Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]1([C:32]2[N:37]=[C:36]3[NH:38][CH:39]=[C:40]([CH:41]=O)[C:35]3=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:41]/[C:40]3[C:35]4[C:36](=[N:37][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:33][CH:34]=4)[NH:38][CH:39]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2nc(-c3ccccc3)ccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(-c5ccccc5)ccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.026 g, 0.075 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.013 g, 0.059 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.019 g, 46%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13](O)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].FC([CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)(F)F>>[C:7]1([N:6]2[CH:5]([C:13]([N:37]3[CH2:38][CH2:33][N:34]([C:39]4[C:44]([C:25]([F:28])([F:27])[F:26])=[CH:43][CH:42]=[CH:41][N:40]=4)[CH2:35][CH2:36]3)=[O:14])[CH2:4][N:3]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])(=[O:18])=[O:17])[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Reactant: FC(F)(F)C1CNCCN1c1ccccn1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid (example 11) was coupled with 1-[3-(trifluoromethyl(pyrid-2-yl]piperazine to give the title compound as an off-white solid. MS: 627.8 ([M+H]+)
Reaction SMILES: [N:1]1([CH:7]([CH3:25])[CH2:8][C:9]2[C:10](=[O:24])[NH:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.N>>[N:1]1([CH:7]([CH3:25])[CH2:8][C:9]2[C:10](=[O:24])[NH:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2=C(CC(C)N3CCCCC3)C(=O)NCCC2)cc1
Agent: Br
Agent: N
Product: CC(CC1=C(c2ccc(O)cc2)CCCNC1=O)N1CCCCC1

Procedure:
The mixture of 22.1 g of 3-(2-piperidinopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone and 128 ml of 48% hydrobromic acid is stirred under reflux for six hours. It is cooled, basified with concentrated ammonia and extracted with chloroform. The extract is dried, evaporated, the residue crystallized from diethyl ether and recrystallized from acetone, to yield the 3-(2-piperidinopropyl)4-(4-hydroxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 178°-181°.
Reaction SMILES: [C:1]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23]>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([OH:23])[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cccc2ccccc12
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1cccc2ccccc12

Procedure:
With 2.81 g of 1-naphthyl bromide 4.34 g, 5-chloroisatin as starting material, 4.30 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:10]=[C:11]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[NH:36][CH2:35][CH2:34]2>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:41])[F:42])[N:36]([C:14](=[O:22])[NH:13][C:11]1[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=[C:9]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:10]=1)[CH2:35][CH2:34]2
Reactant: O=C(Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1)Oc1ccccc1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(-c3ccccc3)cc(-c3cccnc3)c1)CC2
Yield: 198.9 %

Procedure:
The title compound (0.74 g, 47%) was prepared as an off white solid using the methodology of example 28, with phenyl N-(5-phenyl-3-(pyrid-3-yl)phenyl)carbamate (D31) (0.27 g, 0.76 mmol) and 5-methoxy-6-trifluoromethyl indoline (D11) [0.182 mg, 0.83 mmol] in DMF (10 ml). Melting point: 150°-151° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1([CH3:28])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:27])[C:11]([CH3:26])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH3:17])[O:8]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([O:18][C:12]1[C:13]([CH3:17])=[C:14]2[C:9](=[C:10]([CH3:27])[C:11]=1[CH3:26])[O:8][C:7]([CH2:6][CH2:5][OH:4])([CH3:28])[CH2:16][CH2:15]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)OCCC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2

Procedure:
To a solution of 0.5 g. of (±)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman in 15 ml. of methanol was added a solution of 358 mg. of potassium carbonate in 1.5 ml. of water. The mixture was heated at reflux under N2 for 40 minutes, cooled, poured into water and extracted with methylene chloride. The methylene chloride solutions were washed with brine, dried over magnesium sulfate and stripped of solvent to give (±)-6-benzyloxy-2-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman as an oil.
Reaction SMILES: [CH:1]1([C@H:4]2[C@H:8]([OH:9])[CH2:7][C:6](=[O:10])[N:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:2]1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C>[Si:22]([O:9][C@@H:8]1[CH2:7][C:6](=[O:10])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:4]1[CH:1]1[CH2:2][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@@H](O)[C@@H]1C1CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C1CC1
Yield: 90.2 %

