Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1.[Sn].[OH-].[Na+]>Br.C(Cl)Cl>[CH3:1][NH:2][C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: CNC1(c2ccccc2)CC=C(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Reaction time: 20 h

Procedure:
Ex. 254 (350 mg, 0.86 mmol) was dissolved in hydrogen bromide/glacial acetic acid (33% HBr, 18 ml). Tin powder (1.02 g, 8.6 mmol) was then added to the mixture in portions at room temperature in the course of 40 min. A yellow suspension was formed. The mixture was stirred for a further 20 h. The mixture was then diluted with methylene chloride (50 ml) and rendered alkaline with 5 N sodium hydroxide solution (50 ml), while cooling with ice. The phases were separated. The aqueous phase was extracted with methylene chloride (3×30 ml). The combined organic phases were dried with Na2SO4 and then filtered. The volatile constituents of the filtrate were removed completely in vacuo. A pale yellow solid (534 mg) remained. This was separated by chromatography [silica gel 60 (50 g); ethyl acetate/methanol 4:1 (500 ml); methanol/ethyl acetate 3:2 (500 ml); 4:1 (500 ml)]. It was possible for N-methyl-1-phenyl-4-(3-(2-(pyridin-4-yl)ethyl)-1H-indol-2-yl)cyclohexanamine (less polar diastereoisomer) (178 mg, 50%, m.p.: 251-256° C.) and the more polar diastereoisomer (97 mg, 28%, m.p.: 224-227° C.) to be obtained in this way.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: C1COCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and morpholine. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-acetamide (45 mg) in N,N-dimethylformamide (10 mL) was added potassium phosphate (68 mg) and morpholine (0.017 mL). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered (30 mg). 1H-NMR (300 MHz, DMSO-d6), 11.68 (br s, 1H), 9.85 (br s, 1H), 8.64 (s, 1H), 8.33 (d, J=9.0 Hz, 2H), 7.89 (t, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.66 (t, 1H), 7.32 (d, J=9.0 Hz, 1H), 3.68 (d, 4), 3.17 (s, 2H), 2.55 (m, 4H).
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=O)=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:26]=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)Cl.C(O)(=O)C>C(OCC)(=O)C>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([NH2:26])=[O:19])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1S2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: NC(=O)Cc1ccc2c(c1)CCc1cccnc1S2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.1 %

Procedure:
A mixture of 100 mg of (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetic acid, 100 mg of dicyclohexylcarbodiimide and 20 ml of chloroform was stirred under a nitrogen atmosphere at 0° C. for 20 minutes. To the resulting mixture was slowly added 1 ml of chloroform containing excess ammonia. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. To this was added 500 g of ice water, and the mixture was acidified with acetic acid and extracted with 50 ml of chloroform. The extract was washed with water, a 5% sodium hydrogen carbonate solution and then with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, to which was added ethyl acetate, and the mixture was filtered to remove any unsoluble substance. Thereafter, the solvent was removed by distillation to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/ethanol (100/1) to obtain a solid. This was recrystallized from benzene/n-hexane to give 24 mg (yield: 24%) of (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetamide as a colorless powder having a melting point of 165°-166° C.
Reaction SMILES: CS(Cl)(=O)=O.[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C.[OH:30][C:31]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35](O)[CH:34]=[CH:33][C:32]=1[C:41](=[O:43])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.CN(C)C=O.C(OCC)C>[C:41]([C:32]1[CH:33]=[CH:34][C:35]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([S:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH:11]=[CH:12][CH:13]=2)=[C:36]([CH2:37][CH2:38][CH3:39])[C:31]=1[OH:30])(=[O:43])[CH3:42]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(Sc2cccc(CO)c2)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1c(OCc2cccc(Sc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Reaction time: 1 h
Yield: 76 %

