Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:38]1[CH:39]=[CH:40][C:41]2[O:45][N:44]=[C:43]([C:46]3[CH:51]=[C:50]([CH:52]([CH3:54])[CH3:53])[CH:49]=[C:48]([CH:55]([CH3:57])[CH3:56])[C:47]=3[O:58][CH2:59][CH3:60])[C:42]=2[CH:61]=1>CN(C=O)C.[Cl-].[Na+].O.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]>[CH3:7][O:6][C:1](=[O:5])[CH:2]=[C:3]([C:38]1[CH:39]=[CH:40][C:41]2[O:45][N:44]=[C:43]([C:46]3[CH:51]=[C:50]([CH:52]([CH3:53])[CH3:54])[CH:49]=[C:48]([CH:55]([CH3:56])[CH3:57])[C:47]=3[O:58][CH2:59][CH3:60])[C:42]=2[CH:61]=1)[CH3:4]
Reactant: C/C=C/C(=O)OC
Reactant: CCOc1c(-c2noc3ccc(Br)cc23)cc(C(C)C)cc1C(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1c(-c2noc3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Temperature: 120 °C
Reaction time: 12 h
Yield: 31.5 %

Procedure:
Methyl crotonate (0.087 ml, 0.82 mmol), tris(dibenzylideneacetone)-dipalladium(0) (6.8 mg, 0.007 mmol), tri-o-tolylphosphine (91 mg, 0.30 mmol), and triethyl amine (0.208 ml, 1.5 mmol) was added to a solution of 5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazole (300 mg, 0.75 mmol) in DMF (5 ml). The reaction mixture was then heated to 120° C. under an atmosphere of nitrogen. After 12 h, the reaction was cooled and poured into brine, then extracted with ethyl acetate (2×10 mL). The organic layer was dried over MgSO4 and evaporated to a residue. The residue was purified by silica gel chromatography (5% ethyl acetate in hexanes) to give 3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazol-5-yl]-but-2-enoic acid methyl ester as a clear oil (99.6 mg, 32%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([OH:13])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)=O>>[N+:1]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:13])=[O:12])([O-:4])=[O:2]
Reactant: O=C(O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)=O
Product: O=C(O)c1cccc([N+](=O)[O-])c1

Procedure:
Netherlands Appln. No. 66-01366 (Chemical Abstract, Vol. 68 95548A) discloses a process for the preparation of 3-nitrobenzoic by adding anhydrous nitric acid to a mixture of benzoic acid and sulfur trioxide. After the addition is completed, the sulfor trioxide is evaporated to obtain a white solid which is recrystallized from a mixture of alcohol and water to obtain pure 3-nitrobenzoic acid, m.p. 141° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:42][CH:43]=[CH:44][N:45]=1)=[O:40].C1COCC1>CC(OC)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Reactant: CON(C)C(=O)c1nccs1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3nccs3)c(F)c2F)C[C@@H](C)O1

Procedure:
Starting materials (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 43) and N-methoxy-N-methylthiazole-2-carboxamide (MTBE was used as solvent instead of THF).
Reaction SMILES: [N:1]1([CH2:6]/[C:7](/[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:6][CH:7]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(/C=C(/Cn2ccnc2)c2nccs2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CC(Cn2ccnc2)c2nccs2)cc1-c1ccccc1

Procedure:
Product from step B (0.39 g; 0.96 mmol) and NaOH 2N, (1.25 ml) in MeOH (8 ml) was heated at reflux for 2 hours. After evaporation of the solvent and neutralisation at pH6, the residue was purified on reverse phase silica eluting with MeOH/(NH4)2CO3 buffer (2 g/l, pH7) 20/80 to give 4-[3-(imidazol-1-yl)-2-(thiazol-2-yl)-propyl]-2-phenyl-benzoic acid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]1[O:14][CH2:13]1>[Cr].CC(CC(C)C)=O>[OH:14][CH2:13][CH2:12][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C1CO1
Agent: [Cr]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCO

