Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[F:30])[CH3:21].[H-].[Na+]>C1COCC1>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:2][CH:3]2[CH2:8][CH2:7][CH:6]([CH:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]3)[CH2:5][CH2:4]2)=[CH:25][C:24]=1[F:30])[CH3:21]
Reactant: CCCCCC1CCC(C2CCC(CI)CC2)CC1
Reactant: CCOc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(COc3ccc(OCC)c(F)c3)CC2)CC1
Yield: 39 %

Procedure:
1-Iodomethyl-4-(4-pentylcyclohexyl)cyclohexane (9.8 g, 26 mmol) was reacted with 4-ethoxy-3-fluorophenol (3.7 g, 24 mmol) in THF (60 ml) in the presence of NaH (ca. 24 mmol) used as a base. After treatment was carried out by the same method as in Example 3 to obtain 1-ethoxy-2-fluoro-4-(4-(4-pentylcyclohexyl)cyclohexyl)methyloxybenzene (yield: 39%).
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:24]([O:26]C)=[O:25])[CH2:5][CH2:4]1)=[O:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:24]([OH:26])=[O:25])[CH2:5][CH2:4]1)=[O:2]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v. 24.0 ml) was dissolved methyl 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (501 mg). To the solution was added 1N sodium hydroxide solution (15.0 ml), and the mixture was stirred at room temperature for 16 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (482 mg) as white crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:28])[CH2:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3.O.[OH-].[Li+].C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CO.O>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH2:5][CH:4]([CH3:28])[C:3]([NH2:34])=[O:2])=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: COC(=O)C(C)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C(N)=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-2-methyl-propionic acid methyl ester (150 mg, 0.38 mmol) in methanol (5 mL) and H2O (0.5 mL) was added lithium hydroxide monohydrate (30 mg, 0.76 mmol) and the reaction mixture heated at 45° C. for 72 h. The reaction mixture was concentrated in vacuo and the residue azeotroped with acetonitrile (3×10 mL). The resultant residue was suspended in DMF (3 mL) and HATU (289 mg, 0.76 mmol), ammonium chloride (61 mg, 1.14 mmol) and triethylamine (159 μL, 1.14 mmol) added. The reaction mixture was stirred at RT for 30 min. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to yield 435 as a white solid (61 mg, 42%). LCMS: RT=7.27 min, [M+H]+=381. 1H NMR 400 MHz δ (DMSO-d6): 8.25 (1H, d, J=8.4 Hz), 7.86 (1H, s), 7.85 (1H, s), 7.21 (1H, br s), 6.93 (1H, dd, J=8.4, 1.8 Hz), 6.83 (1H, d, J=1.8 Hz), 6.66 (1H, br s), 5.85 (1H, sept, J=6.7 Hz), 4.50-4.39 (4H, m), 2.86-2.74 (1H, m), 2.56-2.42 (2H, m), 1.44 (6H, d, J=6.7 Hz), 0.97 (3H, d, J=6.6 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)/[CH:22]=[CH:23]/[CH3:24].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14]/[CH:21]=[CH:22]/[CH2:23][CH3:24])[CH:7]=1)=[O:4]
Reactant: C/C=C/CCl
Reactant: COC(=O)Nc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC/C=C/Oc1cc(NC(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
The N-methoxycarbonyl-3-hydroxy-4-methoxyaniline (34.0 g) was dissolved in dimethylformamide (200 ml). Potassium carbonate (29.0 g) and trans-crotyl chloride (32.2 g) were added to the solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and extraction was carried out with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude crystal thus obtained was recrystallized from ethyl acetate-n-hexane to obtain N-methoxycarbonyl-3-(2-trans-butenyl)oxy-4-methoxyaniline (39.5 g).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:4]=1[CH:5]=O)[CH3:2].[C:13]([Br:17])(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:14][C:13]([Br:17])=[CH:5][C:4]1[C:3]([CH2:1][CH3:2])=[C:10]([F:11])[CH:9]=[CH:8][C:7]=1[F:12]
Reactant: CCc1c(F)ccc(F)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1c(F)ccc(F)c1C=C(Br)Br

