Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:21]([C:12]1[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:11]=1[O:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][CH:5]=1)([O-:23])=[O:22]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 3,4-dichlorophenol (25 gram (hereinafter g), 0.153 mol), 4-chloro-3-nitrobenzo-trifluoride (52 g, 0.23 mol) and potassium carbonate (63 g, 0.459 mol) in dimethylformamide (450 mL)was stirred under argon at 120° C. for 24 h. The reaction mixture was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was flash chromatographed (silica gel, methylene chloride/hexane), to give the title compound as a yellow oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:39]=[CH:38][C:13]([CH2:14][C:15]3([CH3:37])[C:19](=[O:20])[O:18]C(C4C=CC=CC=4)[N:16]3[C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[CH:12][CH:11]=2)=[N:8][CH:9]=1>CO.O>[CH2:30]([O:29][C:27]([NH:16][C:15]([CH3:37])([CH2:14][C:13]1[CH:38]=[CH:39][C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][N:8]=2)=[CH:11][CH:12]=1)[C:19]([OH:20])=[O:18])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(Cc2ccc(-c3ccc(F)cn3)cc2)C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Cc1ccc(-c2ccc(F)cn2)cc1)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5N Aqueous sodium hydroxide (1.45 mL) was added to an ambient temperature solution of benzyl 4-[4-(5-fluoropyridin-2-yl)benzyl]-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate (180 mg, 0.36 mmol) in methanol (2 mL) and water (2 mL). After stirring at 80° C. for 2 h, the reaction mixture was concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated in vacuo to afford 2-{[(benzyloxy)carbonyl]amino}-3-[4-(5-fluoropyridin-2-yl)phenyl]-2-methylpropanoic acid which was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[N:40][CH:41]=1)[CH3:35]>CN(C=O)C.[Cu]I>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][CH:37]=3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(F)cc3c2C1
Reactant: CC(=CBr)c1ccc(C)nc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(F)ccc31)CN(C)CC2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (203 mg, 0.8 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (19 mg, 0.10 mmol), L-proline (23 mg, 0.20 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 5-(1-Bromoprop-1-en-2-yl)-2-methylpyridine (212 mg, 1 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 9.0 (s, 1H), 8.10 (d, 1H), 7.50 (d, 1H), 7.0 (m, 4H), 4.70 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H), 3.30 (m, 2H), 3.05 (s, 3H), 2.90 (m, 1H), 2.80 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.ClC(Cl)(Cl)C(=N)O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[O:16][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCCCC1O)c1ccccc1
Reactant: COc1ccc(CCOC(=N)C(Cl)(Cl)Cl)cc1OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CCO[C@H]2CCCC[C@H]2OC(=O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 72 h
Yield: 67.3 %

Procedure:
A 250 mL round bottom flask equipped with an argon inlet and magnetic stir bar was charged with 2-hydroxycyclohexyl benzoate (7.39 g, 33.6 mmol) in anhydrous CH2Cl2 (50 mL). The solution was cooled to 0° C. prior to the successive addition of trimethylsilyl trifluoromethanesulfonate (3.0 mL, 1.9.4 mmol) and 3,4-dimethoxyphenethyl 2,2,2-trichloroacetimidate (16.5 g, 50.4 mmol) dissolved in anhydrous CH2Cl2 (30 mL). The reaction mixture was stirred at r.t. for 3 days. The reaction was then quenched by the addition of H2O (100 mL). The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed successively with brine (2×100 mL) and distilled water (100 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude material was purified by flash column chromatography (EtOAc-hexanes, 1:7, v/v,) to afford a yellow oil (8.69 g, 67%). Rf 0.77 (EtOAc-hexanes, 1:2, v/v,); 1H-NMR (300 MHz, CDCl3) δ 1.36 (m, 2H), 1.62 (m, 4H), 1.85-2.03 (m, 2H), 2.75 (t, 2H), 3.53 (m, 1H), 3.62 (m, 1H), 3.72 (m, 2H), 3.79 (s, 6H, OCH3), 6.76 (m, 3H, Ar), 7.38 (m, 2H, Ar), 7.53 (m, 1H, Ar), 8.00 (m, 2H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH:24]=[O:25])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[OH:25][CH2:24][CH2:23][S:22][C:11]1[S:12][C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1
Reactant: COc1ccc(-c2nc(SCC=O)sc2-c2ccc(OC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Reaction time: 0.25 h

