Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:20][CH2:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:43]=2)[C:38]1=[O:50])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].O.[OH-].[Li+]>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.CN(C=O)C>[C:46]([C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:50])[N:37]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:22]=1[CH2:21][OH:20])[CH2:45]2)([CH3:49])([CH3:47])[CH3:48]
Reactant: Cn1nc(Cl)cc(Nc2ccccn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.7 %

Procedure:
A 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 104a (236 mg, 1.00 mmol), 102f (536 mg, 1.20 mmol), sodium carbonate (318 mg, 3.00 mmol), DMF (5 mL), water (2.5 mL) and 1,4-dioxane (8 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.100 mmol) was added, and the reaction mixture was heated at reflux for 14 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a mixture of THF (8 mL), methanol (4 mL) and water (4 mL). To the resulting solution was added lithium hydroxide monohydrate (420 mg, 10.0 mmol). The mixture was stirred for 4 h at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 38% yield (187 mg) of 104 as an off-white solid: mp 236-237° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.58 (s, 1H), 8.28 (dd, 1H, J=5.0, 1.6 Hz), 7.71 (m, 3H), 7.61 (dd, 1H, J=7.9, 1.5 Hz), 7.50 (m, 4H), 6.96 (m, 1H), 4.93 (s, 2H), 4.68 (t, 1H, J=4.9 Hz), 4.42 (d, 2H, J=5.0 Hz), 3.79 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 496.2 (M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[Li])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH3:30])[C:24]=1[C:31]([N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[O:32])(=[O:22])[CH3:21].C1(S(N2C3C(=CC(OC)=CC=3)C=C2[Li])(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH3:30])[C:24]=2[C:31]([N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[O:32])([OH:22])[CH3:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1nccc(C(C)=O)c1C(=O)N(C(C)C)C(C)C
Reactant: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1
Agent: [Li]c1cc2cc(OC)ccc2n1S(=O)(=O)c1ccccc1
Product: COc1nccc(C(C)(O)c2cc3cnccc3n2S(=O)(=O)c2ccccc2)c1C(=O)N(C(C)C)C(C)C

Procedure:
Starting from 1-benzenesulfonyl 2-lithio 5-aza indole and 4-acetyl 3-diisopropylaminocarbonyl 2-methoxy pyridine as reagent with electrophilic character, prepared according to paragraph (a) (stabilization reagent: tetramethylethylenediamine).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=O)=O)=[CH:7][N:6]=1)(=O)=O.BrC1C=CC(Br)=CN=1.C[S-].[Na+]>>[CH3:1][S:2][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:14])=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: Brc1ccc(Br)nc1
Agent: C[S-]
Agent: [Na+]
Product: CSc1ccc(SC)nc1