Procedure:
Add methanesulfonyl chloride (0.119 g, 1.04 mmol) to a solution of 3-(3-hydroxymethyl-phenylsulfanyl)-benzonitrile (0.250 g, 1.04 mmol) and triethylamine (0.210 g, 2.07 mmol) in dichloromethane (0.2 M). Stir for 1 h. Evaporate solvent. Dissolve the residue in N,N-dimethylformamide and add 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (0.201 g, 1.04 mmol). Add cesium carbonate (0.673 g, 2.07 mmol) and stir for 1 h at 60° C. Dilute the reaction mixture with diethyl ether and wash with water (3×). Purify the residue by flash chromatography, eluting with hexanes, ramping to 50% ethyl acetate/hexanes to elute the title compound (0.331 mg, 0.790 mmol, 76%): MS (m/z): 416 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:21]I>CC(N(C)C)=O>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N:11]([S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH3:21])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CCS(=O)(=O)NC1CCCCc2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)N(C)C1CCCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A solution of 0.81 g (3 mmol) of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepte (Example 1) in 10 ml of DMA was added dropwise under argon to a suspension of 0.12 g (4.1 mmol) of 80 percent sodium hydride in 5 ml of DMA. After stirring at RT for 3 h, 0.63 g (4.5 mmol) of methyliodide was added dropwise and the mixture was stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 0.64 g of 3-fluoro-5-(N-ethylsulfonyl-N-methylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene was obtained.
Reaction SMILES: Cl.[N+]([O-])(OCCC(C)C)=O.[CH3:11][O:12][C:13]1[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]([NH:21][C@H:22]([C:29]([N:31]=[N+]=[N-])=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:20])=[CH:15][CH:14]=1.[N-]=[N+]=[N-].[CH:39]([O:42][C:43](=[O:55])[CH:44]([OH:54])[C@@H:45](N)[CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:41])[CH3:40]>CN(C)C=O.C(N(CC)CC)C>[CH:39]([O:42][C:43](=[O:55])[CH:44]([OH:54])[C@@H:45]([NH:31][C:29](=[O:30])[C@H:22]([CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)[NH:21][C:19]([O:18][CH2:17][C:16]1[CH:34]=[CH:35][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:20])[CH2:46][CH:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1)([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)C(O)[C@@H](N)CC1CCCCC1
Reactant: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N=[N+]=[N-])cc1
Agent: CC(C)CCO[N+](=O)[O-]
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CC2CCCCC2)C(O)C(=O)OC(C)C)cc1

Procedure:
In 15 ml of N,N-dimethylformamide was suspended 1.37 g of the hydrazide compound, and to the suspension were successively added a solution of a 5.95N-dry hydrogen chloride in 2.29 ml of N,N-dimethylformamide and 0.66 ml of isoamyl nitrate with stirring at -20° C. After disappearance of the hydrazide compound, the reaction mixture was cooled to -30° C., and then neutralized by an addition of 1.89 ml of triethylamine to prepare a cold solution of N-(4-methoxybenzyloxycarbonyl)-L-histidine azide. The cold azide solution was added to a solution of 1.00 g of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester in 40 ml of N,N-dimethylformamide with stirring under ice-cooling. The mixture was still stirred for 16 hours, and then the reaction mixture was evaporated under reduced pressure. To the residue was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1) to obtain 1.70 g of (2RS, 3S)-3-[N-(4-methoxybenzyloxycarbonyl)-L-histidyl]amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester as a white powder. In 50 ml of methanol was 1.70 g of the butyric acid isopropyl ester compound, and to the solution were added 10 ml of a 2N hydrochloric acid and 200 mg of a 10% palladium charcoal. The mixture was hydrogenated under an atmospheric pressure. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 1.36 g of (2RS, 3S)-3-(L-histidyl)amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester dihydrochloride as a white powder.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.C([Li])CCC.[CH2:21]([O:23][C:24]([CH:26]1[CH:28]([CH:29]=O)[C:27]1([CH3:32])[CH3:31])=[O:25])[CH3:22].O>O1CCCC1.CCCCCC>[CH2:21]([O:23][C:24]([CH:26]1[CH:28]([CH:29]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:27]1([CH3:31])[CH3:32])=[O:25])[CH3:22]
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1C(C=Cc2ccccc2)C1(C)C
Temperature: -70 °C
Yield: 69.6 %