Procedure:
0.10 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde is dissolved in 3 ml of methanol, 0.01 g of sodium borohydride is added and the mixture is stirred for 15 minutes. It is then concentrated to dryness by evaporation under reduced pressure and digested with 20 ml of ice-water. After some time crystallisation occurs. After 2 hours the crystals are filtered with suction, washed with water and sucked dry. 2-[2-hydroxyethylthio]-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 82°-83° is obtained.
Reaction SMILES: C(O)(=O)C.C(O[CH:8](OCC)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=1)C.[ClH:24].[OH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[OH:35])[CH2:29][CH2:30][NH2:31]>Cl.O>[ClH:24].[S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH:8]2[C:32]3[C:28](=[CH:27][C:26]([OH:25])=[C:34]([OH:35])[CH:33]=3)[CH2:29][CH2:30][NH:31]2)=[CH:16][CH:15]=1)(=[O:19])(=[O:20])[NH2:18]
Reactant: CCOC(COc1ccc(S(N)(=O)=O)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(OCC2NCCc3cc(O)c(O)cc32)cc1
Temperature: 110 °C
Yield: 73.5 %

Procedure:
To a mixture of acetic acid (23 ml), water (6.6 ml) and concentrated hydrochloric acid (15 drops) was added (4-sulfamoylphenoxy)acetaldehyde diethyl acetal (2.3 g), and the mixture was heated for 20 minutes at 110°C. To the solution was added 3,4-dihydroxyphenethylamine hydrochloride (1.2 g), and the mixture was heated for 3.5 hours at the same temperature. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of methanol and acetone to give 1-(4-sulfamoylphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.8 g), mp 270°C (dec.).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH2:8][CH3:9].Cl[C:20]1[C:25]([S:26]([N:29]([C:39]([O:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[C:30]2[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=2)(=[O:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.C(O)C>O.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.C1(C)C=CC=CC=1>[CH2:42]([O:41][C:39]([N:29]([C:30]1[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=1)[S:26]([C:25]1[C:20]([C:13]2[CH:14]=[CH:15][C:10]([CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:28])=[O:27])=[O:40])[CH:43]([CH3:45])[CH3:44]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Reactant: CCCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (60 mg) was added to a deoxygenated solution of sodium carbonate (212 mg), 4-propylphenylboronic acid (328 mg) and 2-chloro-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (828 mg) in a mixture of water (5 ml), ethanol (8 ml) and toluene (16 ml). The mixture was stirred and heated under argon at 80° C. for 17 hours and then allowed to cool to ambient temperature. Ice water (25 g) was added and the reaction extracted with ethyl acetate (3×50 ml). The combined organic layers were dried (MgSO4) and evaporated to afford an amber oil. This was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 20% ethyl acetate/isohexane to give N-(isobutoxycarbonyl)-2-(4-propylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (760 mg) as a solid, mass spectrum (+ve ESP): 499 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:11]1=[O:20].C(OC)(OC)OC.O.[C:29]1(C)[CH:34]=CC(S(O)(=O)=O)=C[CH:30]=1>CC(C)=O>[OH:9][CH2:8][C@@H:5]1[C@H:6]2[O:7][C:29]([CH3:34])([CH3:30])[O:1][C@H:2]2[C@H:3]([N:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:11]2=[O:20])[O:4]1
Reactant: COC(=O)c1nccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: COC(OC)OC
Solvent: O
Product: COC(=O)c1nccn([C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1=O
Yield: 865.6 %

Procedure:
In 5 mL of acetone was suspended 0.50 g of methyl 4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, 1 ml of trimethyl orthoformate and 33 mg of p-toluenesulfonic acid monohydrate were successively added, the mixture thus obtained was heated under reflux for one hour, and the solvent was removed under reduced pressure. By purifying the residue by column chromatography [eluent: ethyl acetate], 0.49 g of methyl 4-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained as a white-colored solid product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11].CO.C1(C)C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[O:11][CH:25]=[N:24][CH:23]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Product: c1ccc2[nH]c(-c3cnco3)cc2c1
Yield: 79.8 %