Procedure:
The 2,5-bismethanesulfonylpyridine was obtained by reacting 2,5-dibromopyridine with sodium thiomethoxide to obtain 2,5-bis-methylthiopyridine, and then oxidizing it with metachloroperbenzoic acid. The reaction between 2,5-dibromopyridine and sodium methoxide and the oxidation of 2,5-bis-methylthiopyridine with metachloroperbenzoic acid may be carried out according to ordinary methods.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9](S(C2C=CC(F)=CC=2F)(=O)=O)[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])(=[O:11])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(F)cc1F)N(c1cc(Br)cnc1Cl)S(=O)(=O)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of N-(5-bromo-2-chloropyridin-3-yl)-N-(2,4-difluorophenylsulfonyl)-2,4-difluorobenzenesulfonamide (19.3 g, 34.4 mmol) in dioxane (340 ml) was heated at 80° C. And then 2 N aq. KOH (86.0 ml, 172 mmol) was added to the mixture. After stirring for 30 min, the reaction mixture was cooled to room temperature, and then quenched with 1 N aq. HCl until pH 3. The resulting solid was collected by filtration and washed with water to give the N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide (8.36 g, 63.4%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.25 (1H, t, J=8.4 Hz), 7.58 (1H, t, J=9.2 Hz), 7.77-7.83 (1H, m), 8.03 (1H, d, J=2.0 Hz), 8.44 (1H, d, J=2.0 Hz), 11.04 (1H, brs).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39](Br)[CH:38]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:34][O:35][C:36]([C:37]1[CH:38]=[C:39]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)[C:40]([CH3:43])=[CH:41][CH:42]=1)=[O:45]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
3-trifluoromethylphenylboronic acid (278 mg, 1.46 mmol), tris(dibenzylideneacetone)-dipalladium(0) (61 mg, 0.066 mmol), potassium fluoride (255 mg, 4.38 mmol) and tri-tert-butylphosphonium tetrafluoroborate (46 mg, 0.159 mmol) in a flask were thoroughly flushed with argon. 3-bromo-4-methylbenzoic acid methyl ester (304 mg, 1.32 mmol) was added as solution in dioxane (5 ml). the mixture was stirred at 70° C. for 3 h, filtered over silica and evaporated to dryness. The raw material was purified by silica gel chromatography with a hetane/ethyl acetate gradient to yield the title compound (323 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(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>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:34]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: COCCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COCCOCCn1cc(-c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)cn1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 50 mg, 0.160 mmol), 1-[2-(2-methoxy-ethoxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 233.1, 47 mg, 0.160 mmol), Pd(PPh3)2Cl2 (6 mg, 0.008 mmol) and 2 M K2CO3 (216 μL, 0.432 mmol) in DME (1 mL) was stirred at 95° C. for 1 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified twice by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound as a foam (tR 3.56 min (conditions 3), MH+=447.1, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.42 (s, 1H); 8.33 (d, 1H); 8.08 (m, 2H); 8.01 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.55 (s, 2H); 4.31 (t, 2H); 3.79 (t, 2H); 3.50 (m, 2H); 3.36 (m, 2H); 3.15 (s, 3H)).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)=O.C(O)(C)C.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:59]1([CH2:65][CH2:66][NH2:67])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:67][CH2:66][CH2:65][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCc1ccccc1
Reactant: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCCCc1nc2ccc(C(=O)NCCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: -20 °C

Procedure:
484 mg (1 mmol) of tert.-butyl 4'-[(2-n-butyl-6-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate are dissolved in 10 ml of absolute tetrahydrofuran and cooled to -20° C. with stirring and cooling with dry ice/isopropanol. At this temperature 101 mg (1 mmol) of N-methylmorpholine are added. The resulting mixture is then cooled to -30° C. and a solution of 136 mg (1 mmol) of isobutylchloroformate dissolved in 5 ml of absolute tetrahydrofuran is slowly added dropwise. To complete the formation of the mixed anhydride the mixture is stirred for a further hour at -40° C. At -40° C. 134 mg (1.1 mmol) of 2-phenylethylamine dissolved in 2 ml of absolute tetrahydrofuran are slowly added dropwise. Then the mixture is allowed to rise slowly to ambient temperature and stirred for 16 hours at ambient temperature. The solvent is distilled off, the remaining viscous oil is taken up in saturated common salt solution/ethyl acetate and extracted 3 times in all with ethyl acetate. The ethyl acetate phases are dried over sodium sulphate and evaporated down. The viscous oil is dissolved in methylene chloride and purified over a silicon gel column (eluant: methylene chloride/ethanol 50:1 and 25:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18]Br>CN(C=O)C>[Br:16][CH2:17][CH2:18][O:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: BrCCBr
Reactant: Oc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1OCCBr
Temperature: 100 °C
Yield: 48.9 %

Procedure:
Into a 10 mL round bottom flask was added 2,6-dichlorophenol (326 mg, 2 mmol) and DMF (2 mL). Potassium carbonate (276 mg, 2 mmol, 10 eq) and 1,2-dibromoethane (3.76 g, 20 mmol, 10 eq) was added. The flask was fitted with a reflux condenser and nitrogen inlet and the reaction heated to 100° C. for 2 hours. The mixture was partitioned between water (20 mL) and chloroform (20 mL). The organic layer was separated and the aqueous layer was further extracted with chloroform (3×20 mL). The organic layers were combined, washed twice with 10% sodium carbonate (20 mL) and once with brine (20 mL). The combined organic phase was dried over sodium sulfate and filtered. Solvent was removed under vacuum to leave a brown oil of 2A (264 mg, 49%) which was analytically pure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[NH:12][CH:11]=[CH:10][C:9]=2[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2].[CH3:27][N:28]([CH2:30][CH2:31][CH2:32]Cl)[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[N:12]([CH2:32][CH2:31][CH2:30][N:28]([CH3:29])[CH3:27])[CH:11]=[CH:10][C:9]=2[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)Nc2ccn(CCCN(C)C)c(=O)c2C1c1cccc([N+](=O)[O-])c1

