Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Li+].Cl[CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl>COCCOC.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:17])([CH3:18])[C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:32][CH:31]=[CH:30][CH2:29]2)=[O:16])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: ClC/C=C\CCl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: COCCOC
Product: CCOC(=O)C1(C(=O)C(C)(C)N2COC(C)=C(c3ccccc3)C2=O)CC=CC1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (2.0 g), lithium hydride(0.11 g) in 1,2-dimethoxyethane and hexamethylphosphoramide was stirred at 40° C. for 1 hour. cis-1,4-Dichloro-2-butene was then added, and the mixture stirred at 65° C. for 48 hours. The mixture was extracted with ether, washed with brine, dried (magnesium sulphate), evaporated and purified by column chromatography eluting with ethyl acetate/hexane (1:5) to give ethyl 1-[2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionyl]cyclopent-3-enylcarboxylate (Compound 9, 0.62 g), NMR: 1.20(3H, t), 1.52(6H, s), 1.91(3H, s), 3.0-3.25(4H, m), 4.14 (2H, q), 5.17(2H, s), 5.56(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=[C:23]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:33]=[C:27]12
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)cc3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)#[N:22]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]#[N:22])[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: N#Cc1ccccc1B(O)O
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccccc3C#N)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2-cyanophenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 262; HRMS: calcd for C18H15NO+H+, 262.12264; found (ESI, [M+H]+), 262.1234.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([O:33]CC)=[O:32])[CH2:21][CH2:20][N:19]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([OH:33])=[O:32])[CH2:21][CH2:20][N:19]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(C/C=C/c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(C/C=C/c4ccccc4)CC3)c2c1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To 1.8 mL of an ethanol solution containing 0.11 g of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-((2E)-3-phenyl-2-propen-1-yl)piperidine-4-carboxylate, 0.6 mL of 20% aqueous sodium hydroxide solution was added at room temperature and refluxed with heating for 7 hours. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure, water was added, adjusted to pH 6.6 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to give 82 mg of 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-((2E)-3-phenyl-2-propen-1-yl)piperidine-4-carboxylic acid as a white solid.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)[C:18]2=[O:25].FC1C=C2C(=CC=1)NC(=O)C2=O>>[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[C:19](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:18]2=[O:25]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc(I)ccc2-n2c1nc1ccccc1c2=O
Yield: 31 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-iodoisatin for 5-fluoroisatin gave the title compound in 31% yield: mp 296.5°-297.3° C.; 1H NMR (300MHz, DMSO-d6) δ 8.16-8.36 (m, 4H) 7.96 (2, H) 7.70-7.83 (m, 1H); MS (M+H)+ 374.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=[C:4]([NH:9][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cc(Cl)nc(NC(=O)OCC)n1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A solution of 7.25 g (50 mmol) of 6-chloro-2,4-diaminopyrimidine in 100 ml of dimethylformamide and 20 ml of triethylamine is cooled to 0° and treated dropwise with 10 ml of ethyl chloroformate. The mixture is stirred at room temperature for 70 hours, the precipitated material is filtered off under suction, the filtrate is evaporated and the residue is taken up in methylene chloride. The organic phase is washed with 1N hydrochloric acid, dried over magnesium sulphate and evaporated under vacuum. The crude product obtained is chromatographed on silica gel, there being obtained pure diethyl 6-chloro-2,4-pyrimidinedicarbamate of melting point 153°-154°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1.[O:15]1[CH:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1>>[OH:15][CH:17]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Nc1ccccc1SCc1ncon1
Product: OC(CNc1ccccc1SCc1ncon1)COc1ccccc1

