Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:29][O:30]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:29]([C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:30]
Reactant: COC(Cl)Cl
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (650 mg, 1.71 mmol) obtained in Example 3 and 1,1-dichloromethyl methyl ether (237 mg, 2.06 mmol) in dichloromethane (5 mL) was added dropwise at 0° C. under an argon atmosphere and ice-cooling titanium tetrachloride (0.34 mL, 3.07 mmol), and the mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction solution and the product was extracted with dichloromethane. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 520 mg (yield: 75%) of the title compound. Melting point: 177-178° C (ethyl acetate-hexane).
Reaction SMILES: [OH:1][CH:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1[F:21])[C:3]1[C:4]([CH3:12])=[CH:5][C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[CH3:22][S:23]([O:1][CH:2]([C:3]1[CH:8]=[N:7][C:6]([C:9](=[O:10])[NH2:11])=[CH:5][C:4]=1[CH3:12])[C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1[F:21])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(N)=O)ncc1C(O)c1c(F)ccc(F)c1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)ncc1C(OS(C)(=O)=O)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 5-[hydroxy(2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (7.11 g, 24.0 mmol) in N,N-dimethylformamide (150 ml), methanesulfonyl chloride (3.72 ml, 48.0 mmol) and then triethylamine (13.4 ml, 96.0 mmol) were added in a nitrogen atmosphere at 0° C., and the mixture was stirred for 2 hours at room temperature. Water and ethyl acetate were added to the reaction mixture at 0° C., the organic layer was separated, and the organic layer was washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with dichloromethane:methanol=49:1 was concentrated under reduced pressure, to obtain the title compound (4.71 g, 12.6 mmol, 52%) as a pale brown foamy substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:9]([Cl:23])[CH:8]=1)[CH3:2].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:9]([Cl:23])[CH:8]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Product: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Yield: 61 %

Procedure:
[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamino]-acetic acid ethyl ester (10.0 g, 0.02 mol) was stirred with ethyl chloroformate (95 mL) at reflux temperature for 16 hrs. From the reaction mixture ethyl chloroformate was evaporated under reduced pressure and the residue was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give {[3,5-Dichloro-4-(4-methoxy-phenoxy)-phenyl]-ethoxycarbonyl-amino}-acetic acid ethyl ester (7.25 g, 61% Yield)
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])=[CH:4][C:3]=1[N+:26]([O-])=O.C([O-])=O.[NH4+]>O1CCCC1.O.[Fe]>[NH2:26][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:2]=1[NH2:1])[C:6]([C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 977.4 %

Procedure:
A 1 L three-neck flask equipped with a mechanical stirrer was charged with a mixture of benzyl 2-(4-amino-3-nitrobenzoyl)benzoate (50 g, 133 mmole), iron powder (74 g, 1.30 mol), and ammonium formate (167 g, 2.60 mol) in tetrahydrofuran (300 mL) and water (200 mL). The mixture was stirred vigorously at 80° C. for 90 minutes, cooled to room temperature and filtered through celite. The celite was washed with ethyl acetate (500 mL), and the filtrate was partitioned. The organic portion was washed with 2N sodium hydroxide (2×100 mL), water, brine, dried over sodium sulfate and concentrated in-vacuo to afford benzyl 2-(3,4-diaminobenzoyl)benzoate (47 g, 1.30 mol) as a brown oil. 1H NMR (400 MHz, d6-DMSO): 7.94 (d, 1H), 7.70-7.66 (m, 1H), 7.61-7.58 (m, 1H), 7.37-7.21 (m, 6H), 6.98 (s, 1H), 6.70 (d, 1H), 6.47 (d, 1H), 5.54 (s, 2H), 5.09 (s, 2H), 4.72 (s, 2H); MS (EI) for C21H18N2O3: 349 (MNa+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17](Cl)[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:32]2[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]2[CH3:30])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 140 °C
Yield: 62.9 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-1-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol), 2-methylbenzimidazole (76 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.06 mmol), XPhos (58 mg, 0.10 mmol) and Cs2CO3 (320 mg, 0.95 mmol) in toluene (4 mL) was purged with argon then heated at 140° C. for 2 h in a microwave reactor. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-100%) affording the title compound as an off-white solid (156 mg, 64%). LCMS (method A): RT 3.11 min [M+H]+ 517.3
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([CH3:33])[C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])[CH3:2].O.[OH-].[Li+]>>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([CH3:33])[C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C[C@H](OCC)C(=O)O)cc2)c1