Procedure:
To a 100 mL round-bottom flask was added 1H-indole-2-carbaldehyde 18 (1.52 g, 10.48 mmol), methanol (50 mL), p-toluene sulfonylmethyl isocyanide (2.25 g, 11.52 mmol), followed by potassium carbonate (1.86 g, 13.45 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq.NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (3×30 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-(1H-indol-2-yl)oxazole 19 (1.54 g, 79% yield). MS (ES) m/z 185 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33].C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])=[O:6]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
A mixture of 2-amino-6-methylbenzoic acid (45 g, 297 mmol) and CDI (45 g, 278 mmol) in acetonitrile (500 mL) was stirred at room temperature for 1.5 hours. To the suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (45 g, 273 mmol) and sodium hydrogen carbonate (34 g, 409 mmol), and the mixture was heated at 50° C. for 21 hours. The suspension was cooled to room temperature for 1 hour. The suspension was filtered. The solid was stirred with water (150 mL) and ethyl acetate (150 mL) for 3 hours. The suspension was filtered and washed with water (2×50 mL) and ethyl acetate (2×50 mL). The solid was dried in a vacuum oven overnight to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide as a white solid (41.3 g, 58% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 5/95 grad to 95/5 for 5 min CH3CN/0.1% H3PO4, 4.44 (91%); 1H NMR (DMSO-d6) δ 1.98-2.17 (m, 5H, CH2, CH3) 2.51-2.56 (m, 1H, CHH), 2.74-2.86 (m, 1H, CHH), 4.68-4.77 (m, 1H, NCH), 5.18 (s, 2H, NH2), 6.38 (d, J=7 Hz, 1H, Ar), 6.50 (d, J=7 Hz, 1H, Ar), 6.94 (t; J=7 Hz, 1H, Ar), 8.59 (d, J=8 Hz, 1H, NH), 10.90 (s, 1H, NH); 13C NMR (DMSO-d6) δ 19.14, 23.75, 30.99, 49.10, 112.37, 17.21, 122.28, 128.96, 134.61, 145.22, 168.36, 172.84, 173.00; LCMS: MH=262.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:16][CH2:15][O:14][C:5]2=[C:6]([C:12]=1[NH2:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:17]N1C(=O)CCC1=O>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[C:12]([NH2:13])=[C:2]([Cl:17])[CH:3]=[C:4]2[O:16][CH2:15][O:14][C:5]=12)[CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1c(N)c(Br)cc2c1OCO2
Product: CCOC(=O)c1c(N)c(Cl)cc2c1OCO2
Yield: 75 %

Procedure:
Following the procedure employed in Example 27, treatment of ethyl 5-bromo-2,3-methylenedioxy-6-aminobenzoate with N-chlorosuccinimide instead of N-bromosuccinimide, gave the title compound in 75% yield after silica gel chromatography, mp 77°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7]O[C:9]2=[O:12])=[CH:4][CH:3]=1.[NH2:13][C@@H:14]([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15](=[O:16])[C@@H:14]([N:13]1[CH:7]([NH:13][CH:14]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:22][CH3:23])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:12])[CH2:22][CH3:23])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=c1occc2ccc(Cl)cc12
Product: CCC(NC1Cc2ccc(Cl)cc2C(=O)N1[C@@H](CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 64.2 %