Procedure:
A mixture of 3-(2-aminophenylthiomethyl)1,2,4-oxadiazole (2.07 g; 10-2 mol) and 1,2-epoxy-3-phenoxy propane (1.5 g; 10-2 mol) was warmed on a steam bath during 48 hours. The so produced mixture was chromatographed on silica gel, elution with diethyl ether/hexane (1:1) producing 2-hydroxy-1-[2-(1,2,4-oxadiazol-3-yl-methylthio)anilino]-3-phenoxypropane as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1.O>[CH2:16]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:3]1[C:2]([F:1])([F:12])[F:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1cc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
8.6 g of 2-trifluoromethyl-(1H)-indole and 100 ml of tetrahydrofuran were mixed together under an inert atmosphere and cooled to 0° C. Over 15 minutes, about 2.4 g of a suspension of sodium hydride at 50% in oil was added in small fractions and 6.5 ml of benzyl bromide in solution in 10 ml of tetrahydrofuran were introduced over 5 minutes. The mixture was stirred for 42 hours at ambient temperature and then was poured into water saturated with monosodium phosphate. The mixture was extracted with ethyl ether, and the extracts were dried and concentrated to dryness by distillation under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (9/1) to obtain 12.54 g of 1-benzyl-2-trifluoromethyl-(1H)-indole melting at approx. 20° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc(Br)cnc1OC
Product: COc1ccc(-c2cnc(OC)c(OC)c2)cc1
Yield: 44.8 %

Procedure:
According to Scheme 4 Method B: The title compound was prepared from 5-bromo-2,3-dimethoxypyridine (1 eq, 1.83 mmol, 0.40 g) and 4-methoxyphenyl boronic acid (1 eq, 1.83 mmol, 0.28 g) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography on silica gel using cyclohexane/AcOEt 90/10 as eluent to afford the title compound 2,3-dimethoxy-5-(4-methoxyphenyl)pyridine (0.82 mmol, 0.20 g, 45%) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([NH:16][C@:17]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C@H:18]1[CH:20]=[CH2:21])=[O:15])=O)(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([NH:16][C@:17]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:15])[CH2:10]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Yield: 97 %

Procedure:
A stirred slurry of ethyl 1(R)-[1-tert-butoxycarbonyl-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate (5.0 g, 13.6 mmol) was treated with 4N HCl/dioxane (20 mL) for 3 h. The reaction mixture was concentrated in vacuo to give 4.5 g (97%) of ethyl 1(R)-[4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate hydrochloride as a white solid: 1H NMR (300 MHz, CD3OD) δ 1.26 (t, J=7.14 Hz, 3 H), 1.46 (dd, J=9.70, 5.31 Hz, 1H), 1.80 (dd, J=8.23, 5.31 Hz, 1 H), 2.00-2.15 (m, 1 H), 2.18-2.30 (m, 1 H), 2.45 (dd, J=13.36, 7.50 Hz, 1 H), 3.36-3.48 (m, 1 H), 4.11-4.24 (m, 2 H), 4.44 (dd, J=10.25, 7.68 Hz, 1 H), 4.58-4.65 (m, 1 H), 4.84-4.94 (m, 1 H), 5.17 (d, J=1.83 Hz, 1 H), 5.27-5.42 (m, 1 H), 5.67-5.89 (m, 1 H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: OC(CCl)CCCl
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCC(O)CCCl)cc1
Yield: 42 %

Procedure:
Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-methoxyphenol to give white title compound, m.p. 65°-68° C. in 42% yield. The recrystallizing solvent was diethyl ether.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][N:12]=1)=[CH:8][C:7]([N+:22]([O-:24])=[O:23])=[CH:6][CH:5]=2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.N#N.C[Al](C)C>C1C=CC=CC=1>[N:25]1([C:15]([C:14]2[CH:20]=[CH:21][C:11]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=4)[NH:3][C:2]=3[OH:1])=[N:12][CH:13]=2)=[O:16])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(-c2c(O)[nH]c3ccc([N+](=O)[O-])cc23)nc1
Agent: C[Al](C)C
Agent: N#N
Solvent: c1ccccc1
Product: O=C(c1ccc(-c2c(O)[nH]c3ccc([N+](=O)[O-])cc23)nc1)N1CCOCC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 59.7 %

