Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NCCCl
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNC(C)=O)CCC3)cc1
Temperature: 0 °C
Yield: 38.7 %

Procedure:
A solution of 2.07 g (3.36 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester in 6 ml of acetonitrile was treated successively with 0.82 g (6.72 mmol, 2.0 equiv.) of N-2-chloroethyl acetamide, 0.53 g (5.04 mmol, 1.5 equiv.) of anhydrous sodium carbonate, and 0.056 g (0.34 mmol, 0.1 equiv.) of potassium iodide. This mixture was refluxed for 48 hours. Subsequently, it was poured into 100 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed three times with 20 ml of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was separated on silica gel using ethyl acetate as the eluent and yielded 0.91 g (1.30 mmol, 39.2% of theory) of (3R,4R)-3-[1-(2-acetylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 702 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:19][CH3:20])[CH:9]=2)[N:4]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC.CN(C=O)C>CCOC(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>[CH2:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][CH3:18])[C:11]=1[C:8]1[CH:9]=[C:10]2[C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)=[CH:3][N:4]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=3)[C:5]2=[CH:6][N:7]=1)[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CCc1cccc(CC)c1-c1cc2c(Br)cn(-c3ccc(C(C)C)cc3)c2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1cc2c(-c3nccs3)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (50 mg, 0.11 mmol), 2-tributylstannanyl-thiazole (83 mg, 0.22 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol), and DMF (3 mL) is stirred under nitrogen at 100° C. for 18 h. The mixture is diluted with EtOAc (15 mL) and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue gives 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-thiazol-2-yl-1H-pyrrolo[2,3-c]pyridine as colorless oil: 1H NMR (CDCl3) 9.03 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=1 Hz, 1H), 7.56 (d, J=12 Hz, 2H), 7.46 (d, J=12 Hz, 2H), 7.32 (t, J=7 Hz, 1H), 7.31-7.26 (m, 3H), 7.20 (s, 1H), 3.05 (m, 1H), 2.39 (m, 4H), 1.35 (d, J=8 Hz, 6H), 1.09 (t, J=8 Hz, 6H); LCMS m/z 452.23 (2.93 min).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[C:4]([CH3:16])[CH:3]=1.C(OC([N:24]1[CH2:28][C@H:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][C@H:25]1[C:37](O)=[O:38])=O)(C)(C)C>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:37]([C@@H:25]3[CH2:26][C@@H:27]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH2:28][NH:24]3)=[O:38])=[CH:9][CH:8]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(F)cc2)C[C@H]1C(=O)O
Product: Cc1cc(F)ccc1Oc1ccc(NC(=O)[C@@H]2C[C@@H](Cc3ccc(F)cc3)CN2)cc1
Yield: 93 %