Procedure:
A mixture of 7-chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert butyl ester (22 g) were heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%). 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:24][C:18]3=[CH:19][N:20]=[C:21](Cl)[CH:22]=[C:17]3[CH:16]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:24][C:18]3=[CH:19][N:20]=[C:21]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:22]=[C:17]3[CH:16]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester and 4-methanesulfonyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 4): tR=1.71 min; Mass spectrum (ESI+): m/z=471 [M+H]+.
Reaction SMILES: C[Si](CC(N)=O)(C)C.[NH2:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:15][S:16][C@H:11]12.S(Cl)(Cl)=O.[CH3:37][O:38][N:39]=[C:40]([C:44]1([O:49][CH2:48][CH2:47][O:46]1)[CH3:45])[C:41](O)=[O:42]>C(OCC)(=O)C.O.CO.CN(C)C=O>[CH3:37][O:38][N:39]=[C:40]([C:44]1([O:46][CH2:47][CH2:48][O:49]1)[CH3:45])[C:41]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:42]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12
Reactant: CON=C(C(=O)O)C1(C)OCCO1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12)C1(C)OCCO1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
Trimethylsilylacetamide (6.57 g.) was added to a suspension of 7-amino-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (3.8 g.) in ethyl acetate (80 ml.), and stirred at room temperature for an hour. On the other hand, thionyl chloride (1.5 g.) was added to a stirred solution of N,N-dimethylformamide (0.92 g.) in ethyl acetate (10 ml.), and stirred under ice-cooling for 30 minutes. To the solution was added 2-methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer, 2.27 g.) and stirred at 5° to 10° C. for 2 hours. Thus obtained activated acid solution was added to the above solution at -30° C. over 45 minutes, and stirred as the same temperature for 2 hours. The resultant mixture was diluted with water (100 ml.) and stirred for 10 minutes. After removing the insoluble substance from the resultant mixture by filtration, the fitrate was extracted with a mixture solvent (200 ml.) of ethyl acetate and methanol (4:1) twice. The insoluble substance obtained above was suspended in the mixed solvent (200 ml.) of ethyl acetate and methanol (4:1), stirred for 30 minutes, and filtered. The filtrate and the above extract were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Diisopropyl ether was added to the residue and allowed to stand in a refrigerator. After removing the solvent by decantation, the residue was triturated with n-hexane to give 7-[2-methoxyimino-3,3-ethylenedioxybutyramido]-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.7 g.).
Reaction SMILES: C([C:3]1[CH:43]=[CH:42][C:6]([C:7](/[N:9]=[C:10]2/[N:11]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([C:34]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[O:35])[CH2:30][CH2:29]3)[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[N:15]=[CH:14][C:13]=3[NH:27]/2)=[O:8])=[CH:5][CH:4]=1)#N.[F:44]C1C=CC(C(N=C=S)=O)=CC=1>>[F:44][C:3]1[CH:43]=[CH:42][C:6]([C:7](/[N:9]=[C:10]2/[N:11]([C@H:28]3[CH2:29][CH2:30][C@@H:31]([C:34]([N:36]4[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]4)=[O:35])[CH2:32][CH2:33]3)[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[N:15]=[CH:14][C:13]=3[NH:27]/2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Reactant: N#Cc1ccc(C(=O)/N=c2\[nH]c3cnc(OCCN4CCCCC4)cc3n2[C@H]2CC[C@@H](C(=O)N3CCNCC3)CC2)cc1
Product: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)N2CCNCC2)CC1)c1ccc(F)cc1

Procedure:
The title compound was prepared using a method analagous to the preparation of (E)-4-cyano-N-(1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide, using 4-fluorobenzoyl isothiocyanate. MS m/z=578.2 [M+H], calc 577.69 for C31H40FN7O3. 1H NMR (CDCl3) δ ppm: 8.35 (dd, J=8.7, 5.7 Hz, 2H), 8.09 (s, 1H), 7.01-7.20 (m, 3H), 4.75-4.96 (m, 1H), 4.50 (t, J=1.0 Hz, 2H), 3.64-3.77 (m, 2H), 3.46-3.59 (m, 2H), 2.80-3.03 (m, 10H), 2.53-2.69 (m, 4H), 2.08-2.19 (m, 2H), 1.72-1.90 (m, 5H), 1.60-1.71 (m, 4H), 1.40-1.55 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH:11]1([C:14](=[O:21])[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH2:13][CH2:12]1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:21])[C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Product: N#Cc1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1

Procedure:
The procedure described in Example 19 was repeated by using 3.78 g 4-cyanobenzaldehyde and 2.23 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.5 g, mp 100°-102° C.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.O1CCCC1.N1(O[C:23](=[O:39])[CH2:24][C@H:25]2[O:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)C2C=CC=CC=2N=N1>C(OCC)(=O)C>[CH3:1][NH:2][C:23](=[O:39])[CH2:24][C@H:25]1[O:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:27][CH2:26]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC(=O)On2nnc3ccccc32)OC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Methylamine/tetrahydrofuran solution (2.0 mol/l, 1 ml) was added to a tetrahydrofuran (5 ml) solution of the compound (378 mg, 1.00 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine in that order and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [methanol:ethyl acetate=5:95 (v/v)] to give 135 mg (49%) of the title compound as a solid.