Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O>CN1CCCC1=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CSc1nccc(C(Br)C(=O)c2ccc(F)cc2)n1
Reactant: Nc1nccnc1Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(Cl)nccn23)n1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a solution of 3-chloropyrazin-2-ylamine (1.3 g, 10 mmol) in 1-methyl-2-pyrrolidinone (1 mL) heated to about 150° C. was added dropwise over about 15 min a solution of 2-bromo-1-(4-fluorophenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethanone (prepared according to WO2003000682; 0.34 g, 1 mmol) in 1-methyl-2-pyrrolidinone (1 mL). After about 30 min of stirring at about 150° C., the mixture was cooled to ambient temperature, diluted with DCM, extracted three times with 1N HCl and six times with 2N NaOH. The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography with heptane/EtOAc (stepwise gradient, 5:1, 3:1) to give 0.019 g (5%) of the title compound: LC/MS (Table 1, Method b) Rt=2.28 min; MS m/z: 372.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([O:18][CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][C:15]2[CH:16]=[CH:17][C:12]([O:18][CH2:19][CH3:20])=[CH:13][CH:14]=2)[CH:10]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: CCOc1ccccc1
Product: CCOc1ccc(Cc2cc(Br)ccc2C)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-methylbenzoic acid (synthesized in reference to International Patent Publication WO0127128) and phenetole.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:26]C(=O)OC(C)(C)C)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.[CH2:35]([O:42][C:43]1[CH:44]=[C:45]([SH:49])[CH:46]=[CH:47][CH:48]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:26][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:44]=3)[CH:14]=2)[CH:9]=1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)COC(C)(C)OC1
Reactant: Sc1cccc(OCc2ccccc2)c1
Product: NC(CO)(CO)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1

Procedure:
The compound was prepared from tert-butyl 2,2-dimethyl-5-(6-(trifluoromethylsulfonyloxy)naphthalen2-yl)-1,3-dioxan-5-ylcarbamate and 3-benzyloxy-benzenethiol in reactions analogous to those described in Examples 154 and 191. 1H NMR (MeOD) δ: 7.82 (s, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.48 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (dd, J=8.6, 1.5 Hz, 1H), 7.11-7.26 (m, 6H), 6.80-6.89 (m, 3H), 4.93 (s, 2H), 3.95-4.03 (m, 2H), 3.86-3.94 (m, 2H). MS (M+1): 432.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]([CH3:21])=[C:12]([CH2:14][C:15]([CH3:20])([N+:17]([O-])=O)[CH3:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]([CH3:21])=[C:12]([CH2:14][C:15]([NH2:17])([CH3:16])[CH3:20])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CC(C)(C)[N+](=O)[O-])c(C)[nH]2)cc1F
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc(CC(C)(C)N)c(C)[nH]2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
To a solution of 2-(3-fluoro-4-methyl-phenyl)-5-methyl-4-(2-methyl-2-nitro-propyl)-1H-imidazole (1.6 g) in acetic acid (32 ml) was added in 2 equal portions of Zn dust (5.2 g) in 15 minutes at 20-25° C. The slightly exothermic reaction was stirred at RT for 1.5 h, the inorganic salts filtered off, and washed with acetic acid. The filtrate was concentrated almost to dryness, the residue quenched with cold conc. NaOH and brine, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to dryness to obtain 2-[2-(3-fluoro-4-methyl-phenyl)-5-methyl-1H-imidazol-4-yl]-1,1-dimethyl-ethylamine (1.16 g) as a light yellow foam, pure enough to be used in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=1)[N:5]=[CH:4][NH:3][C:2]2=[O:1])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c(=O)[nH]cnc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c(=O)[nH]cnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a suspension of 4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (500 mg, 2.63 mmol) in 3 mL of sulfuric acid at 0° C., fuming nitric acid was added portionly. The resulting mixture was then stirred at 60° C. overnight. After cooling to rt, the reaction mixture was poured into ice-water slowly. The yellow precipitate was collected by filtration, and washing with water as the desired product in 84% yield. 1HNMR (in DMSO): 8.60 (s, 1H), 8.89 (d, J=2.6 Hz, 1H), 8.91 (d, J=2.6 Hz, 1H). Mass: M+H+: 236.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][C:11]=1[C:19]([O:21][CH3:22])=[O:20].C1COCC1.B.C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ccc1F