Procedure:
Proceeding as in Reference 6, but substituting 4-(4-fluoro-2-methylphenoxy)aniline and (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid, gave (2S,4R)—N-(4-(4-fluoro-2-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (359 mg, 93%).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:15]=[CH:14][C:13]=1[C:24]([O:26]C1C=CC=CN=1)=S>O1CCCC1>[NH2:11][C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[N:15]=[CH:14][C:13]=1[C:24](=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: Nc1c(C(=S)Oc2ccccn2)cnn1-c1ccc(F)cc1
Reactant: COc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Into an oven dried flask containing magnesium turnings (0.408 g, 17 mmol) and tetrahydrofuran (10 ml) was added 3-bromoanisole (3.1 g, 17 mmol ) and the reaction mixture was heated at reflux. After 2 h, the reaction mixture was cooled to room temperature and 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (1.5 g, 4.8 mmol) was added and the stirring was continued for 1 h. The reaction mixture was quenched with water and the product was extracted into ethyl acetate. The organic layer was washed with aqueous ammonium chloride and brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was filtered and washed with hexane to give 5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)pyrazole (1.20 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[ClH:33].[F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCCN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc43)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3C[C@@]4(CCCNC4)c4cc(F)ccc43)c21
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 5-fluoro-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-piperidine]-1′-carboxylate (0.110 g, 0.251 mmol) in DCM (3 mL) was added 4N HCl in dioxane (0.63 mL). The reaction mixture was stirred overnight and then filtered. Evaporation of the mother liquid gave (R)-4-((S)-5-fluorospiro[indoline-3,3′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochlorid. LCMS (APCI+) m/z 339 [M+H]+; Rt=2.29 min. The solid collected by filtration was suspended in 5:1 MeCN/MeOH (1 mL) and heated at reflux for about 5 minutes. After cooling, the precipitated solid was filtered and dried in air to give (R)-4-((R)-5-fluorospiro[indoline-3,3′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride. LCMS (APCI+) m/z 339 [M+H]+; Rt=2.31 min.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][O:5][C:3]1=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[S:18])[NH2:17])=[CH:12][C:11]=1[CH2:19][CH2:20][CH3:21]>C(O)C>[S:18]1[C:2]2[CH2:8][CH2:7][CH2:6][O:5][C:3]=2[N:17]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[C:11]([CH2:19][CH2:20][CH3:21])[CH:12]=1
Reactant: CCCc1cc(C(N)=S)ccc1O
Reactant: O=C1OCCCC1Br
Solvent: CCO
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1O
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A stirred mixture of α-bromo-δ-valerolactone (77% pure; 300 g, 1.3 mol), 4-hydroxy-3-propylbenzenecarbothioamide (229.09 g; 1.2 mol) (Example 504), and absolute ethanol (2.5 L) was gradually heated under nitrogen. A significant gas evolution occurred. When the latter had slowed, the mixture was brought to reflux. After 16 h at reflux, the mixture was cooled to rt, and then concentrated in vacuo. The residue was taken-up in 50% dichloromethane/hexanes, filtered, and the solid triturated and washed with more of the solvent mixture (700 mL total). After washing with hexanes and drying in vacuo, 207.1 g (58%) of the title compound were obtained as a yellow solid. The filtrate was concentrated in vacuo, and the residue chromatographed on silica gel to afford a thick oil containing impure product in which crystals formed. Filtration, trituration, and washing of the solid with ethanol afforded 27.6 g (234.7g total; 66.1% yield) of opaque, pastel orange crystals, mp 152-154° C.; 1H NMR (DMSO-d6): δ 9.8δ (broad exchangeable s, 1H), 7.5 (d, 1H), 7.4 (dd, 1H), 6.8 (d, 1H), 4.2 (t, 2H), 2.7 (t, 2H), 2.5 (t, 2H), 2.0 (m, 2H), 1.5 (m, 2H), 0.9 (t, 3H); LCMS: RT=3.0 min, (M+H)+ 276.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C@H:21]3[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:22])[N:14]([CH2:23][CH2:24]Br)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C@H:21]3[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:22])[N:14]([CH2:23][CH2:24][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C2=NN(CCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(C2=NN(CCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
A solution of 2 g of compound 112 and 3 g of imidazole in methanol was left for 18 h at room temperature. After evaporating the solvent, the residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was dissolved in ethyl acetate and filtered over silica. The compound crystallized as the hydrochloride from tetrahydrofuran. M.p. 198°-199° C.
Reaction SMILES: O.C([O:5][C@H:6]([CH2:11]Br)[CH2:7][C:8]([OH:10])=[O:9])(=O)C.CO.[OH-].[CH2:16]([N+:20]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32].[O:5]1[CH2:11][C@@H:6]1[CH2:7][C:8]([O-:10])=[O:9]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])C[C@H]1CO1
Reaction time: 2 h

