol) of triethylamine are suspended in 80 ml of tetrahydrofuran (THF) and, at 0° C., a solution of 3.1 g (0.0165 mol) of para-toluenesulfonic acid chloride in 20 ml of THF is added dropwise. After 4 hours, the ice-bath is removed and the reaction mixture is stirred overnight at room temperature. Then 40 ml of CH2Cl2 are added and the resulting ammonium salts are filtered off. The filtrate is washed with water and saturated NaCl, dried over magnesium sulfate and concentrated in a rotary evaporator. The resulting crude product is purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 2:1). The fraction containing the main product is taken up in 100 ml of hot ethanol and the solution is filtered while hot. On cooling, the product precipitates and is filtered off and dried in vacua. 3.2 g (52%) of 9-(4-methylphenylsulfonyl-oxyimino)-3,6-dimethoxyfluorene are obtained in the form of yellow crystals having a melting point of 143-148° C. The UV spectrum (acetonitrile) of the substance shows absorption bands with a maximum at 314 nm (ε=21100) that extend to 450 nm. Elemental analysis: C22H19NO5S (409.6)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5](I)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.CN([CH:26]=[O:27])C.C([Li])CCC>COC1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:5]([CH:26]=[O:27])=[C:4]([CH3:22])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(C)cc(Cl)c32)cc1
Agent: [Li]CCCC
Solvent: COC1CCCC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(Cl)c32)cc1

Procedure:
To a solution of 7-chloro-4-iodo-5-methyl-1-tosyl-1H-indole (98 mg, 0.220 mmol) and DMF (34 μL, 0.440 mmol) in cyclopentyl methyl ether (2 mL) at −78° C., was added n-butyllithium (2.5 M in hexanes, 114 μL, 0.286 mmol). After 80 minutes additional n-butyllithium (2.5 M in hexanes, 0.11 mL, 0.286 mmol) was added. After 15 more minutes the reaction was quenched with MeOH (0.5 mL) and sat. aq. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 347.9 (M+H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[Cl:11]([O-])(=O)=O.[K+]>Cl>[Cl:11][C:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:1]=[CH:2][C:3]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [K+]
Product: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
p-nitrophenol (69.55 g, 0.5 mole) was dissolved in 10 N HCl (200 ml) in a 1000 ml flask with heating and then cooled down. To the mixture was added 600 ml potassium chlorate (61.25 g, 0.5 mole) solution, gradually with stirring. Stirring was continued for 1 hour after completion of addition and mixture was left overnight at room temperature. After filtration with vacuuming, the filtrate was washed with distilled water and recrystallized with dilute acetic acid solution to yield pale yellow acicular crystal, 2-chloro4-nitro-phenol (80.2 g, m.p. 110–111° C., yield rate 91%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1)=[O:10].IC>CN(C=O)C>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH3:1])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1c2ccccc2CC1c1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a mixture of 9.40 g K2CO3 and 10.05 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2yl)phenyl]propanamide in 125 ml DMF at 0° C., was added 3.64 ml iodomethane. The resulting mixture was stirred twenty-eight hours at room temperature. Upon dilution with water, a solid precipitated, which was collected and washed with water. Recrystallization from EtOH/water yielded 4.86 g solid, m.p. 133°-135° C.