Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24](Cl)(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=1>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH3:28])[C:20]([S:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][OH:7])(=[O:25])=[O:26])=[C:21]([CH3:23])[CH:22]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OC[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCC[C@H]2CO)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-pyrrolidin-2-ylmethanol (2.2 g, 8.54 mmol) in dichloro-methane (20 ml) was added triethylamine (2.9 ml, 21.36 mmol) and the mixture was cooled to 0° C. Then a solution of 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (2 g, 8.547 m.mole) in dichloromethane (10 ml) was added and the mixture was stirred at room temperature for 2 h. TLC showed complete consumption of the starting material. The reaction mixture was diluted in dichloromethane and was washed with water and brine. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:46]=[N:45][CH:44]=[CH:43][N:42]=3)[S:39][CH:40]=2)[CH:33]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:46]=[N:45][CH:44]=[CH:43][N:42]=3)[S:39][CH:40]=2)[CH:33]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCc3ccccc3)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2cc(OCc3ccccc3)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A mixture of ethyl 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-pheny-3-pyrrolyl]propionate (347 mg), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred overnight under reflux conditions, and then 1N hydrochloric acid (5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (274 mg, yield: 83%). This was recrystallized from ethanol-hexane. Melting point: 109–110° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C[O-].[Na+:33]>CO>[Na+:33].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[C:26]([C:28]([O-:30])=[O:29])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(/C=C/c2cn3ccnc(N4CCOCC4)c3n2)nc2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1cc(/C=C/c2cn3ccnc(N4CCOCC4)c3n2)nc2ccccc12
Reaction time: 0.17 h

Procedure:
To a slurry of (E)-2-(2-(8-morpholinoimidazo[1,2-a]pyrazin-2-yl)vinyl)quinoline-4-carboxylic acid (32 mg, 0.08 mmol) in MeOH (0.6 mL), 1.5 M NaOMe in MeOH (0.16 mL, 0.08 mmol) was added. The resulting mixture was stirred for 10 min, concentrated, and dried under reduced pressure to obtain the title compound 8. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.36 (d, J=8.6 Hz, 1H), 7.92-8.04 (m, 3H), 7.67-7.82 (m, 4H), 7.55 (t, J=7.6 Hz, 1H), 7.32 (d, J=4.4 Hz, 1H), 4.24-4.32 (m, 4H), 3.89 (t, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H19N5O3: 402.2 (M+H). Found 402.4.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[C:10](Br)([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:18][C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)=[O:17])[CH3:20]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Ex-1A: Catechol (2.2 g, 20 mmol) was dissolved in acetone. Diethyl dibromomalonate (7.0 g, 22 mmol) and potassium carbonate (2.76 g) were added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and water was added to the residue. The residue was extracted with dichloromethane, and the organic phase was washed with brine, dried over magnesium sulfate and evaporated. Chromatography (hexanes/ethyl acetate, 4:1) gave 3.9 g of benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester. 1H-NMR (CDCl3) δ 6.90–6.97 (m, 4H), 4.37 (q, J=7 Hz, 4H), 1.32 (t, J=7 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[C:14]([OH:16])[CH:15]=[C:11]3[CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:27][C:28]([F:43])([S:39](F)(=[O:41])=[O:40])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]>C1COCC1.CCOC(C)=O>[F:43][C:28]([F:27])([S:39]([O:16][C:14]1[CH:15]=[C:11]2[CH2:10][CH2:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]2[N:13]=1)(=[O:41])=[O:40])[C:29]([F:37])([F:38])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]
Reactant: Oc1cc2n(n1)C(c1ccccc1)=CCC2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cc2n(n1)C(c1ccccc1)=CCC2)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Step AAH (7): To a soln of 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-ol (500 mg, 2.356 mmol) in THF (15 mL) was added NaHMDS (1.0 M in THF, 2.94 mL, 2.94 mmol) at −78° C. under nitrogen. After stirring for 10 min, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1281 mg, 4.24 mmol) was added. The mixture was allowed to warm from −78° C. to rt over 3 h. The reaction was diluted with EtOAc (200 mL) and washed sequentially with 0.1 N aqueous sodium hydroxide, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (30% EtOAc/hexanes) to afford 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.0 g, 86% yield). LC-MS (M+H)+ 495.12.
Reaction SMILES: C(O[C:6]([N:8]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)C)=O)(C)(C)C.[ClH:19]>>[ClH:19].[CH3:6][NH:8][N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)N1Cc2ccccc2C1
Agent: Cl
Product: CNN1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
To the crude N-(t-butyloxycarbonyl-N-methylamino)dihydroisoindole from the above preparation was added 25 ml of concentrated hydrochloric acid. The reaction mixture was allowed to stir for one hour. Evaporation of the mixture to dryness and recrystallization of the residue from ethanol-ether gave 5.6 g of the desired product as a gummy solid, mp: 79°-89°. The IR and NMR were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:46]=[CH:45][C:37]([CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:42]4[CH2:41][CH2:40][N:39]([CH2:38][C:37]5[CH:45]=[CH:46][C:34]([O:33][CH3:32])=[CH:35][CH:36]=5)[CH2:44][CH2:43]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: COc1ccc(CN2CCNCC2)cc1
Product: COc1ccc(CN2CCN(C(=O)c3cccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)c3)CC2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-methoxybenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=636.01 (M+H+); retention time=0.62 minutes.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)[NH2:27]>>[CH3:38][N:37]([CH3:39])[S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:27]2)[CH:29]=1)(=[O:36])=[O:35]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: CN(C)S(=O)(=O)c1cccc(NN)c1
Product: CN(C)S(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-hydrazino-N,N-dimethyl-benzenesulfonamide according to the method described for example 91.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]1.Br[C:65]1[C:70]([Cl:71])=[CH:69][CH:68]=[CH:67][N:66]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:71][C:70]1[C:65]([N:53]2[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]2)=[N:66][CH:67]=[CH:68][CH:69]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1cccnc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ncccc2Cl)CC1
Reaction time: 4 h
Yield: 38.8 %