Procedure:
A solution of distilled water (10 ml), (S)-3-acetoxy-4-bromobutyric acid (0.9 g, 0.004 mol) and 1.0M methanol (12 ml, 0.012 mol) in tetrabutylammonium hydroxide was charged to 100 ml flask equipped with a thermometer, pH meter and agitator, and stirred at 0˜5° C. for 2 hours to give (S)-3,4-epoxybutyric acid tetrabutylammonium salt. It was confirmed by a NMR analysis that more than 99% (S)-3,4-epoxybutyric acid tetrabutylammonium salt was converted.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cl)c(B(O)O)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1ccc(Cl)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 29.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-chloro-5-methoxyphenylboronic acid (available from Combi-Blocks Inc.; 75 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-methoxy-biphenyl-2-carboxylic acid (29 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br s, 1H), 8.45-8.58 (m, 2H), 8.34 (d, J=2.0 Hz, 1H), 8.26 (dd, J=7.9, 1.9 Hz, 1H), 8.09 (dd, J=8.4, 1.9 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 3.0 Hz, 1H), 6.92 (d, J=3.0 Hz, 1H), 3.79 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23](OC)=[O:24])[C:4]=2[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:21]=[C:22]([CH2:23][OH:24])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc3c(CO)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of methyl 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 30 (0.37 g, 0.827 mmol) in Tetrahydrofuran (THF) (10 mL) was cooled to 0° C. LiAlH4 (0.038 g, 1 mmol) in THF (3 mL) was added in and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water (0.04 mL), NaOH (15%, 0.04 mL) then water (0.12 mL). Anhydrous MgSO4 was added and the reaction mixture was filtered through celite and washed with EtOAc. Evaporation of the solvent gave the crude product. The crude product was purified on a silica column (1-4% MeOH/DCM) to give the solid (0.32 g, 88%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]=[N:17]1>>[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:7]=4)[NH:11][C:10]3=[O:15])=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]nnc3c1)C(=O)N2
Yield: 25.5 %

Procedure:
The compound was synthesized according to the method described for Example A6 except reacting N-methyl-2-oxoindoline-5-sulfonamide (14 mg, 0.0618 mmol) with 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (10 mg, 0.0680 mmol) to obtain 5.6 mg, 12% of the title compound as a mixture of (E) and (Z) isomers (69:21 by NMR). 1H NMR (400 MHz, d6-DMSO) δ 16.02, 16.00 (bs, 1H), 11.10, 11.15 (s, 1H), 8.55-8.10 (m, 2H), 7.95-7.80 (m, 3H), 7.77-7.60 (m, 1H), 7.27, 7.21 (q, J=5.2 Hz, 1H), 7.07, 7.03 (d, J=8.3 Hz, 1H), 2.44, 2.36 (s, 3H); MS ESI 356.1 [M+H]+, calcd for [C16H13N5O3S+H]+ 356.08.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[S:23]([NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH2:14])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1cc(N)c(S(N)(=O)=O)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.9 %

Procedure:
2-Amino-5-fluoro-4-methoxybenzenesulfonamide (200 mg, 0.91 mmol) and 2,3-dichlorobenzene-1-sulfonyl chloride (290 mg, 1.18 mmol) were dissolved in anhydrous dichloromethane (5 mL). Anhydrous triethylamine (0.290 mL, 2.09 mmol) was added and the reaction was stirred at room temperature for 48 hours under an inert atmosphere. The reaction was quenched using 2 M hydrochloric acid (20 mL) and was extracted with dichloromethane. The combined organic phase were washed with water, dried over magnesium sulfate and concentrated under vacuum. Purification by preparative HPLC gave 23 mg (6% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:3]=1N.Cl.N([O-])=O.[Na+].[I-:18].[K+]>O.CCOC(C)=O>[I:18][C:3]1[CH:5]=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1ccc(S(C)(=O)=O)cc1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(C)(=O)=O)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A cooled (0° C.) solution of 2-methyl-5-(methylsulfonyl)aniline (Intermediate 16; 556 mg; 3.00 mmol) in aqueous hydrogen chloride (5 M, 10 mL; 50 mmol) was treated with sodium nitrite (248 mg; 3.60 mmol) and the resulting mixture was stirred at 0° C. for 30 minutes, before being treated with a solution of potassium iodide (4.98 g; 30 mmol) in water (8 mL). The resulting mixture was stirred at RT for 1 hour, the EtOAc was added and the phases separated. The organic layer was washed twice with an aqueous, saturated sodium thiosulfate solution, then with brine, dried over MgSO4 and concentrated to afford a residue which was purified by column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc to afford the title compound (649 mg, 73%) as a colorless liquid.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[ClH:11].[Cl:12][CH2:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([S:22][CH2:23][CH2:24][CH2:25][Cl:26])[CH:17]=[CH:16][N:15]=1>C(O)(C)C.O>[ClH:12].[ClH:11].[Cl:26][CH2:25][CH2:24][CH2:23][S:22][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:19]=1[O:20][CH3:21]
Reactant: COc1c(SCCCCl)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Yield: 67 %

