Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[CH:23]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH2:11][S:12][CH2:13][C:14]([O:16]C)=[O:15])(=[O:5])=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][N:2]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[CH:23]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH2:11][S:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:5])=[O:4]
Reactant: COC(=O)CSCc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CSCC(=O)O
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of methyl ({[3-({methyl[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]amino}sulfonyl)-2-thienyl]methyl}thio)acetate (300 mg) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and 1N hydrochloric acid (5 mL) was added to the residue. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (276 mg, yield 96%) as colorless crystals. melting point 193° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[CH:6][CH:5]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:44])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:44])[NH:14]3)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To the suspension of 4-(4-trifluoromethoxy-phenyl)-1H-indole (4.93 g, 17.78 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (261 mL) was added pyridinium tribromide (17.06 g, 53.34 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (105 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (2.05 g, 39%) as a tan solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:16]([Cu])#[N:17]>CN1C(=O)CCC1>[C:16]([C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1)#[N:17]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1cccc2c(Br)c[nH]c12
Solvent: CN1CCCC1=O
Product: N#Cc1c[nH]c2c(C(=O)O)cccc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
7 g of ethyl 3-bromoindole-7-carboxylate are dissolved in 70 g of NMP, and 4 g of CuCN are added. The mixture is heated to 100-140° C. with stirring. After 3 hours, the mixture is subjected to conventional work-up, giving 3-cyanoindole-7-carboxylic acid.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 8 h

Procedure:
To a mixture of the product of Step 1 (100 mg, 0.211 mmol) in methanol was added 10% palladium on carbon (6.74 mg). The reaction mixture was stirred under an atmosphere of hydrogen (balloon) overnight then filtered. The filtrate was concentrated under vacuum to afford the title compound which was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:4][CH:3]=1
Reactant: CSc1ccc(N=Cc2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CSc1ccc(NC(C#N)c2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-fluorobenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2=[CH:11][S:12][CH:13]=[C:9]2[N:8]=[C:7]1[S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[O:5])[CH3:2].C(=O)(O)[O-:25].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2=[CH:11][S:12][CH:13]=[C:9]2[N:8]=[C:7]1[S:14]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)n1c(SCc2cc(OC)ccn2)nc2cscc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)n1c(S(=O)Cc2cc(OC)ccn2)nc2cscc21

Procedure:
To 750 mg (2.1 mmol) of 1-ethoxycarbonyl-2-(4-methoxy-2-picolylmercapto)-1H-thieno[3,4-d]imidazole in 30 ml of methylene chloride and 25 ml of 0.5 N aqueous sodium bicarbonate solution were added dropwise, with stirring, initially 420 mg (2.1 mmol) and then a further 210 mg (1.05 mmol) of 3-chloroperbenzoic acid CH2Cl2. The organic phase was dried over MgSO4 and concentrated in vacuo, and the residue was crystallized from ethyl acetate. Melting point 143° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:22](=[NH:24])[CH3:23])C.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:24][C:22]([CH3:23])=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.19 g, 5 mmol) was mixed with ethylacetimidate hydrochloride (0.91 g, 7 mmol) in DMF (5 ml) and Et3N (2 ml, 15 mmol) was added. The reaction was stirred for 1 h after which time the DMF was evaporated, the residue redissolved in AcOH and 0.5 g of ammonium acetate added and the reaction heated to 100° C. for a further 3 h. The reaction was then concentrated, redissolved in CH2Cl2, washed with NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (CH2Cl2:MeOH 1:0-9:1) to afford the title product (0.14 g, 10%) as a colourless gum. MS: 267.4 (MH+)
Reaction SMILES: [F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:3]=1.C(N(CC)CC)C.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>CN(C)C=O>[F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][N:23]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:24][CH:25]=2)[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CN1C=C2C(=C(C3=CCNCC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C=C2C(=C(C3=CCN(CC(=O)N(C)C)CC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Temperature: 70 °C

Procedure:
To a suspension of Example 48 (100 mg, 0.284 mmol) in N,N-dimethylformamide (4 mL) was added triethylamine (0.237 mL, 1.703 mmol) and 2-chloro-N,N-dimethylacetamide (41.4 mg, 0.341 mmol) and the mixture was heated at 70° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 10-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.57-2.62 (m, 2H), 2.79 (t, J=5.04 Hz, 2H), 2.84 (s, 3H), 2.89 (s, 3H), 3.03 (s, 3H), 3.30-3.37 (m, 4H), 4.07 (s, 2H), 5.85 (s, 1H), 7.26-7.32 (m, 1H), 7.36-7.39 (m, 1H), 7.62-7.66 (m, 1H), 8.24 (d, J=5.19 Hz, 1H), 11.62 (s, 1H). MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: NCCN1CCNCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCCN1CCNCC1