Procedure:
Sodium tert-butoxide (0.936 g, 9.74 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.364 g, 0.585 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.178 g, 0.195 mmol) were added to a solution of ethyl piperidine-4-carboxylate (2.45 g, 15.6 mmol) and 2-bromo-3-chloropyridine (1.50 g, 7.79 mmol) in toluene (30 mL) under a nitrogen atmosphere, and the mixture was stirred for 4 hours under heating to reflux. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=90/10] to obtain the title compound (0.813 g, yield: 39%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:18][NH2:19]
Reactant: NN
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Solvent: OCCO
Solvent: O
Product: COc1cccc(C(=NN)c2sccc2Br)c1
Temperature: 130 °C

Procedure:
A mixture of (3-bromothien-2-yl) (3-methoxyphenyl)methanone (10.0 g), hydrazine hydrate (10 ml, above 99% purity), and 75 ml of ethylene glycol was heated at 130° C. for three hours. The reaction mixture was then quenched with water and extracted with ether. The ether solution was washed three times with water and dried over anhydrous magnesium sulfate. The ether was then evaporated to give 5.5 g of an oil. This was then column chromatographed on a silica gel column packed in hexane using 15% ether/hexane as an eluent. The solid from the column was then recrystallized from ether/hexane.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[CH:14])=[CH:11][CH:12]=1)[CH3:20]
Reactant: CCN(CC)CCOc1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(OCCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere a solution of 1.4 g (4.8 mmol) diethyl-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-amine in 50 mL THF is combined with 1.68 g (5.3 mmol) TBAF and stirred overnight at RT. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH 95:5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N+:41]([O-:43])=[O:42])[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2-c2ccccc2[N+](=O)[O-])cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 125 °C

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (25 mg, 0.53 mmol), 1-fluoro-2-nitrobenzene (14 mg, 0.13 mmol), and potassium carbonate (18.2 mg, 0.13 mmol) were combined in acetonitrile (1.0 mL) and heated via microwave at 125° C. for 30 h. The reaction was concentrated, dissolved in methylene chloride, and washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Purification by column chromatography afforded 20.4 mg (65%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]5[NH:24][CH:23]([C:12]=4[C:11]=3[C:10]=2C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)(=[O:8])=[O:7])=[CH:2]1.Cl>C(OCC)C>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[CH2:19][CH:20]4[NH:24][CH:23]([C:12]3=2)[CH2:22][CH2:21]4)(=[O:8])=[O:7])=[CH:2]1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccsc4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccsc4)ccc31)C1CCC(C2)N1
Yield: 83 %