Procedure:
Ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (0.327 g, 1.0 mmol) was suspended in benzene (13 mL) followed by the addition of morpholine (0.218 g, 2.5 mmol). The mixture was stirred (N2 atmosphere) for 5 min at 0° C. To this mixture, trimethyl aluminum (2 M solution in hexane, 2 mL, 4 mmol) was added via a syringe. After 10 min the temperature was raised to 70° C. and the reaction mixture was stirred for 20 h then poured onto an ice-cold aqueous saturated NaHCO3 solution and extracted with chloroform. The combined organic layer was concentrated and the light brown residue was purified on a silica gel column using chloroform/methanol/triethylamine, (50:10:1), as eluent to give 0.22 g (60% yield) of the title compound: 1H NMR (acetone-d6, 400 MHz) δ 8.47 (s, 1 H), 8.41 (s, H), 8.05 (d, J=8 Hz, 1 H), 7.99 (d, J=8 Hz, 1 H), 7.90 (d, J=8 Hz, 1 H), 7.19 (d, J=8 Hz, 1 H), 3.79 (br s, 2 H), 3.73 (br s, 4 H), 2.68 (br s, 4 H); MS (EI) m/z 369 (M+1+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([C:8]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[CH:7][CH:6]=[N:5]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: Clc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(Cl)ccc23)c1
Temperature: 25 °C

Procedure:
The product from Example 13d (0.67 g, 3.36 mmol) and the product from Example 4c (0.78 g, 3.36 mmol) in 10 mL ethanol were heated under reflux for 5.5 hr. The reaction mixture was cooled to room temperature and the solvent was removed concentrated under vacuum leaving yellow solid that was used without further purification (1.43 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1.C(O)(=O)C.[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[Br:22][C:5]1[C:6](=[O:7])[C:2]([CH3:17])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CS(=O)c1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)c1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2,2-dimethyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone (135 mg) in 25 ml of CCl4, were added 1 ml acetic acid and 0.1 ml bromine. The reaction mixture was stirred at room temperature for 2.5 hr. Then the reaction was quenched by adding 10 ml of saturated aqueous sodium thiosulfate. The volatile materials were removed in vacuo, which was followed by extraction with dichloromethane (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate and the magnesium sulfate was filtered off. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (hexane/ethylacetate=1:1) to give 68 mg of 4-bromo-2,2-dimethyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. mp: 117-118° C. NMR: δ1.55 (s, 6H), 2.79 (s, 3H), 7.81 (d, J=8.2 Hz, 2H), 8.38 (d, J=8.2 Hz, 2H). IR (cm−1): 1706, 1601,1555, 1191, 1052.
Reaction SMILES: C1(CCC2C=CN=CC=2)C=CC=CC=1.C(Cl)C1C=CC=CC=1.[Cl-].[CH2:24]([N+:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH4-].[Na+]>CC(C)=O.CO>[CH2:24]([N:31]1[CH2:32][CH:33]=[C:34]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:35][CH2:36]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CCc2cc[n+](Cc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: ClCc1ccccc1
Product: C1=C(CCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 88.3 %