Procedure:
(2S,3R)-tert-Butyl 2-cyclopropyl-3-hydroxy-5-oxopyrrolidine-1-carboxylate (16) (1.34 g, 5.55 mmol) was placed in a flame-dried flask under nitrogen. DMF (12 mL) was added and the mixture stirred until dissolved. tert-butylchlorodimethylsilane (1.06 g, 7.02 mmol) and imidazole (0.558 g, 8.19 mmol) were added and the reaction stirred for 16 hr at rt. DMF was removed in vacuo and EtOAc (100 mL) was added and the organics were washed with sat. NaHCO3 (100 mL), brine (100 mL), dried with sodium sulfate, and concentrated in vacuo. The resulting crude product was purified via column chromatography using EtOAc/hexane gradients to yield (2S,3R)-tert-butyl 3-(tert-butyldimethylsilyloxy)-2-cyclopropyl-5-oxopyrrolidine-1-carboxylate (17) (1.78 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:5].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:5][O:21]1)=[O:12]
Reactant: C=C(C(=O)OC)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C1(c2ccccc2)CO1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized according to a literature method (Whitman Tetrahedron 1985, 41, 1183). To a mixture of 2-phenylacrylic acid methyl ester (7.92 g, 45 mmol) in 60 ml of methylene chloride was added mCPBA (13.1 g, 58.5 mmol) and the reaction was stirred at 45° C. overnight. The reaction mixture was then filtered and the solid was washed with methylene chloride. The filtrate was washed three times with 50 ml of equal parts solution consisting of saturated Na2S2O3 and saturated NaHCO3. The organic layer was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to afford the title compound in greater than 95% purity according to 1H NMR (85% yield). 1H NMR (CDCl3, 300 MHz) δ: 7.50-7.30 (m, 5H), 4.22 (q, J=7.2 Hz, 2H), 3.40 (d, J,=7.1 Hz, 1H), 2.95 (d, J=7.1 Hz, 1H), 1.26 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])(=[O:16])=[O:15].Cl.[OH-].[Na+]>C1COCC1.O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])(=[O:16])=[O:15]
Reactant: CC(C)(C#N)S(=O)(=O)c1ccccc1Br
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CN)S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
BH3.THF (4 mL, 1 M in THF) was added drop-wise to a solution of 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile (258 mg, 1.00 mmol) in THF (1 mL) at rt. The mixture was refluxed for 4 hours and then cooled to rt. Aqueous HCl (5 mL, 6 N) was added and stirring continued for an additional 1 hour. The mixture was basified to pH=9 by addition of NaOH (6 N), diluted with water (20 mL), and extracted with DCM (3×20 mL). The combined extracts were washed with water (2×30 mL) and brine (60 mL), dried over Na2SO4, filtered, and concentrated to dryness to give the crude title compound (203 mg, 70%), which was used in the subsequent step without further purification. MS (ESI): mass calcd. for C10H14NO2S, 290.99; m/z found, 292.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:17])[CH3:16].[NH2:19][C@@H:20]([CH:28]([CH3:30])[CH3:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][CH:28]([CH3:30])[C@H:20]([NH:19][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([B:5]2[O:4][C:3]([CH3:17])([CH3:16])[C:2]([CH3:1])([CH3:18])[O:6]2)=[CH:15][CH:14]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.0 g, 8.1 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate (2.0 g, 9.5 mmol) in DMF (10 mL) were added HATU (6.1 g, 16 mmol) and DIEA (4.2 g, 33 mmol). The reaction mixture was stirred at rt overnight. The reaction was then quenched with water (100 mL). The resulting mixture was extracted with DCM (2×100 mL), and the organic layer was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:50)) to obtain compound 43a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H34BNO5: 404.3 (M+H). Found 404.1.
Reaction SMILES: CN1CCOCC1.Cl.[C:9]([Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH2:30][CH2:31][CH2:32][NH2:33])(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCCCCC>ClCCl.C(O)C.C(OCC)(=O)C>[ClH:17].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH:29]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH2:30][CH2:31][CH2:32][NH:33][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Under a nitrogen atmosphere and 0° C., N-methylmorpholine (44.6 μl, 0.406 mmol) and nicotinic acid chloride hydrochloride (36.1 mg, 0.203 mmol) were added to a dichloromethane solution (4 ml) of 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butylamine hydrochloride (67.0 mg, 0.169 mmol). After stirring at room temperature for 3 hours, the reaction mixture was diluted with dichloromethane, washed successively with a saturated aqueous solution of ammonium chloride, water and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:3 eluate was concentrated. The resulting solid was dissolved in ethanol. To the resulting solution was added 1N hydrochloric acid-ethanol (0.5 ml), followed by concentration. The solid thus obtained was recrystallized from ethanol-ethyl acetate, whereby the title compound (67.1 mg, 0.134 mmol, 79%) was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:24][CH2:23]4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:24][CH2:23]4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-yl)-amide (177 mg, 0.37 mmol) was dissolved in CH2Cl2 (3 mL). Trifluoroacetic acid (1.1 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (5 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (2.5 mL) and ethylenediamine (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight then diluted with MeOH and the solid precipitate was collected via filtration. The solid residue was rinsed with hot water and EtOAc then dried under high vacuum to afford 56 mg (43%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-yl)-amide as a white solid. MS: (M+H)+=350; mp>300.
Reaction SMILES: [N:1]1([C:13](=[O:14])[C:12]2[N:10]([CH3:11])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].S(=O)(=O)(O)O.[F:20][C:21](I)([F:23])[F:22].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:20][C:21]([F:23])([F:22])[C:9]1[N:10]([CH3:11])[C:12]2[C:13](=[O:14])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: FC(F)(F)I
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(nc(C(F)(F)F)n2C)n(C)c1=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
0.19 g (1.0 mmol) of caffeine and 0.056 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l of dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethylcaffeine (19F-NMR yield: 17%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (6.9 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (100 mg.) in dimethylformamide (30 ml.) is added lauroyl chloride (7 ml.) during a 1/2 hour period. The reaction mixture is stirred for 2 hours at room temperature, poured into ice water and hydrochloric acid, extracted into ether, washed with water, ammonium hydroxide (3 ml. diluted with water) dilute hydrochloric acid and dried over magnesium sulfate. The ether is evaporated at reduced pressure to give 2.2 g of 2-sulfamoyl-6-benzothiazolyl dodecanoate which melts at 112°-114° C. after recrystallization from butyl chloride.
Reaction SMILES: [CH:1](O)=O.C=O.[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:27])=[C:16]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:17]=3[O:19][CH3:20])[C:12](=[O:28])[C:11]([C:29]([OH:31])=[O:30])=[CH:10]2)[CH2:8][CH2:7]1.O>C([O-])=O.[Na+]>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:27])=[C:16]([N:21]4[CH2:26][CH2:25][N:24]([CH3:1])[CH2:23][CH2:22]4)[C:17]=3[O:19][CH3:20])[C:12](=[O:28])[C:11]([C:29]([OH:31])=[O:30])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: O=CO
Reactant: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: C=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2 h