Procedure:
2-(2,2-Dibromo-vinyl)-3-ethyl-1,4-difluoro-benzene was prepared from 2-ethyl-3,6-difluoro-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.15 (3H, t, CH3), 2.60 (2H, qd, CH2), 6.89 (1H, ddd, ArH), 7.00 (1H, ddd, ArH), 7.26 (1H, s, CH═CBr2).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[Si](C)(C)[CH3:17]>CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:17])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc2cccc(C(=O)O)c2n1
Solvent: CO
Product: COC(=O)c1cccc2ccc(C)nc12
Yield: 32.5 %

Procedure:
To a stirred solution of 2-methylquinoline-8-carboxylic acid (0.830 g, 4.43 mmol) in MeOH (20 mL) was added dropwise chlorotrimethylsilane (2.41 g, 22.2 mmol). The reaction mixture was heated at reflux overnight. After cooling, the reaction was concentrated under reduced pressure. The residue was dissolved in water and basified by dropwise addition of saturated aqueous NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc) to give methyl 2-methylquinoline-8-carboxylate (0.290 g, 33%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([NH:19][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)nc(NCc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a solution of 2,6-dichloro-4-nitropyridine (0.1 g, 0.518 mmol) and benzyl amine (0.062 mL, 0.570 mmol) in 10 mL toluene was added cesium carbonate (0.253 g, 0.777 mmol). The mixture was degassed with nitrogen and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.016 g, 0.026 mmol) and palladium acetate (5.82 mg, 0.026 mmol) were added. The mixture was heated at 100° C. for 2 hours, filtered through diatomaceous earth and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Recrystallization from 1:10 ethyl acetate-hexane afforded the title compound.
Reaction SMILES: C(O)(C)C.[CH:5]1[CH:10]=[N+:9]([C@@H:11]2[O:15][C@H:14]([CH2:16][O:17][P:18]([O:21][P:22]([O:25][CH2:26][C@H:27]3[O:31][C@@H:30]([N:32]4[C:36]5[N:37]=[CH:38][N:39]=[C:40]([NH2:41])[C:35]=5[N:34]=[CH:33]4)[C@H:29]([O:42][P:43]([OH:46])([OH:45])=[O:44])[C@@H:28]3[OH:47])([OH:24])=[O:23])([OH:20])=[O:19])[C@@H:13]([OH:48])[C@H:12]2[OH:49])[CH:8]=[C:7]([C:50]([NH2:52])=[O:51])[CH:6]=1>CC(C)=O>[CH:38]1[N:39]=[C:40]([NH2:41])[C:35]2[N:34]=[CH:33][N:32]([C@@H:30]3[O:31][C@H:27]([CH2:26][O:25][P:22]([O:21][P:18]([O:17][CH2:16][C@H:14]4[O:15][C@@H:11]([N:9]5[CH:8]=[C:7]([C:50]([NH2:52])=[O:51])[CH2:6][CH:5]=[CH:10]5)[C@H:12]([OH:49])[C@@H:13]4[OH:48])([OH:20])=[O:19])([OH:24])=[O:23])[C@@H:28]([OH:47])[C@H:29]3[O:42][P:43]([OH:46])([OH:45])=[O:44])[C:36]=2[N:37]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
This example illustrates a prescreening assay used to identify variant genes encoding ketoreductases capable of reducing isopropanol in the presence of NADP+ to produce acetone and NADPH. An E. coli colony containing a plasmid encoding an engineered ketoreductase was picked using a Q-Bot® robotic colony picker (Genetix USA, Inc., Boston, Mass.) into 96-well shallow well microtiter plates containing 180 μL Terrific Broth (TB), 1% glucose and 30 μg/mL chloramphenicol (CAM). Cells were grown overnight at 30° C. with shaking at 200 rpm. A 10 μL aliquot of this culture was then transferred into 96-deep well plates containing 390 μL Terrific Broth (TB), 1 mM MgSO4 and 30 μg/mL CAM. After incubation of the deep-well plates at 30° C. with shaking at 250 rpm for 2 to 3 hours, recombinant gene expression within the cultured cells was induced by addition of IPTG to a final concentration of 1 mM. The plates were then incubated at 30° C. with shaking at 250 rpm for 18 hours.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]1)C1C=CC=CC=1>[Pd].C(O)C>[C:16]([N:12]1[CH2:13][CH2:14][O:15][CH:10]([CH2:9][OH:8])[CH2:11]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N1CCOC(COCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)N1CCOC(CO)C1
Reaction time: 48 h
Yield: 102.1 %