Procedure:
The product was made from D-glucose and N-(β-aminoethyl)-piperazine comparable as in Example A. A resin-like, pale pink product was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (362.3 mg) in a mixture of THF-methanol (5-10 ml) was added 1N sodium hydroxide solution (2.8 ml) at room temperature, and the mixture was stirred at 50° C. for 15 hours. After concentration under reduced pressure, 1N hydrochloric acid was added to pH 3-4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether and hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (283 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-2′,5′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G45) (160 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (115 mg, 0.5 mmol) according to the general procedure K. Obtained as an amorphous white substance (110 mg).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH:10]([C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][CH:17]=1)=[CH2:11]>>[CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH:7]=[CH:6][CH:5]=1)=[CH2:3]
Reactant: CC(Cl)c1ccccc1
Reactant: C=Cc1cccc([Mg]Br)c1
Product: C=Cc1cccc(C(C)c2ccccc2)c1

Procedure:
(1-Chloroethyl)benzene (formula VI) is subjected to coupling reaction with a Grignard reagent of 3-vinylphenylmagnesium bromide (formula VII) in the presence of a catalyst of nickel chloride (II)-diphosphine complex, to obtain 1-(3-vinylphenyl)-1-phenylethane. The reaction is carried out in a nitrogen atmosphere under atmospheric pressure at a temperature of 0° to 80° C. The ratio of (VI)/(VII) may be in the range of about 1.0 to 1.5. ##STR9##
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C[O-].[Na+]>CO>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of N-tert-butyl-1H-indole-6-sulfonamide (3.60 g, 14.2 mmol) and cyclohexanone (4.50 ml, 43.4 mmol) in methanol (72 ml) was added 28% sodium methoxide in methanol solution (17 ml), and the mixture was stirred for 12 hr with heating under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 2N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give N-tert-butyl-3-(cyclohex-1-enyl)-1H-indole-6-sulfonamide (2.82 g, yield 59.7%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[N+:7]([O-])([OH:9])=[O:8].S(=O)(=O)(O)O>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc[nH]c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
4-Methylimidazole (10 g, 0.12 moles), was cooled in a flask, and fuming nitric acid (11 ml, 0.24 moles) was added dropwise. This was followed by the addition of sulfuric acid (11 ml). The reaction was then heated with stirring at 100° C. for 21/2 hours. The cooled reaction mixture was then added to 500 ml of ice water, and the precipitate was filtered off. The filtrate was neutralized with ammonium hydroxide, and filtered again. The combined precipitates were then recrystallized from water to give 6.35 g of 4-methyl-5-nitroimidazole.
Reaction SMILES: CN(CCN(C)C)C.C([Li])(C)(C)C.[CH3:14][C:15]1([CH3:63])[O:19][C:18]2[C:20]([C:29]([C:47]3[C:57]4[O:58][C:59]([CH3:62])([CH3:61])[O:60][C:56]=4[CH:55]=[C:49]4[O:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=34)([C:31]3[C:41]4[S:42][C:43]([CH3:46])([CH3:45])[S:44][C:40]=4[CH:39]=[C:33]4[S:34][C:35]([CH3:38])([CH3:37])[S:36][C:32]=34)[OH:30])=[C:21]3[O:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]3=[CH:28][C:17]=2[O:16]1.[C:64](=[O:66])=[O:65]>C1CCCCC1.CCOCC>[C:64]([C:28]1[C:22]2[O:23][C:24]([CH3:26])([CH3:27])[O:25][C:21]=2[C:20]([C:29]([C:47]2[C:48]3[O:52][C:51]([CH3:54])([CH3:53])[O:50][C:49]=3[C:55]([C:24]([OH:25])=[O:23])=[C:56]3[O:60][C:59]([CH3:62])([CH3:61])[O:58][C:57]=23)([C:31]2[C:32]3[S:36][C:35]([CH3:37])([CH3:38])[S:34][C:33]=3[C:39]([C:15]([OH:19])=[O:16])=[C:40]3[S:44][C:43]([CH3:45])([CH3:46])[S:42][C:41]=23)[OH:30])=[C:18]2[C:17]=1[O:16][C:15]([CH3:63])([CH3:14])[O:19]2)([OH:66])=[O:65]
Reactant: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4SC(C)(C)S6)SC(C)(C)S5)c2O1)OC(C)(C)O3
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)O)c5c3SC(C)(C)S5)SC(C)(C)S4)c3c(c2C(=O)O)OC(C)(C)O3)O1
Reaction time: 0.33 h