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1-c1cc(OC)ccc1F
Temperature: 23 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
To a stirred solution of 2′-fluoro-5′-(methyloxy)-2-((methyloxy)carbonyl)-1,1′-biphenyl-4-carboxylic acid 66.13D (35.60 g, 117 mmol) in THF (1170 mL, 117 mmol) at 0° C. was added borane-THF (234 mL, 234 mmol). The reaction was warmed to 23° C. and stirring was continued for 6 hours. The mixture was then concentrated in vacuo. 1 N HCl was added to the reaction, and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel (0-40% EtOAc in hexane) to give methyl 2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-carboxylate 66.13E as a clear oil (30.00 g, 88% yield). MS ESI (pos.) m/e: 308.0 (M+H2O)+, 291.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:33][O:34][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCC1CCCCC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC3CCCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and cyclohexylmethanol (59.4 mg; 0.515 mmol), example 57 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH:17]=O)=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].C1COCC1.[CH3:34][NH:35][CH3:36]>ClCCl.C(O)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH2:17][N:35]([CH3:36])[CH3:34])=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: CNC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
In a 50 ml round bottom flask 5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde (0.456 gm, 1.0 mmol) was stirred in dichloromethane (5 mL). To this mixture was added a 2M THF solution of dimethyl amine (1.25 ml, 2.5 mmol). The mixture was allowed to stir under nitrogen atmosphere and at room temperature for 2 hours. To this mixture was then added triacetoxy sodium borohydride (0.37 g, 1.75 mmol) followed by two to three drops of acetic acid. The mixture was then stirred at rt overnight. The solvents were then removed by evaporation and the residue was taken up in ethyl acetate (30 ml) and washed with aqueous sodium bicarbonate and brine. The organics were then combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography using a solvent gradient of (3:1) ethyl acetate-hexane to (0:100) ethyl acetate to give 0.14 g (30% yield) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.73-7.58 (m, 2H), 7.42-7.30 (m, 3H), 7.22 (dt, J=8.73, 2.60 Hz, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 3.04 (s, 2H), 1.96 (s, 6H); ES-MS m/z 485.0 (M+H). ES-HRMS m/z 485.0457 (M+H calcd for C21H18BrF4N2O2, requires 485.0489).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:5][Mg]Cl.C(OCC)C.CN(CCN(C)C)C.[Si:25]([O:32][C@H:33]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])/[CH:34]=[N:35]/[S@:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1>[Si:25]([O:32][C@H:33]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[C@@H:34]([NH:35][S@:36]([C:38]([CH3:39])([CH3:40])[CH3:41])=[O:37])[CH2:5][C:4]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26]
Reactant: Fc1cc(Cl)cc(C[Mg]Cl)c1
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A 500 mL RB flask containing (3-chloro-5-fluorobenzyl)magnesium chloride, 0.25 M in diethyl ether (13040 μl, 3260 μmol) was allowed to stir at −78° C. for 5 minutes. At this time, TMEDA (492 μl, 3260 μmol) was added via a syringe and then THF (10 mL) was added via a syringe and the mixture was allowed to stir for 15 min before the addition of (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (550.00 mg, 1304 μmol) (14 mL THF) via a syringe. The reaction was allowed to stir for 30 min and then quenched with ammonium chloride (sat, 100 mL). The aq. layer was extracted with EtOAc (3×100 mL). The combined organics were washed with brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give 1.30 g of a crude oil that was purified on a 120 g ISCO column to give the title compound. Rf=0.40 in 20% EtOAc in hexanes.