Procedure:
A mixture of 2-[(benzyloxy)methyl]-4-tert-butylmorpholine (268 mg) and 10% palladium on carbon (200 mg) in ethanol (10 mL) was evacuated and purged with hydrogen three times and the left under an atmosphere of hydrogen over the weekend at room temperature. The mixture was filtered through a short pad of celite and the cake was washed with ethanol (10 mL). To the filtrate was added 10% palladium on carbon (200 mg) and the mixture was evacuated and purged with hydrogen three times and the left under an atmosphere of hydrogen for 48 hours. The mixture was filtered through a short pad of celite and the cake was washed with ethanol. The filtrate was concentrated at reduced pressure to give the title compound as a colourless oil (180 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[F:12].[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[F:12]
Reactant: CC1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1Cc2c(F)c(F)c([N+](=O)[O-])c3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C
Yield: 50.6 %

Procedure:
8,9-Difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (11.5 g) is dissolved in conc. sulfuric acid (120 ml), and thereto is added potassium nitrate (17 g), and the mixture is reacted at an inner temperature of 70° C. for 2 hours. After the reaction, the reaction mixture is added to ice-water (1 liter), and the precipitated crystals are separated by filtration and recrystallized from dimethylformamide to give 8,9-difluoro-2-methyl-7-nitro-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (6.8 g) as white cubic crystals. m.p. 265°-268° C. (decomp.)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:4]=2)=[CH:10][CH:11]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCl
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(Cc2nc(-c3ccc(Cl)cc3)oc2C)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
The mixture of 4-(chloromethyl)-2-(4-chlorophenyl)-5-methyloxazole (1.21 g, 5 mmole, commercially from Fluorochem) and ethyl piperidine-4-carboxylate (0.81 mL, 1.05 equiv.), K2CO3 (1.03 g, 1.5 equiv) in dioxane was stirred at 70° C. for 2 h. The reaction solution was cooled to room temperature and the solid was filtered off, rinsed with dichloromethane. The filtrate was concentrated and the residue was recrystallized from hexane to furnish Ethyl 1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxylate (1.65 g, 91%).
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1.O>CS(C)=O.C(OCC)C>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:21])([F:23])[F:22])[CH:13]=2)[CH2:2][CH2:3]1
Reactant: O[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(OC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 60 %