Procedure:
6.9 g (19.4 mmol) of 1,4,5,6-tetrahydro-2-methyl-4-(3-nitrophenyl)-5-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester prepared according to Example 1, and 2.4 g (19.4 mmol) of N,N-dimethylaminopropylchloride are kept at boiling temperature for 48 hours with 10.7 g (77.6 mmol) potassium carbonate in 500 ml acetone. The product is reduced in volume to dryness under vacuum, the residue is taken up in 500 ml water and 500 ml methylene chloride and the organic phase washed with 500 ml water and dried over sodium sulfate. The brown crude product obtained after removing the solvent in vacuo is recrystallized twice from acetonitrile/ethanol. There is obtained 1,4,5,6-tetrahydro-6-(3-dimethylaminopropyl)-2-methyl-4-(3-nitrophenyl)-5-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester in the form of yellow needles with a melting point of 212°-213° C.
Reaction SMILES: C([NH:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)C(F)(F)F)[C:11]2=[O:22])=[CH:7][C:6]=1[N+:25]([O-:27])=[O:26])(=O)C.[OH-].[Na+]>CCO>[NH2:15][C@H:12]1[CH2:13][CH2:14][N:10]([CH2:9][C:8]2[CH:23]=[CH:24][C:5]([NH2:4])=[C:6]([N+:25]([O-:27])=[O:26])[CH:7]=2)[C:11]1=[O:22]
Reactant: CC(=O)Nc1ccc(CN2CC[C@H](NC(=O)C(F)(F)F)C2=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(CN2CC[C@H](N)C2=O)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 52.7 %

Procedure:
To a solution of N-[1-(4-acetylamino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2 -trifluoroacetamide (0.65 g, 1.67 mmol) in EtOH (4 mL) is added 1 N NaOH (6 mL) solution. The yellow mixture is heated at 50° C. for 3 hours as a brown solution resulted. The reaction mixture is allowed to cool and then concentrated in vacuo. The crude residue is diluted with water and 1N NaOH 10 mL) and the aqueous phase is extracted with CHCl3 (4×50 mL). The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (0.22 g, 0.88 mmol) as a yellow solid which is used as is in the subsequent step.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:31]([C:32]#[N:33])=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[S:29][C:28]=2[CH:42]=1>O1CCCC1>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:31]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)([CH:32]=[NH:33])[CH:30]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[S:29][C:28]=2[CH:42]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C#N)cc1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(C2Sc3cc(OC)ccc3C2(C=N)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-[2-(1-piperidinyl)ethoxy]bromobenzene (114.5 mg, 0.357 mmol) in tetrahydrofuran (2 ml) at -78° C. is added secbutyl lithium (0.275 ml of a 1.3 M solution, 0.358 mmol). The resulting solution is stirred at that temperature for 30 minutes, then a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonitrile (98.5 mg, 0.333 mmol) in tetrahydrofuran (1 ml) is added. The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction is then quenched by addition of saturated aqueous ammonium chloride (2 ml) and partitioned between methylene chloride and water. The layers are separated, and the aqueous layer extracted again with methylene chloride. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated to an oil, which is chromatographed on silica gel (95:5:0.2 dichloromethane:methanol:triethylamine) to afford a fraction containing desired product. This fraction is concentrated and further chromatographed on silica gel (10:5:1 hexanes:dichloromethane:triethylamine) to afford, after drying in vacuo, 78.6 mg (47%) of title compound as an oil. IR (KBr) 2933, 1607, 1501, 1249, 1032 cm-1 ; 1H NMR (CDCl3): δ7.71 (d, 2 H, J=8.4 Hz), 7.42 (d, 2 H, J=8.7 Hz), 7.26 (m, 2 H), 6.90 (dd, 1 H, J=8.9, 2.2 Hz), 6.80 (m, 4 H), 4.10 (t, 2 H, J=6.0 Hz), 3.87 (s, 3 H), 3.76 (s, 3 H), 22.76 (t, 2 H, J=6.0 Hz), 2.50 (m, 4 H), 1.58 (m, 4 H), 1.44 (m, 2 H); 13C NMR (CDCl3): d 173.4, 161.4, 159.6, 157.7, 139.9, 138.5, 134.0, 131.1, 130.5, 129.9, 129.7, 125.9, 123.8, 114.7, 114.5, 114.2, 104.8, 66.2, 57.9, 55.7, 55.3, 55.1, 26.0, 24.3. Anal. Calcd. for C30H32N2O3S: C, 71.97; H, 6.44; N, 5.60; S, 6.40. Found: C, 71.73; H, 6.36; N, 5.41; S, 6.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1cccs1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COc1ccc2c(c1)c(C1CCN(Cc3cccc(C(=O)O)c3)CC1)cn2Cc1cccs1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.4 g (7.4 mmol) of 5-methoxy-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole (example 89, part C) and 1.9 g (8 mmol) 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 1.4 g (41% of yield) of the expected acid were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>CN(C=O)C.O>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:38][CH2:37]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Indole-5-carboxylic acid (4.09 g, 25.4 mmol) was dissolved in DMF (200 mL), and the solution was added with EDCI (9.74 g, 50.8 mmol) and HOBT monohydrate (1.95 g, 12.7 mmol) under ice-cooling, followed by stirring at the same temperature for 10 minutes. Then, the reaction mixture was added with N-methylpiperazine (8.45 mL, 76.2 mmol), followed by stirring at room temperature for 3.7 hours. The reaction mixture was added with water and extracted with ethyl acetate and chloroform. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=100/0, 90/10) to obtain 5-(4-methylpiperazin-1-ylcarbonyl)indole (5.81 g, yield 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C(O)=O)=[CH:6][CH:7]=1.[C:11]([Cl:14])(Cl)=[O:12]>ClC1C=CC=CC=1>[C:2]1([CH3:1])[C:7]([C:11]([Cl:14])=[O:12])=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: Clc1ccccc1
Product: Cc1ccccc1C(=O)Cl
Reaction time: 3 h

