Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([NH:14][CH3:15])[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[NH:20]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]1>C(#N)C>[CH3:30][C:28]([CH3:31])([O:27][C:26]([NH:25][CH:22]1[CH2:23][CH2:24][N:20]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7][N:8]3[NH:14][CH3:15])=[CH:3][C:2]=2[F:1])[CH2:21]1)=[O:32])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To 1.00 g (3.68 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.56 g (1.0 equivalent) of 1,8-diazobicyclo-[5,4,0]undec-7-ene and 0.68 g of 1,1-dimethylethyl 3-pyrrolidinylcarbamate. The mixture was refluxed for one hour and stirred at room temperature overnight. The solids were filtered and washed with ether to give 0.92 g of 7-[3-[[(1,1dimethylethoxy)carbonyl]amino]-1-pyrro-lidinyl]-6,8-difluoro-1,4-dihydro-1-(methylamino)-4-oxo-3quinolinecarboxylic acid. A portion of this material (0.38 g) was treated with 10 ml of trifluoroacetic acid for 2 hours and was concentrated. The residue was taken up in aqueous sodium hydroxide to pH 12.5 and then treated with hydrochloric acid to pH 7.0. The solids were filtered to give 0.24 g of 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid, mp 210°-211° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.BrC1C=CC2C3CC(C3)N3C(I)=C(C(N)=O)N=C3C=2C=1.[I-].[C:45]([O:49][C:50]([N:52]1CC([Zn+])C1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:19]4[CH2:20][N:52]([C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:51])[CH2:21]4)=[C:14]([C:16](=[O:17])[NH2:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Reactant: NC(=O)c1nc2n(c1C1CC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: NC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Agent: [I-]
Product: CC(C)(C)OC(=O)N1CC(c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)C1

Procedure:
Similar to as described for 10-bromo-3-cyclopropyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide above, 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was coupled with (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide to give the titled compound after purification by flash column chromatography.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:12]CC)(=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C>[C:4]([NH:2][NH2:3])(=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCC(=O)NN
Yield: 51.2 %

Procedure:
12.2 g of hydrazine hydrate was added to a solution of 15 g of ethyl heptanoate in 20 ml of ethanol, followed by heat-refluxing for 4.5 hours. After the reaction, the reaction mixture was cooled to precipitate a crystal. The crystal was recovered by filtration and recrystallized from 20 ml of ethanol to obtain 7 g of heptanohydrazide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8]([OH:11])(=[O:10])=[O:9])[C:5](N)=[CH:4][C:3]=1[CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:3]1([CH3:13])[CH:4]=[CH:5][C:6]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:7][CH:2]=1
Reactant: Cc1cc(N)c(S(=O)(=O)O)cc1Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
In a typical process for preparing an aqueous solution of an alkali metal salt of 2-chloro-5-amino-4-toluene sulfonic acid, toluene is first reacted with sulfuric acid to produce para-toluene sulfonic acid as the principal product. The sulfonic acid is then reacted with chlorine to produce 2-chloro-para-toluene sulfonic acid as a principal product which is reacted with a mixture of 50 percent nitric acid and 50 percent sulfuric acid to produce 2-chloro-5-nitro-para-toluene sulfonic acid. The nitrated product is then neutralized in an aqueous lime slurry which is subsequently filtered. The aqueous nitrated product is then iron reduced to form an amine and the reaction mixture is neutralized with sodium hydroxide to a pH of about 9.5-10.5 and the resulting solution is subsequently filtered.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([OH:21])=[O:20])[CH:10]=2)=[CH:5][CH:4]=1.CC1C=C(C2C=CC=C([N+:39]([O-:41])=[O:40])C=2)C2C(=CC=CC=2)N=1.[Se](=O)=O.OO>>[N+:39]([C:4]1[CH:5]=[C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([OH:21])=[O:20])[CH:10]=2)[CH:7]=[CH:8][CH:3]=1)([O-:41])=[O:40]
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)c2ccccc2n1
Reactant: COc1ccc(-c2cc(C(=O)O)nc3ccccc23)cc1
Agent: O=[Se]=O
Agent: OO
Product: O=C(O)c1cc(-c2cccc([N+](=O)[O-])c2)c2ccccc2n1