Procedure:
4-(2-Phenylethyl)pyridine (8.5 g, 46 mmol) and benzyl chloride (11.64 g, 92 mmol) were refluxed in acetone for 48 h. The precipitated 1-benzyl-4-(2-phenylethyl)pyridinium chloride was filtered, washed with acetone and dried in vacuo at 50° C. to obtain 9.35 g (65%) off the white solid. 1-Benzyl-4-(2-phenylethyl)pyridinium chloride (9.0 g, 29.0 mmol) was suspended in MeOH (100 mL) and cooled to 0° C. in an ice bath. NaBH4 (4.73 g, 207.2 mmol) was added portionwise with vigorous stirring over 40 min. After cooling and stirring for an additional 1 h, the reaction mixture was concentrated under reduced pressure and partitioned between H2O (50 mL) and CH2Cl2 (50 mL). The layers were separated, and the aqueous phase was re-extracted with CH2Cl2 (50 mL). The combined CH2Cl2 extracts were dried over Na2SO4, and concentrated under reduced pressure to provide 7.1 g (91%) of 1-benzyl-4-(2-phenylethyl)-1,2,3,6-tetrahydropyridine as a pale yellow oil. 1H NMR ((CDCl3) δ2.14 (br s, 2, N--CH2 --C H2 --CH =), 2.27 (t, 2, J=8 Hz, N--C H2 --CH2 --), 2.57 (t,2, J=6 Hz, Ph--C H2 --CH2 --), 2.73 (m, 2, Ph--CH2 --C H2 --), 2.97 (br s, 2, N--C H2--CH=), 3.59 (s, 2, Ph-CH2 --N), 5.41 (m, 1, CH=C--), 7.14-7.38 (m, 10, phenyl). 1-Benzyl-4-(2-phenylethyl)-1,2,3,6-tetrahydropyridine (7.1 g, 25.6 mmol) was refluxed in 85% H3PO4 (50 mL) for 80 h. The reaction mixture was basified with 6N NH4OH and extracted with ether (2×100 mL). The ethereal extracts were dried over MgSO4 and concentrated under reduced pressure to a residue. The crude product was purified by radial flow chromatography on silica (hexane,9:acetone,1) to yield 2.3 g (32%) of 1'-benzyl-2,3-dihydrospiro[indene-1,4'-piperidine] as a straw colored liquid. 1H NMR (CDCl3) δ1.53 (br d, 2, piperidyl β-Heq.), 1.96 (dt, 2, piperidyl β-Hax),2.02 (t, 2, Ph--CH2 --C H2 --, J=6 Hz, ), 2.20 (dt, 2, piperidyl α-Hax), 2.90 (m, 4, Ph-C H2 --CH2 -- & piperidyl α-Heq), 3.59 (s, 2, benzyl), 7.14-7.40 (m, 9, phenyl).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CS(C)=O.O>[Br:22][C:9]1[C:10]([NH2:20])=[N:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=2)[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ncc(N)nc2-c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5,6-di-p-tolylpyrazin-2-amine (step 2) (4.94 g, 17.94 mmol) in DMSO (40 ml), was treated with N-bromosuccinimide (3.19 g, 17.94 mmol). The reaction mixture was stirred at room temperature for 2 hours to give a beige coloured suspension. The suspension was diluted with water (700 ml) and the pH was adjusted to pH 8-9 using a sat. NaHCO3 solution. The suspension was filtered, washed with water (×3) and dried under vacuum to afford the titled compound as a beige coloured solid;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according the general procedure for the synthesis of N-aryl-benzenesulfonamides using (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 4-oxazol-5-yl-benzenesulfonyl chloride and purified by HPLC. MS: m/z 485 (M++1).
Reaction SMILES: C([S:8][CH:9]([CH2:42][N:43]1[CH2:48][CH2:47][S:46][CH2:45][CH2:44]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)(O)[O-:58].[Na+]>ClCCl>[CH:39]1([CH2:38][N:28]([C:17]2[CH:18]=[C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:20]=[C:21]3[C:16]=2[NH:15][C:14]([C:12]2[S:8][CH:9]([CH2:42][N:43]4[CH2:48][CH2:47][S:46](=[O:58])[CH2:45][CH2:44]4)[CH2:10][N:11]=2)=[CH:22]3)[S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:31])[CH2:40][CH2:41]1
Reactant: O=C([O-])O
Reactant: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A mixture of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[(cyclopropylmethyl)(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)-1H-indole-2-carboxamide (355 mg), thioanisole (0.12 mL) and dichloromethane (3 mL) was added thereto at 0° C., and the mixture was stirring at 0° C. for 10 min. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was extracted with concentrated hydrochloric acid, and after basified with the aqueous layer with potassium carbonate, the whole mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the amorphous solid from a fraction eluted with ethyl acetate. To the mixture of the obtained amorphous solid, tetrahydrofurane (5 mL), ethanol (5 mL) and water (5 mL) was added OXONE (registered trade mark, 369 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. To the resulting mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give amorphous solid, which was crystallized from diisopropyl ether to give the title compound (146 mg, yield 47%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][C@H:29]([OH:31])[CH3:30]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][C@H:29]([OH:31])[CH3:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: C[C@@H](O)CN
Solvent: c1ccncc1
Product: C[C@@H](O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 95.7 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) and (R)-1-amino-2-propanol (150 mg) were added to pyridine (450 mg), and the mixture was stirred at 55° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (150 mg) was added to the resultant residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (164 mg) as a colorless powder.