Procedure:
Dry TMEDA (1.21 mL, 8.04 mmol) and t-butyllithium (5.36 mL, 1.5M in pentane) were dissolved in dry cyclohexane (12 mL) at 0° C. Bis-(2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxol-4-yl)-mono-(2,2,6,6-tetramethyl benzo[1,2-d:4,5-d']-bis(1,3)dithiol-4-yl)methanol (0.608 g, 0.804 mmol) was then added at ambient temperature as a solid. After 20 min, solid carbon dioxide was added followed by dry ether (50 mL). After stirring for 17 h, the reaction mixture was filtered and the precipitate was dried. The acid was purified by preparative HPLC.
Reaction SMILES: C=O.[F:3][C:4]([F:31])([F:30])[C:5]1[CH:29]=[CH:28][C:8]2[NH:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)[C:7]=2[CH:6]=1.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:31][C:4]([F:30])([F:3])[C:5]1[CH:29]=[CH:28][C:8]2[NH:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH3:32])[C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)[C:7]=2[CH:6]=1
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Reaction time: 0.03 h
Yield: 81 %

Procedure:
Add aqueous 37% formaldehyde (1.1 equiv.) to a solution of (S)-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (470 mg) in dichloroethane (0.2M). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (1.5 equiv). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry over magnesium sulfate, filter and concentrate. Purify the residue via chromatography on silica gel (methylene chloride/methanol (90:10) to afford the title compound as a yellow solid (394 mg, 81%): mp 48-56° C.; 1H NMR (CDCl3): δ 1.70-1.56 (m, 1H), 2.04-1.92 (m, 1H), 2.31 (m, 1H), 2.37 (s, 3H), 2.43 (dt, 1H), 2.81 (t, 1H), 2.89 (d, 1H), 3.13 (t, 1H), 3.25 (s, 3H), 3.38 (t, 2H), 3.73 (bs, 2H), 5.10 (s, 1H), 6.69 (dd, 1H), 6.93-6.88 (m, 2H), 7.00 (dt, 1H), 7.10 (dd, 1H), 7.56-7.50 (m, 2H); MS (ESI/neg) m/z (rel intensity) 417.4 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>C1C=CC=CC=1>[CH2:13]([O:15][C:16](=[O:37])/[CH:17]=[CH:11]/[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][CH:6]=1)[CH3:14]
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/c1c[nH]c2ccc(C)cc12
Temperature: 80 °C
Yield: 95 %

Procedure:
5-methyl-1H-indole-3-carbaldehyde (900 mg, 5.65 mmol) was dissolved in benzene (100 ml), and ethyl(Triphenylphosphoranylidene)acetate (2954.1 mg, 8.48 ml) was drop-wise added. The temperature of mixture was raised to 80° C. and stirred under reflux for 12 hr. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and refined through silica gel chromatography (n-hexane:EtOAc=4:1) to give target compound (1230 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[N:9]=[C:10]([CH3:16])[S:11][C:12]=2C(O)=O)[CH:7]=1.BrC1SC([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=C(C2C=C(Cl)C=CC=2OC)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[N:9]=[C:10]([CH3:16])[S:11][C:12]=2[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nc(C)sc1C(=O)O
Reactant: COc1ccc(Cl)cc1-c1nc(Br)sc1NC(=O)OC(C)(C)C
Product: COc1ccc(Cl)cc1-c1nc(C)sc1NC(=O)OC(C)(C)C

Procedure:
Using 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylic acid, the title compound was prepared following the synthetic procedures described for tert-butyl 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate to give tert-butyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-ylcarbamate. LCMS (ESI) m+H=355.3; 1H NMR (400 MHz, DMSO-d6): δ 7.40 (dd, 1H); 7.32 (d, 1H); 7.11 (d, 1H); 3.77 (s, 3H); 2.55 (s, 3H); 1.42 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH2:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[CH:5]=2)=[O:3])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CC(=O)c1ccc(C(=O)O)c(C)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 13 h

Procedure:
4.46 g of 4-acetyl-2-methylbenzoic acid, 6.08 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 18.2 g of toluene and 3.79 g of triethylamine were fed and the mixture was stirred for 13 hours at 60° C. 12.2 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 11.3 g of triethylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](OC)=O.[NH:14]1C2=NC=CC=C2C=C1CN>>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][NH2:14]
Reactant: COC(=O)c1cc2ncccc2[nH]1
Reactant: NCc1cc2cccnc2[nH]1
Product: NCc1cc2ncccc2[nH]1

Procedure:
Intermediate I was prepared from methyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate (1-1) following similar procedures for synthesizing intermediate H, as described above. MS (m/z): 148 (M+1)+.