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 88:12 chloroform/methanol) to give 2-(3-thienyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (84 mg, 83%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.18 (d, J=1.8 Hz, 1H), 8.00-8.05 (m, 1H), 7.68 (dd, J=8.7, 1.8 Hz, 1H), 7.28-7.35 (m, 3H), 4.60 (d, J=5.1 Hz, 1H), 4.05-4.15 (m, 1H), 3.60 (s, 3H), 3.17 (dd, J=16.5, 4.5 Hz, 1H), 2.53 (d, J=16.5 Hz, 1H), 1.95-2.29 (m, 3H), 1.51-1.65 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)CCc1cccc(Br)c1
Reactant: CO
Product: COC(=O)CCc1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 34, Step 1, using 3-(3-bromo-phenyl)-propionic acid and methanol.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15](=[O:35])[CH:16]([NH:27]C(OC(C)(C)C)=O)[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:38]>>[ClH:38].[NH2:27][CH:16]([C:15](=[O:35])[CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The product of part (d) was treated with ethereal hydrogen chloride for one hour. The precipitated white solid was filtered and dried, mp=84°-86° C.; found: C,54.40; H, 4.25; N, 6.10; C21H18F6N2O. HCl requires C, 54.26; H, 4.12; N, 6.03%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl.O>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][O:32][C:39]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:40])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Reactant: O=C(O)C1CCCC1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution (20 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (962 mg, 2.066 mmol) synthesized in the same manner as in Example 1, cyclopentanecarboxylic acid (0.448 ml, 4.13 mmol), 2-chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) in methylene chloride was added triethylamine (1.267 ml, 9.09 mmol), and the mixture was stirred at room temperature for 1 hr. 2-Chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) was added, and the mixture was heated under reflux for 1 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was purified by moderate-pressure basic silica gel column (hexane:ethyl acetate=1:3) and concentrated under reduced pressure to give the title compound (yield 261 mg, 22.49%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:29][CH:28]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:25][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:31][CH:32]=1
Reactant: CC1Cc2ccccc2N1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC1Cc2ccccc2N1Cc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of 2-methylindoline (21 μL, 0.16 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (88 mg, 0.415 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (11-20% acetone/CH2Cl2) to give 3-[4-(2-methyl-2,3-dihydro-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (25 mg, 54%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.98 (br. s., 1H), 7.85 (d, J=8.2 Hz, 2H), 7.56 (s, 1H), 7.48 (d, J=7.8 Hz, 2H), 6.99 (d, J=7.2 Hz, 1H), 6.84-6.94 (m, 1H), 6.53 (t, J=7.4 Hz, 1H), 6.31 (d, J=7.8 Hz, 1H), 4.45 (d, J=16.3 Hz, 1H), 4.14-4.27 (m, 1H), 3.57-3.76 (m, 1H), 3.12 (dd, J=15.8, 8.6 Hz, 1H), 2.56 (dd, J=16.0, 9.4 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH2:18][C:32](=[O:33])[C:31]([F:38])([F:37])[F:30])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)nc(SC)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
1-[5-(6-Ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 0.71 mmol) was dissolved in anhydrous THF (7 mL) and cooled to −78° C. under nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide (0.71 mL, 1.0 M) in THF was added. The reaction mixture was stirred at −20° C. under nitrogen atmosphere for 1 h. The reaction mixture was then cooled to −78° C. To this reaction mixture was added ethyl trifluoroacetate (170 μL, 1.43 mmol). The vigorously stirred solution was allowed to warm to ambient temperature overnight. The reaction mixture was poured into 20 mL of ice and water and was brought to pH=3˜4 by adding 10% HCl aqueous solution. The mixture was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo to give crude product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-4,4,4-trifluoro-butane-1,3-dione (272 mg, 98% yield). 1H-NMR (CDCl3): δ 7.81 (m, 1 H), 7.68 (m, 1 H), 6.70 (s, 1 H), 6.47 (s, 1 H), 4.47 (q, J=7.1 Hz, 2 H), 2.61 (s, 3 H), 1.41 (t, J=7.1 Hz, 3 H).