Reaction SMILES: C(OC(CCC[O:11][C:12](=[O:32])[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([Cl:20])=[CH:15][C:14]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)(C)(C)C.[Li+].[OH-].OS([O-])(=O)=O.[Na+]>C1COCC1>[Br:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])=[C:13]([CH:18]=1)[C:12]([OH:32])=[O:11]
Reactant: CC(C)(C)OC(=O)CCCOC(=O)c1cc(Br)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
A mixture of 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid 3-tert-butoxycarbonyl-propyl ester (8.2 g, 15.3 mmol) and LiOH (19.1 mL, 4 N, 76.6 mmol) in THF (150 mL) was stirred at rt for 16 hrs. The mixture was acidified by saturated NaHSO4 (50 mL) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash chromatography (eluting with 50% ethyl acetate in hexane), followed by crystallization in hexane/ethyl acetate (10/1) to afford 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid as white crystals (2.5 g). MS [M−(iso-butene+OH)]+: 320.8; tR=2.38 min. (method 1)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCCCCNC1CCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound (28.8 mg) obtained in Example 3-2 was dissolved in methanol (0.5 ml). The solution was added with cyclohexanone (8.80 μl) and sodium cyanoborohydride (4.40 mg) and then adjusted to approximately pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by the addition of 1 mol/l hydrochloric acid to extract the objective substance. Subsequently, the aqueous layer was concentrated under reduced pressure and then the residue was purified through a solid-phase extraction column (Bond Elut® C18 (manufactured by Varian Inc.), 200 mg), thereby obtaining hydrochloride (17.6 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([PH2:5])[CH:2]([CH3:4])[CH3:3].[CH:6]([CH:8]=[O:9])=[O:7]>O1CCCC1>[CH2:1]([P:5]1[CH:6]([OH:7])[CH:8]([OH:9])[P:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]([OH:7])[CH:8]1[OH:9])[CH:2]([CH3:4])[CH3:3]
Reactant: O=CC=O
Reactant: CC(C)CP
Solvent: C1CCOC1
Product: CC(C)CP1C(O)C(O)P(CC(C)C)C(O)C1O
Yield: 97 %

Procedure:
In a suitable autoclave, equipped with mechanical stirring and external heating are added 200 parts of mono-isobutylphosphine (85%) and 300 parts of tetrahydrofuran, as solvent. With no external heating applied to the reactor, 275 parts of a 40% aqueous glyoxal solution are added with stirring at 20-25° C. The resultant solid product is filtered, and dried to give 276 parts (97% yield) of 1,4-diisobutyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 173-175° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[C:14]([OH:16])=[O:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(O)ccc1/C=C/C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a stirring solution of 4-hydroxy-2-methoxybenzaldehyde (1.02 g, 6.70 mmol) and malonic acid (728 mg, 7.00 mmol) in pyridine (9.2 mL) at ambient temperature under nitrogen was added piperidine (0.20 mL, 2.02 mmol) drop-wise. The mixture was then heated to 80° C. over 20 mins and then stirred at this temperature for 2 h. The reaction was then quenched with water (50 mL), acidified to pH 1 with concentrated HCl and then partitioned with EtOAc (50 mL) and the layers separated. The aqueous layer was re-extracted with EtOAc (50 mL) and the combined organic layer washed with brine (80 mL) and then concentrated under vacuum to give a bright yellow solid. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 0:1) afforded the title compound (674 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].N1C=CC=CC=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:2]([C:4]1[CH:9]=[C:8]([O:10][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Under an argon atmosphere, 3-hydroxyacetophenone (0.68 g, 5 mmol) was dissolved in dichloromethane (5 mL), and pyridine (2.0 mL, 25 mmol) and benzoyl chloride (0.70 mL, 6.0 mmol) were added thereto, and then, the mixture was stirred at room temperature for 4 hours. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a 2 mol/L aqueous sodium hydroxide solution, 2 mol/L hydrochloric acid, and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 50/50) to give benzoic acid (3-acetylphenyl)ester (1.19 g, 4.96 mmol, yield: 99%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=O>O1CCCC1.[C].[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CCCCCl)cc1
Yield: 98.5 %

Procedure:
4-Chloro-1-(4-methoxyphenyl)-1-butanone (5 g, 23.5 mmol) was dissolved in tetrahydrofuran (50 ml). 10% Palladium carbon (water-containing product, 500 mg) was added and the mixture was subjected to catalytic reduction under hydrogen pressure (0.8 MPa, 50° C. for 3 h). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 1-(4-chlorobutyl)-4-methoxybenzene (4.6 g, yield 99%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:26]([NH2:28])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[C:10]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>[I-].[K+].CN(C)C=O>[Cl:25][C:21]1[CH:20]=[C:19]([C:17]2[N:18]=[C:14]([N:11]3[C:10]4[CH:29]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH:7]=[CH:8][C:9]=4[N:13]=[CH:12]3)[S:15][C:16]=2[C:26]([NH2:28])=[O:27])[CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCCl)cc32)nc1-c1cccc(Cl)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN4CCCC4)cc32)nc1-c1cccc(Cl)c1
Reaction time: 6 h
Yield: 74.7 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(3-chloro-propoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.34a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.025 mL (0.3 mmole) of pyrrolidine was stirred at 100 degrees for 6 hours. The mixture was concentrated under reduced pressure, and diluted with 20 mL of water. The precipitate was collected by filtration and the solid triturated with diethyl ether to give 0.036 g of 4-(3-chloro-phenyl)-2-[6-(3-pyrrolidin-1-yl-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.34) as a white solid. MH+/Z=482
Reaction SMILES: [CH3:1][CH:2]([S:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:3].[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].C1(C)C=CC=CC=1.O>N1CCCCC1.C(O)(=O)C.CC(C)=O>[CH3:3][CH:2]([S:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[C:29]3[S:25][C:26](=[O:31])[NH:27][C:28]3=[O:30])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:1]
Reactant: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 58.6 %

Procedure:
1.4 g (4 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl 2-propanesulfonate, 0.94 (8 mmole) 2,4-thiazolidinedione, 5 drops of piperidine, 6 drops of acetic acid and toluene were refluxed with water separation in a Dean-Stark apparatus. When the starting material was consumed the heat was removed and the formed crystals were recrystallized in water:acetone to give 1.5 g (yield 58.6%) of 5-(4-[2-(4-(2-propanesulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [ClH:1].N1C=CC=CC=1.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28]C)[CH:24]=3)[C:19]=2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:33][CH:32]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>>[ClH:1].[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:33][CH:32]=3)=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Cc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 200 °C
Yield: 79.3 %

Procedure:
Add pyridine hydrochloride (4 g) to the compound of Example 77 (110 mg, 0.21 mmol). Purge with nitrogen, cap the vessel and heat to 200° C. for 2 hours. Cool the reaction mixture and dilute with saturated aqueous NaHCO3. Extract with CH2Cl2, dry over Na2SO4, filter and concentrate. Purify the crude product by flash chromatography (0-10% MeOH/CH2Cl2). Dissolve the product in 1:1 CH3CN/1M aqueous HCl and lyophilize to afford 92 mg of the title compound (80%). LCMS: m/z=516 (M+H)+−HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)Cc1cn(CC(=O)OCC)c2cccc([N+](=O)[O-])c12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cn(CC(=O)OCC)c2cccc(N)c12
Reaction time: 1.5 h

Procedure:
A mixture of diethyl 2,2′-(4-nitro-1H-indole-1,3-diyl)diacetate from Step E (140 mg, 0.419 mmol) and 10% Pd/C (20 mg) in EtOH (20 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 1.5 h, the reaction mixture was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: m/z=305 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(NC1CCCC1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a solution of 1-(4-bromophenyl)ethanone (500 mg, 2.5 mmol) in ethanol (16 mL) was added cyclopentanamine (320 mg, 3.8 mmol) and the reaction mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to 0° C. and sodium borohydride (140 mg, 3.8 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was quenched with 2 M aqueous ammonium hydroxide and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired product (600 mg, 90%) as a red oil: ESI MS m/z 269 [C13H18BrN+H]+.