Procedure:
22.8 g (0.1 mol) of benzylphosphonic acid diethyl ester were dissolved in 400 ml of absolute tetrahydrofuran and the solution was cooled to -70° C. 0.11 mol of n-butyl-lithium (as a 15% strength solution in hexane) were added dropwise under a counter-current of nitrogen and while stirring well; the mixture was then stirred at -70° C. for a further 15 minutes, and thereafter 18.6 g (0.1 mol) of 2,2-dimethyl-3-formyl-cyclopropanecarboxylic acid ethyl ester were added dropwise at -65° C., again still under nitrogen. The reaction mixture was then allowed to come to room temperature and was stirred further for 3 hours at 25° C. Thereafter, the reaction batch was poured into 2 liters of water and extracted with 600 ml of ether. The ether phase was dried over sodium sulphate and the solvent was then stripped off in vacuo. The oily residue was distilled at 145°-150° C./3 mm Hg. 2,2 -Dimethyl-3-(2-phenyl-vinyl)-cyclopropanecarboxylic acid ethyl ester having a refractive index nD23 of 1.5022 was obtained in 69.6% yield.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].[CH:6]1[C:16]2[C:15](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C([O-])(=O)/C=C/C([O-])=O.C1C2C(=C3CCN(C)CC3)C3C=CC=CC=3CSC=2C=CC=1>C(O)C>[CH:6]1[C:16]2[C:15](=[C:17]3[CH2:22][CH2:21][N:20]([CH2:5][CH2:4][C:2](=[O:3])[CH3:1])[CH2:19][CH2:18]3)[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)CSc1ccccc1C2=C1CCNCC1
Reactant: C=CC(C)=O
Agent: CN1CCC(=C2c3ccccc3CSc3ccccc32)CC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Product: CC(=O)CCN1CCC(=C2c3ccccc3CSc3ccccc32)CC1

Procedure:
A solution of 2.8 g of methylvinylketone in 5 cc of ethanol is added dropwise within 2 minutes to a solution of 7.8 g of 4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidine [M.P. of the fumarate 245°-247°, produced in a manner analogous to that described in Example 9(a), from 4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-methylpiperidine] in 25 cc of ethanol. The reaction mixture is heated at reflux for 1 hour, is then completely concentrated at reduced pressure, and the oily residue, the title compound, is converted into the hydrogen fumarate form. M.P. 180°-182° (decomp.) from ethanol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1)=[N+]=[N-].N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.CO.C(OCC)(=O)C>[NH2:1][CH2:4][CH2:5][C:6]1[CH:48]=[CH:47][CH:46]=[CH:45][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:22][CH:23]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])[CH2:13]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN=[N+]=[N-])cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.85 g of tert-butyl 3-{2-[2-(2-azidoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12.5 ml of tetrahydrofuran and 2.5 ml of water is admixed at room temperature with a solution of 1.2 ml of 25% conc. ammonia in 11.2 ml of methanol. After 1.7 g of triphenylphosphine have been added, the reaction mixture is stirred at room temperature over 16 hours. The mixture is diluted with ethyl acetate and washed with semisaturated aqueous sodium hydrogencarbonate solution (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.17.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][OH:11])[C:7]([OH:9])=[O:8].CC(C)([O-])C.[K+].Br[C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>CS(C)=O>[C:23]([O:22][C:20]([C:19]([O:11][N:10]=[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([OH:9])=[O:8])([CH3:28])[CH3:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)C(=NO)c1ccco1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)O)c1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(fur-2-yl)-2-hydroxyiminoacetic acid (syn isomer) (14.1g) in dimethyl sulphoxide (100ml) was added all at once to a magnetically stirred solution of potassium t-butoxide (22.4g) in dimethyl sulphoxide (400ml), the reaction mixture being maintained under an atmosphere of dry nitrogen. A gel was formed which, on stirring, became a finely divided, yellow solid. Stirring was continued for one hour, and then a solution of t-butyl 2-bromo-2-methylpropionate (24.0g) in dimethyl sulphoxide (50ml) was added over one hour to the reaction mixture at room temperature. After addition was complete, the resulting solution was stirred for a further hour. The reaction was poured into ice-water (1.5 liters) and acidified under ether (500ml) to pH 1.8 with concentrated hydrochloric acid. The two layers were separated, and the aqueous layer was extracted with more ether. The combined ether extracts were washed once with water, then extracted with aqueous sodium bicarbonate solution. The combined alkaline extracts were acidified under ether to pH 1.8 with concentrated hydrochloric acid, and the acid solution was extracted further with ether. The combined ether extracts were washed (water, saturated brine), dried and concentrated to a yellow oil, which crystallised under high vacuum (22.41g, 83%), λmax (EtOH) 272.5nm (ε 15,400).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Cl:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[N:31]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:29]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+].Cl.S1C(N)=NC=N1>>[Cl:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[N:31]([CH2:33][C:34]([N:7]1[CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]4[S:22][N:21]=[CH:20][N:19]=4)(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH2:3][C@H:2]1[CH3:1])=[O:35])[CH:30]=[CH:29]2
Reactant: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1
Reactant: O=C(O)Cn1ccc2cccc(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1C(=O)Cn1ccc2cccc(Cl)c21
Yield: 288.7 %