Procedure:
4-(3-nitro phenyl) quinoline 2-carboxylic acid is prepared by analogy as 4-(4-methoxy phenyl) quinoline 2-carboxylic acid described in Example 36 starting from 2-methyl 4-(3-nitro phenyl) quinoline (2.46 10-2 mole), 2.73 g of selenium dioxide and 20.9 ml H2O2 110 vol.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[C:31]([CH3:32])=[C:30](Cl)[N:29]=[CH:28][N:27]=1>ClCCl>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]3[O:7][N:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:9]=3)[CH2:11][CH2:12]2)[C:31]=1[CH3:32]
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Temperature: 27 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride (2.0 gm, 0.008369 moles) and diisopropylethylamine (2.78 gm, 0.0215 moles) in dichloromethane (30 ml) was added to an ice-cooled solution of 4,6-dichloro-5-methylpyrimidine (2.1 gm, 0.001295 moles) in dichloromethane (10 ml) and the reaction was stirred at 27° C. for 2 h. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The crude was purified by flash column chromatography (silica gel, 15% ethyl acetate in hexane) to afford the title compound as a white solid (43% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:53]=[CH:54][CH:55]=1)[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[N:34]=[C:33]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:25][C:26]1[CH:27]=[C:28]([CH:53]=[CH:54][CH:55]=1)[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[N:34]=[C:33]2[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(Oc3cccc(Cl)c3)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(Oc5cccc(Cl)c5)cc34)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
2-Bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (103 mg, 250 μmol) and 5-(3-chlorophenoxy)-1-methyl-3-(tributylstannyl)-1H-indazole (219 mg, 400 μmol.6) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (14.4 mg, 12.5 μmol) and CuI (9.52 mg, 50.0 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (40 g column, 50 μm from Analogix, 0-50% over 30 min) to give 2-(5-(3-chlorophenoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 191 μmol, 77%) as a light yellow solid. 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.32 (s, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.17-7.28 (m, 2H), 6.97-7.06 (m, 1H), 6.79-6.90 (m, 2H), 5.71 (s, 2H), 4.28-4.46 (m, 1H), 4.23 (s, 3H), 3.51-3.66 (m, 2H), 1.22 (d, J=6.4 Hz, 6H), 0.85-1.03 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:66])[CH3:2].C(N(S(F)(F)[F:73])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:73])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile deblocking as in Example 64, yielded 17-ethyl-1,14-dihydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])C(OC1C=CC=CC=1)=O)(=[O:15])=[O:14]>>[CH2:5]([O:4][C:2]([N:17]([S:27]([CH3:30])(=[O:29])=[O:28])[N:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:31][CH2:32][Cl:33])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Reactant: O=C(Cl)OCc1ccccc1
Product: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1)S(C)(=O)=O

Procedure:
2-Benzyloxycarbonyl-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (compound 11) was prepared by reacting benzyl chloroformate with compound 2 using a procedure similar to that described for compound 10d. The compound was isolated as a thick oil in a yield of approximately 41.3% by weight. 1H NMR (acetone-d): δ 7.2-7.6 (5H, m, aromatic H), 5.4 (2H, s, ArCH2), 3.5-4.0 (4H, m, CH2CH2Cl), 3.4 and 3.1 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:59]1([CH2:65][CH2:66][NH2:67])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:67][CH2:66][CH2:65][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1ccccc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), EDCI (97 mg, 0.504 mmol), and 1-hydroxybenzotriazole (68.1 mg, 0.504 mmol) were dissolved in DCM (Volume: 3.0 ml). The reaction was stirred at room temperature for 10 minutes before Hunig's Base (0.088 ml, 0.504 mmol) and 2-phenylethanamine (0.063 ml, 0.504 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude material was recrystallized in ether and ethyl acetate to obtain product as a white solid. (Yield: 76 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.85, 7.62, 7.53, 7.36-7.05, 6.71, 5.48, 4.38, 4.01, 3.26, 2.90, 2.69, 2.39-2.28, 1.61, 1.36
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Product: Nc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 9.90 parts of 2-amino-3-nitrobenzoic acid and 32.4 parts of thionyl chloride was stirred for 15 min at reflux temperature under argon. The excess of thionyl chloride was evaporated, yielding 10.8 parts (100%) of 2-amino-3-nitrobenzoyl chloride (interm. 39).
Reaction SMILES: C[C:2]1(C)[CH2:12][C:11](=O)[C:5]2[C:6]([CH2:9][OH:10])=[CH:7][O:8][C:4]=2[CH2:3]1.[Li]CCCC.CCOC(C)=O>C1COCC1>[O:8]1[C:4]2[CH:3]=[CH:2][CH:12]=[CH:11][C:5]=2[C@H:6]([CH2:9][OH:10])[CH2:7]1
Reactant: CC1(C)CC(=O)c2c(CO)coc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@@H]1COc2ccccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The crude oxirane 19 from above (2.4 g, 7.84 mmol) is dissolved in 50 ml of THF and cooled to −78° C. in a dry-ice bath. At this temperature, n-BuLi (1.6M in hexane, 4.9 ml, 7.84 mmol) is added drop wise. The mixture is then stirred for one hour and allowed to warm up to 0° C. After careful hydrolysis and extraction with EtOAc the crude is purified by Flash-chromatography (ethyl acetate/hexanes (from 5:95 to 25:75), silicagel).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]=[C:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23]>C(#N)C>[C:9]1([NH:8][CH2:15][CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]2=[O:23])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C1CCC(=O)NC1=O
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(CNc2ccccc2)C(=O)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
30 ml absolute triethylamine and 2.75 ml freshly distilled aniline were added to a solution of 1.25 g 3-methylene piperidine-2,6-dione (M. J. Wanner and G. -J. Koomen, Tetrahedron Lett. 1992, 33, 1513-1516) in 100 ml acetonitrile and the mixture was stirred for 16 h at 80° C.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[F:34].[CH2:35]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1)[CH3:36]>C1(C)C=CC=CC=1.C(O)C>[CH2:35]([C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1)[CH3:36].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([CH2:35][CH3:36])=[CH:38][CH:39]=2)=[S:47])=[CH:29][C:28]=1[F:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCc1ccc(C(=O)Cl)cc1
Agent: CCc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
4-Ethyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-ethyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-ethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:22])=[C:8]([C:14]3[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:20][C:17]1[N:16]=[CH:15][C:14]([C:8]2[C:9](=[O:13])[O:10][C:11]3[C:6]([C:7]=2[CH3:22])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(C)c(-c3ccc(OC)nc3)c(=O)oc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc2c(C)c(-c3ccc(O)nc3)c(=O)oc2c1