Procedure:
2-Mercapto-1H-benzimidazole (10 g) and 2-chloromethyl-4-(3-chloropropylthio)-3-methoxypyridine hydrochloride (1 equivalent) are stirred at 80° C. for 5 h in 150 ml of isopropanol and 15 ml of water, the mixture is cooled, and the precipitated solid is filtered off and recrystallized from isopropanol/water. The title compound is obtained as a pale brown powder; m.p. 117-119° C. (dec.); yield: 67% of theory.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][OH:17].O>CS(C)=O>[OH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CNCCO
Solvent: O
Solvent: CS(C)=O
Product: CN(CCO)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.3 %

Procedure:
A solution of 4-fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol) in DMSO (3.5 mL) was added with 2-methylaminoethanol (0.52 mL, 6.5 mmol) and stirred at 100° C. for 5.0 hours. The reaction mixture was added with water and was washed with hexane/ethyl acetate (4/1) to remove impurities. After removing the impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4-[N-(2-hydroxyethyl) methylamino]-2-nitrobenzaldehyde (0.20 g, 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:19]=[CH:18]/[CH2:17][CH2:16][C:15]([O:21][CH2:22][CH3:23])=[O:20])[CH3:9]
Reactant: C=CCCC(=O)OCC
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Product: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Yield: 82 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane described in WO 2004/094362 and ethyl pent-4-enoate, the reaction was carried out in the same manner as the method described in Example 3 (3c) to give the title compound as a colorless oily substance (yield 82%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:12]=[C:11]([C:13](OCC2C=CC=CC=2)=[O:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O.[OH-].[Pd+2].[OH-].[C].CC(C)=O>[CH3:23][N:2]([CH3:1])[C:3]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1N(C)C
Agent: [Pd+2]
Agent: CCOC(=O)Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1N(C)C
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
After dissolving 4-benzyl 1-methyl 2-(dimethylamino)terephthalate (1.66 g, 5.3 mmol) in tetrahydrofuran (30 ml), 20% palladium hydroxide-carbon (0.20 g) was added prior to catalytic reduction for 15 minutes at room temperature and normal pressure. The catalyst was separated off, and the solvent was distilled off under reduced pressure to yield a light yellow amorphous substance. This was dissolved in tetrahydrofuran (15 ml), triethylamine (0.81 ml, 5.8 mmol) was added and ethyl chloroformate (0.55 ml, 5.8 mmol) was added dropwise while stirring on ice. After stirring for 30 minutes, the precipitate was filtered off and the filtrate was cooled to −40° C. and stirred. A solution of sodium borohydride (0.44 g, 11.6 mmol) in 5 ml of water was added dropwise, and the temperature of the mixture was gradually increased to −20° C. over a period of 30 minutes. Acetone was added to the reaction mixture, the insoluble portion was filtered off and the solvent was distilled off under reduced pressure. Water was added to the residue and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate). The title compound (1.02 g) was obtained as a light yellow oil. (92% yield)