Procedure:
In a mixture of sodium formate (22 mg), 87% formic acid (0.3 ml) and 37% formalin (25 μl) and 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (60 mg) was stirred for 2 hours at 100° to 120° C. After cooling, water (1 ml) was added to the reaction mixture and then concentrated. To the residue was added water (0.5 ml), adjusted to pH 7 with 1N aqueous sodium hydroxide solution and the solution was allowed to stand in a refrigerator. The resulting precipitate was collected by filtration and washed with water to give the title compound (33 mg) as colorless needles, mp 229°-232° C. (decompd.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)=[CH:6][C:5]=1[CH:31]=[CH2:32])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH2:31]([C:5]1[CH:6]=[C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH3:32]
Reactant: [H][H]
Reactant: C=Cc1cc(-c2nc(-c3ccc(CCC(=O)OC(C)(C)C)cc3C)ns2)ccc1OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3ccc(CCC(=O)O)cc3C)ns2)cc1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
A solution of tert-Butyl 3-(4-(5-(4-ethoxy-3-vinylphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (0.01 g, 0.025 mmol) in methanol (1.5 mL) and ethyl acetate (1.5 mL) was degassed with nitrogen. 10% Palladium/Carbon (0.01 g) was added to the reaction mixture which was stirred under a balloon of hydrogen for 30 min. The reaction was filtered through a disposable frit and concentrated in vacuo. The resulting oil was dissolved in 20% solution of trifluoroacetic acid in dichloromethane (4 mL) and stirred at rt for 2 h after which the reaction was concentrated in vacuo. Silica gel chromatography eluting with 2% methanol/methylene chloride afforded 4.5 mg of the title compound: 1H NMR (500 MHZ, CDCl3) δ 7.86 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 4.20-4.30 (m, 2H), 3.00-3.08 (m, 2H), 2.70-2.79 (m, 4H), 2.65 (s, 3H), 1.48-1.52 (m, 3H), 1.23-1.32 (m, 3H), ESI-MS (m/z) 453.3; HPLC A: 4.68 min.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([NH:31][C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[N:23]1.C(N(CC)CC)C.O>CN(C)C=O>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([NH:31][C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:2]3[S:6][N:5]=[C:4]([CH2:7][O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:3]=3)[CH2:36][CH2:35]2)=[O:33])=[N:23]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(COc2ccccc2)ns1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(COc3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 5-chloro-3-(phenoxymethyl)-1,2,4-thiadiazole (126 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 151 mg (61.7%) of the desired product.