Procedure:
To a solution of 7-methoxy-3-(6-methoxy-pyridin-3-yl)-4-methyl-chromen-2-one in CH2Cl2 (5 mL) at room temperature was added BBr3 (1.0 N, 24.2 mmoL, 24 mL) dropwise. After addition, the reaction was slightly heated to reflux 4 hours. The reaction was quenched with ice sat. NaHCO3, extracted with 3×CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material. The crude material was re-crystallized in 2:1 hexanes:ethyl acetate to afford the title product as a pale reddish solid.
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.[CH3:13][C@@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH2:15]1.C[O:31][C:32]([CH:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:43](Cl)(=[O:45])=[O:44])[CH2:35]1)=[O:33]>>[CH3:13][C@H:14]1[CH2:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][N:21]=2)[CH2:17][CH2:18][N:19]1[S:43]([C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[CH2:42][CH:34]([C:32]([OH:33])=[O:31])[CH2:35]2)(=[O:45])=[O:44]
Reactant: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Agent: O=C(O)C1Cc2ccccc2C1
Product: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
4-|2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid. The compound 4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 7.82-7.76 (m, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (t, 1H), 6.93-6.88 (m, 1H), 4.35-4.18 (m, 2H), 4.18-4.02 (m, 1H), 3.60-3.46 (m, 1H), 3.45-3.10 (m, 7H), 2.97-2.80 (m, 1H), 1.06-1.01 (m, 3H); MS (ESI): 470.0 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:34].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(Cl)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(Cl)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 180 %

Procedure:
Compound 25-3 (760 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.Br[C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:23]([CH3:36])[CH:22]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][N:15]([C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([NH:28][C:29](=[O:35])[CH2:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[C:23]([CH3:36])[CH:22]=1)[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCN(c1cc(C)c(NC(=O)CC(C)(C)C)c(C)c1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (134 mg, 0.67 mmol) and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) were then. added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, filtered through a pad of silica gel, and recrystallized from toluene to afford the title compound as a solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH3:15])(=O)=O)=CC=1.[F:21][C:22]([F:34])([F:33])[CH2:23][CH2:24][S:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:27])=[O:26].[H-].[Na+].Cl>CN(C)C=O>[F:17][C:16]([F:19])([F:18])[C:13]([CH2:14][CH3:15])=[CH:12][CH2:11][CH:28]([S:25]([CH2:24][CH2:23][C:22]([F:21])([F:33])[F:34])(=[O:26])=[O:27])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: CCC(=CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=CCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
To a solution of 3.0 g of 3-trifluoromethyl-2-pentenyl p-toluenesulfonate and 2.3 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of N,N-dimethylformamide was added 0.4 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was stirred at the same temperature for 10 hours, at 60° C. for 6 hours and then at 90° C. for 1 hour. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.86 μg of methyl 5-trifluoromethyl-2-(3,3,3-trifluoropropylsulfonyl)-4-heptenoate (hereinafter referred to as the present compound (36)) as a mixture of (E) and (Z) isomers.