Procedure:
Synthesized according to general procedure 9, method B. The reaction was set up with (R)-4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (400 mg, 1.2 mmol), 2-(7-chloro-1H-indol-1-yl)acetic acid (250 mg, 0.15 mmol), HATU reagent (390 mg, 0.15 mmol), sodium bicarbonate (151 mg, 1.8 mmol), and DMF/CH2Cl2—1/1 (1.0 mL) to obtain the desired amide as a white solid (230 mg, 36% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=531.0; tR=3.21 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(OCC)C>[CH3:1][CH:2]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH:3]=[O:4]
Reactant: CC(CO)CC(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC(C=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
To 2-methyl-4,4,4-trifluoro-1-butanol (7.5 g, 53 mmol) in methylene chloride (CH2Cl2) (125 mL) at 0° C. was added Dess-Martin periodinane (26.5 g, 63.3 mmol). The reaction mixture was warmed to 25° C. and stirred for 20 min. To this mixture was added diethyl ether (Et2O—200 mL) followed by a solution of Na2S2O3 (29.0 g, 185 mmol) in a saturated aqueous solution of sodium bicarbonate (NaHCO3) (200 mL) and 100 mL of water. The milky white mixture was stirred until both phases were homogeneous. The phases were separated and the organic extract was washed with saturated aqueous NaHCO3 (25 mL) and aqueous 1 N Na2S2O3 (25 mL) and dried using magnesium sulfate (MgSO4). Solvents were removed by distillation at atmospheric pressure to give 2-methyl-4,4,4-trifluorobutanal (6.5 g, 88%). 1H nuclear magnetic resonance (NMR) spectrum matched that which was reported in the literature (J. Fluorine Chem. 36: 163-170 (1987).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-n2c(C)ccc2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 60.6 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (400 mg, 1.57 mmol), p-amino-acetophenone (234 mg, 1.73 mmol) and p-toluenesulfonic acid (30 mg) in toluene (40 ml) was heated to reflux for 5 hours. The reaction mixture was cooled, filtered and concentrated. The crude reddish solid (1.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-[4-[2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-1-yl]phenyl]ethanone (336 mg, 61%) as a white solid: mp 179-80° C. Anal Calc'd. for C20H19NSO3 ·0.1 H2O: C, 64.67; H, 5.70; N, 3.77; S, 8.63. Found: C, 64.68; H, 5.52; N, 3.82; S, 8.08.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[CH3:18][C:19]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:20]=1[O:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].Cl>C1COCC1>[CH3:12][N:13]1[C:17]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][O:21][C:20]2[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:19]=2[CH3:18])=[O:26])=[CH:16][CH:15]=[N:14]1
Reactant: Cn1cccn1
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium/n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70° C. to room temperature for 1 hour. The reaction mixture was cooled to −70° C., and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF (10 ml) was added, and the mixture was stirred at −70° C. for 1 hour. After completion of the reaction, 1N hydrochloric acid (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.