Procedure:
In a manner similar to that of Example 13(c), by reacting 180 mg (0.4 mmol) of methyl (S)-2-ethoxy-3-{3′-[(methyloctanoylamino)methyl]biphenyl-4-yl}propionate with 17 mg (0.4 mmol) of lithium hydroxide monohydrate, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (50/50), 130 mg (74%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[CH:15][CH:16]=1>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)=[O:6]
Reactant: COc1cccc(CN)c1
Reactant: CC(C)(CO)C(=O)O
Product: COc1cccc(CNC(=O)C(C)(C)CO)c1

Procedure:
Prepared as in Example 24a from 3-hydroxy-2,2-dimethylpropanoic acid and (3-methoxyphenyl)methanamine as an orange oil (41%). MS 238 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:7])[NH2:6].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:27](OCC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:33]([C:32]1[N:7]=[C:5]([CH2:4][O:3][CH3:2])[NH:6][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:34][CH2:35][CH3:36]
Reactant: COCC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 75 %

Procedure:
To a mixture of 2-methoxyethanimidamide hydrochloride (2.1 g) and methanol (15 mL) were added sodium methoxide (28% methanol solution, 4.8 g), and then a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (3.0 g) in methanol (25 mL) and 1,4-dioxane (10 mL) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and the residue was adjusted to pH 5 with water (50 mL) and 50% aqueous acetic acid solution, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.4 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1F.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:14][CH3:13]
Reactant: CS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(S(C)(=O)=O)ccc1Br
Yield: 53 %

Procedure:
To a solution of 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (Preparation 14, 1.5 g, 5.93 mmol) in MeOH (12 mL) was added sodium methoxide (480 mg, 8.89 mmol) and the reaction mixture was irradiated at 100° C. in the microwave for 1.5 hours. After this time the reaction was quenched with water (50 mL) and the product was extract with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptane to afford the title compound as colourless solid in 53% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.CC(OC)(C)C.C([O-])([O-])=O.[Na+].[Na+].[CH3:23][N:24](C=O)C>CCCCCC.CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[Cl:1][C:2]1[C:7]([C:23]#[N:24])=[N:6][CH:5]=[C:4]([CH2:9][OH:10])[CH:3]=1
Reactant: CN(C)C=O
Reactant: OCc1cnc(Cl)c(Cl)c1
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: [C-]#N
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: N#Cc1ncc(CO)cc1Cl
Temperature: 95 °C
Yield: 28 %

Procedure:
Zn(CN)2 (64.3 mg, 0.548 mmol) and Pd(PPh3)4 (84 mg, 0.073 mmol) were added to a solution of 5,6-dichloro-3-pyridinemethanol (130 mg, 0.730 mmol) in anhydrous DMF (1.5 ml) under N2 and the mixture was heated at 95° C. overnight. Low conversion was observed by HPLC. After heating under reflux for 2 h, the conversion did not increase, so additional Pd(PPh3)4 (84 mg, 0.073 mmol) was added. Two more h under reflux gave full conversion. TBME, and 10% Na2CO3 were added. Extraction, drying (MgSO4), filtration, and removal of the solvent afforded the crude product. Purification by flash chromatography using Flashmaster II, a 5 g spherical silica gel cartridge, and mixtures of hexane and EtOAc as an eluent afforded 3-chloro-5-(hydroxymethyl)-2-pyridinecarbonitrile (34.6 mg, 0.205 mmol, 28% yield) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH:18]=[CH2:19]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH:18]=[CH2:17])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: C=CCO
Reactant: Cc1cc(O)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)cc1C
Yield: 76 %

Procedure:
In a manner analogous to Example 1(a), 5.34 g (32 mmoles) of 4-hydroxy-2-methyl benzoic acid treated at 100° C. for 12 hours with 50 ml of allyl alcohol and 1.5 ml of concentrated sulfuric acid, give 4 g (76% yield) of the expected ester having a melting point of 76°-77° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:18])[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1ccc2c(N)ncnn12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(Br)c2c(N)ncnn12
Reaction time: 96 h
Yield: 154.3 %