Procedure:
81.4 g (0.6 mol) of p-toluic acid and 892 g of monochlorobenzene are introduced into the reactor and 582 g (5.9 mol) of phosgene are then added. The set pressure is adjusted to 11.2 bar relative and the reaction medium is heated. The reaction is complete after 3 hours. Analysis of the final reaction medium is carried out by gas chromatography. The level of residual acid is 0.3 mol % and the level of toluoyl chloride obtained is 99.7 mol %.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([NH:11][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Br)cc2[nH]ccc12
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)cc3[nH]ccc23)cc1
Yield: 118.5 %

Procedure:
6-Bromo-1H-indol-4-amine (500 mg, 1.97 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (446 mg, 2.16 mmol) according to the method described in Preparation 15b to give 890 mg (100% yield) of the title compound. Purity 87%.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:27]([O-:29])=[O:28])=[C:19]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[CH:20]=1.CC(C)=O>C(O)(C)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:27]([O-:29])=[O:28])=[C:19]([NH:21][C:22]([CH3:26])([C:23]([OH:3])=[O:24])[CH3:25])[CH:20]=1
Reactant: CC(C)=O
Reactant: CC(C)(CO)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O

Procedure:
Jones reagent (2.67 M) is added in aliquots (40 ml, 20 ml, 20 ml, 20 ml and 10 ml) every 15 min to a solution of 2-[N-(5-Chloro-2-nitrophenyl)]amino-2-methyl-1-propanol (IX,EXAMPLE 9, 26.9 g) and acetone (2.05 l) at 0° until the reaction is done as measured by TLC. Isopropanol (150 ml) is added and the mixture is allowed to warm to 20°-25°. The mixture is filtered and the solids are washed with acetone several times. The combined filtrates are concentrated and partitioned between ether (800 ml) and potassium hydroxide (10%, 3×100 ml). The basic layers are acidified (3 N hydrochloric acid) and extracted with methylene chloride (3×180 ml). The methylene chloride layers are dried over magnesium sulfate, filtered, and concentrated to provide the title compound, mp 146°-147°; IR (mineral oil) 3363, 2953, 2924, 2855, 1707, 1613, 1573, 1495, 1336, 1272, 1241 and 753 cm-1 ; NMR (CDCl3) 8.48, 8.16, 6.68, 6.64 and 1.74 δ; MS (EI, m/z) 258 and 213.