Procedure:
Trans-cyclohexane-1,4-diol (4.30 mmol) and sodium hydride (60% suspension in oil, 2.15 mmol) are suspended in dry dimethylsulfoxide (4 mL) and a solution of 4-fluoro-2-trifluoromethyl-benzonitrile (2.15 mmol) in dry dimethylsulfoxide (4 mL) is added dropwise. The resulting mixture is stirred at room temperature. After 1 hour reaction time, the reaction is treated with water (10 mL), the precipitate formed is separated by filtration and the filtrate is extracted with dichloromethane (25 mL). The organic phase is washed with aqueous saturated ammonium chloride (5 mL), dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The precipitate is triturated with diethylether (15 mL), filtered and the filtrate concentrated under reduced pressure. Both fractions of crude product are combined, dissolved in dichloromethane and purified by chromatography through a short pad of silica gel (dichloromethane and then diethylether as eluents) to afford the desired product (60% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=O>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=O
Solvent: CCO
Product: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.1 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (86.5 mg, 0.4 mmol) and 3-methyl-4-(piperidine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (88.1 mg, 0.4 mmol) in ethanol (2 mL) was stirred at room temperature for 4 days. The reaction was concentrated and the residue was column chromatographed to give 52 mg (31%) of the title compound as a yellow solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([NH2:22])[C:18]=1[C:19]([OH:21])=[O:20].S(Cl)(Cl)=O>[Cl-].C[N+](C)(C)CC1C=CC=CC=1.O.ClCCCl>[Cl:12][C:13]1[C:18]2[C:19](=[O:21])[O:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:22][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=c1oc(-c2ccccc2)nc2cccc(Cl)c12
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
70.3 g of benzoyl chloride and 40 g of 50% strength aqueous sodium hydroxide solution are added simultaneously via 2 feed apparatuses in the course of 40 minutes at from 23° to 42° C. to a stirred mixture of 85.8 g of finely divided 6-chloroanthranilic acid, 0.9 g of trimethylbenzylammonium chloride and 1,250 g of 1,2-dichloroethane. Stirring is continued for 90 minutes at 28° C., the mixture is refluxed for 1 hour with separation of water, and 63.1 parts of thionyl chloride are added in the course of 45 minutes at 70° C., while stirring. Stirring is continued for 90 minutes at 82° C., after which the mixture is cooled to 40° C., extracted 3 times with water and evaporated down under reduced pressure, in the final stage at 140° C. under 20 mbar, to give 126.2 g (98%) of 5-chloro-2-phenyl-4H-3,1-benzoxazin-4-one of melting point 151°-153° C. Comparison with a purified standard using HPLC shows that the purity is 96%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C(N(CC)CC)C.C[Si](C)(C)Cl>CS(C)=O>[C:21]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:24])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C:26]4[N:35]=[C:34]5[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]5[CH:36]5[CH2:38][CH2:37]5)=[CH:28][C:27]=4[F:43])[CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N[C@@H]3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
A suspension of 119 mg N-{(5S)-3-[3-fluoro-4-(pyrrolidin-3-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.35 mmol), 100 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 148 μl triethylamine (, 1.05 mmol) and 89 μl trimethylchlorosilane (0.70 mmol) in 2 ml DMSO was stirred in a microwave oven at 150° C. for 10 min. The DMSO was evaporated, the residue digested in water and the solid filtrated. The solid was purified by chromatography using a 95/5 dichloromethane/methanol mixture.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>C(O)CCC>[N:20]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: c1ccc2c(c1)CCN2
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 0.5 g (1.82 mmol) of 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo-[2,3-d]pyrimidine and 0.43 ml (2.1 equivalents) of 2,3-dihydroindole in 10 ml of abs. n-butanol are heated at reflux for 1.5 hours until the starting material is no longer present in TLC, the desired product precipitating out and being filtered off. The brown crude product is stirred thoroughly in about 20 ml of 1N NaOH for about 15 minutes, and the suspension is filtered with suction and the residue is washed with water, n-butanol and hexane and dried under a high vacuum. 4-(2,3-Dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained in the form of a rust-brown powder having a melting point of>300° C. FAB-MS: (M+H)+ =358 (corresponds to C20H15N5O2); Rf value (toluene-acetone--4:6)=0.40.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:33]([C:35]2[S:39][C:38]3[C:40]([F:45])=[CH:41][CH:42]=[C:43]([F:44])[C:37]=3[C:36]=2[Cl:46])=[O:34])[CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31][CH3:32])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:49].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+]>[C:1]([O:5][C:6](=[O:47])[N:7]([CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([C:33]([C:35]2[S:39][C:38]3[C:40]([F:45])=[CH:41][CH:42]=[C:43]([F:44])[C:37]=3[C:36]=2[Cl:46])=[O:34])[CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH3:32])=[O:49])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2ccccc2SC)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2S(C)=O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a stirred suspension of thioanisole (286) (75 mg, 0.11 mmol) and NaHCO3 (46 mg, 0.55 mmol) in DCM (2 ml) at 0° C. was added dropwise a solution of m-chloroperbenzoic acid (34 mg, 0.2 mmol) in DCM (1 ml) over 2 min. After 2 h, LCMS showed a mixture of sulphoxide and sulphone. The reaction was diluted with aqueous Na2SO3 and extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and reduced in vacuo before purification by chromatography with EtOAc/heptane to give the title compound.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:34])[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])=[CH:12][C:7]=2[S:6][CH2:5][CH2:4]1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1OCCC1>[CH3:34][C:3]1([CH3:2])[C:8]2[CH:9]=[CH:10][C:11]([C:13]([CH3:14])=[CH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:12][C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CC(c1ccc2c(c1)SCCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=Cc1ccccc1)c1ccc2c(c1)SCCC2(C)C
Yield: 44.5 %

Procedure:
33 g of [1-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)ethyl]triphenylphosphonium bromide and 6.5 g of benzaldehyde were heated under reflux in 300 ml of butylene oxide for 16 hours. After working-up in analogy to Example 49 and recrystallization from hexane, there were obtained 7.9 g of 3,4-dihydro-4,4-dimethyl-7-(α-methylstyryl)-2H-1-benzothiopyran, melting point 67°-69° C.