Procedure:
To a solution of butyl 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (225.0 mg, 0.96 mmol) in DMF (7.5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (137.3 mg, 0.48 mmol) in two portions. The solution was stirred for 4 days and then quenched by addition of saturated aqueous sodium sulfate solution (20 mL) and water (20 mL). The solid was filtered, washed with water and air-dried. The crude material was purified by HPLC using a gradient of 30-80% of MeCN in water to afford 232.0 mg (77%) of the title compound as an off-white solid. 1H-NMR (DMSO-d6) δ 8.42 (bs, 1H), 8.03 (s, 1H), 7.35 (s, 1H), 7.03 (bs, 1H), 4.23 (t, J=6.4 Hz, 2H), 1.69-1.62 (m, 2H), 1.46-1.36 (m, 2H), 0.92 (t, J=7.3, 3H); MS [M+H]+=313.0; LCMS RT=2.83 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[F:10].N1C=CN=C1.[Cl-].[CH:17]([SiH:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C=O)C>[F:8][C:7]1[CH:6]=[C:5]([O:9][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18])[CH:4]=[C:3]([F:10])[C:2]=1[NH2:1]
Reactant: CC(C)[SiH](C(C)C)C(C)C
Reactant: Nc1c(F)cc(O)cc1F
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cc(F)c(N)c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 4-amino-3,5-difluorophenol (580 mg), imidazole (354 mg), triisopropylsilane chloride (848 mg) and DMF (12 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-brown oil (1.0 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:15]=[CH:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:13][C:12]=1[O:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (15.0 g, 94.5 mmol) and tert-butyl (3-hydroxy-4-methylphenyl)carbamate (20.0 g, 90.0 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (18.6 g, 135 mmol), and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water (400 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (400 mL×2). The combined organic layer was washed with saturated brine (300 mL×2), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure. The residue was triturated with hexane to give the title compound (28.6 g, 92%) as a pale-yellow solid.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:23]1[CH2:29][C:27](=[O:28])[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:24]1=[S:25].[Cl-].[NH4+].N>C(O)C>[CH:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=[C:29]3[S:23][C:24](=[S:25])[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:27]3=[O:28])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)NC2CCCCC2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)NC2CCCCC2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared using 1 g of ethyl 2-(3-cyclohexylureido)thiazol-4-ylglyoxylate, 0.58 g of rhodanine-3-acetic acid, 0.3 g of ammonium chloride, 0.3 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.N>[Cl-].[Zn+2].[Cl-].CO.O>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of sulfolane were added 2.72 g of 7-ACA, 9.0 g of zinc chloride and 1.40 g of methanol. The mixture was heated at 60° C. for 100 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture were added 10 ml of water and 20 ml of methanol. Then, the mixture was adjusted to pH 7.7 with aqueous ammonia at a temperature of from -2° C. to 2° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.02 g. The yield of the desired product was 42 %.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>CO>[OH:6][NH:5][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])=[O:8]
Reactant: COC(=O)CCCCCNC(=O)/C=C/C=C/c1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/C=C/c1ccccc1[N+](=O)[O-])NCCCCCC(=O)NO
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
A solution of sodium methylate (6.0 mmol) in methanol (5 ml) was added to a solution of hydroxylamine hydrochloride (0.28 g, 4.0 mmol) (Acros) in methanol (8 ml). The mixture was stirred for 10 min. and the precipitate was filtered off. (2E,4E)-6-[5-(2-Nitrophenyl)penta-2,4-dienoylamino]hexanoic acid methyl ester (13a) (0.35 g, 1 mmol) was added to the filtrate and the obtained mixture was heated to the complete dissolving. The resultant mixture was stirred for 4 hours at ambient temperature and the solvent was removed under reduced pressure. The product was dissolved in water (10 ml) and the solution was acidified with 3% HCl. The precipitate was filtered and crystallized from acetonitrile to give the title compound (0.23 g, 66%) as a yellow solid. M.p. 131-133° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.06-1.73 (6H, m, CH2); 1.87-2.09 (2H, m, CH2); 3.15 (2H, q, J=5.6 Hz, CH2N); 6.26 (1H, d, J=14.8 Hz, CH); 7.00-8.06 (8H, m, CH—CH═CH, C6H4, NH); 8.06 (1H, t, J=5.9 Hz, NH); 10.33 (1H, s, OH). HPLC analysis on Symmetry C18 column: impurities <1.0% (column size 3.9×150 mm; mobile phase acetonitrile −0.1 M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm; sample concentration 0.15 mg/ml). Anal. Calcd for C17H21N3O5, %: 58.78, H, 6.09, N, 12.10. Found, %: C, 58.26, H, 6.08, N, 11.87.
Reaction SMILES: N1([C:7]2[N:12]=[C:11]3NC=C[C:10]3=[CH:9][CH:8]=2)CCNCC1.Cl.[CH:17]1([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[C:32]4[NH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:31]4=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[C:32]4[NH:34][C:35]([C:37]([N:12]5[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)=[O:38])=[CH:36][C:31]4=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)c1cc2ccc(N3CCN(C4CCCC4)CC3)nc2[nH]1
Reactant: c1cc2ccc(N3CCNCC3)nc2[nH]1
Agent: Cl
Product: O=C(c1cc2ccc(N3CCN(C4CCCC4)CC3)nc2[nH]1)N1CCCCC1

Procedure:
According to the procedure described for the synthesis of Example 1 further 6-piperazinyl-1H-pyrrolo[2,3-b]pyridine derivatives have been synthesized from 6-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride (as prepared in step 2) and the respective amine mentioned in table 1. The examples are compiled in table 1 and comprise Example 2 to Example 20.