Procedure:
N-2-Hydroxyethyl phthalimide was prepared by allowing 147.2g (1.0 mole) of phthalimide to react in an autoclave with 53.0g (1.20 moles) of ethylene oxide in the presence of 1.47g (1%) of active chromium III tri-2-ethylhexanoate (COT) and 400 ml of methylisobutyl ketone (MiBK) at 160° to 165°C for two hours. On cooling, the N-2-hydroxyethyl phthalimide crystallized and was collected by filtration. A 94.7% yield of the hydroxyethyl imide was obtained. Under identical experimental conditions but in the absence of COT, the starting material was recovered unchanged.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:20](OC)([CH3:22])[CH3:21].O.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH2:1]([O:8][C@H:9]([C@@H:13]1[C:14](=[O:16])[O:15][C:20]([CH3:22])([CH3:21])[O:17]1)[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](O)[C@@H](OCc1ccccc1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=O)[C@@H]([C@@H](OCc2ccccc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2R,3R)-2-(Benzyloxy)-3-hydroxysuccinic acid (11.1 g, 46.2 mmol) was dissolved in 2,2-dimethoxypropane (46 mL, 374 mmol) and 4-methylbenzenesulfonic acid hydrate (0.0879 g, 0.462 mmol) was added and the reaction was stirred at ambient temperature for 4 hours. Water (30 mL) and NaHCO3 (0.0388 g, 0.462 mmol) were added and extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated to provide (R)-2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid. The crude product was taken on to next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[O:12])[CH:6]=[CH:5]2.OC1C=C2C(=CC=1)N(C(NC1C=CC=C(C(F)(F)F)C=1)=O)CC2.[OH-].[Na+].[Cl:49][C:50]1[N:55]=[C:54](Cl)[CH:53]=[CH:52][N:51]=1>CC(C)=O.O>[Cl:49][C:50]1[N:55]=[C:54]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[O:12])[CH:6]=[CH:5]3)[CH:53]=[CH:52][N:51]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(O)ccc21
Agent: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ccnc(Cl)n3)ccc21
Reaction time: 1.5 h

Procedure:
A mixture of 5-hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and 5-hydroxy-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (6:4) (3 g) is mixed with sodium hydroxide (0.45 g, 11.2 mmol) and 2,4-dichloropyrimidine (1.68 g, 11.2 mmol) in 50 mL of acetone and 50 mL of water at 0° C. and stirred for 1.5 h. Additional sodium hydroxide (0.075 g, 1.88 mmol) and (0.279 g, 1.88 mmol) are added. After additional 30 min stirring the reaction is concentrated, diluted with EtOAc, washed with water and brine before the organic layer is dried over sodium sulfate and concentrated. The residue is separated via FCC (5-50% EtOAc in heptane) to give 5-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J=5.7 Hz, 1 H), 8.24 (d, J=9.0 Hz, 1 H), 7.86 (s, 1 H), 7.78 (d, J=8.2 Hz, 1H), 7.60 (d, J=3.7 Hz, 1 H), 7.55 (t, J=8.0 Hz, 1 H), 7.45-7.50 (m, 2 H), 7.42 (d, J=2.1 Hz, 1 H), 7.15 (dd, J=8.9, 2.3 Hz, 1 H), 6.82 (d, J=5.7 Hz, 1 H), 6.73 (dd, J=3.7, 0.6 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:32][CH2:31][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][N:16]([CH2:25][CH2:26][CH2:27][NH:28][CH3:29])[C:15]2=[O:30])[CH2:13][CH2:12]1.[C:34]([O:38][C:39]([N:41]1[CH2:48][CH2:47][C:44]2([O:46][CH2:45]2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(O)C>[C:34]([O:38][C:39]([N:41]1[CH2:48][CH2:47][C:44]([CH2:45][N:28]([CH2:27][CH2:26][CH2:25][N:16]2[C:15](=[O:30])[C:14]3([CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:6]4[CH2:5][CH2:4][CH:3]5[CH2:8][CH:7]4[C:2]5([CH3:1])[CH3:33])[CH2:32][CH2:31]3)[N:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17]2)[CH3:29])([OH:46])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CNCCCN1CN(c2ccccc2)C2(CCN(CCC3CCC4CC3C4(C)C)CC2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: CN(CCCN1CN(c2ccccc2)C2(CCN(CCC3CCC4CC3C4(C)C)CC2)C1=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Yield: 89.7 %

Procedure:
2.6 g (5.74 mmol) of compound (24) was placed in a flask and diluted with 20 ml ethanol. To this solution was added 1.88 g (8.81 mmol) of the epoxide (32) and the mixture was heated to reflux until TLC showed complete conversion. For work-up the solvent was evaporated and the residue was taken up with ethyl acetate. After washing with aqueous potassium carbonate solution drying over sodium sulphate and concentration in vacuo the raw material was purified via flash column chromatography yielding a light yellow viscous oil (3.51 g, 5.15 mmol, 89.8% yield).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:49]1[C:62]2[CH:61]([CH2:63][CH2:64]O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[O:54][C:53]=2[CH:52]=[CH:51][CH:50]=1>C1COCC1>[CH2:28]([O:27][CH:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:64][CH2:63][CH:61]2[C:62]3[CH:49]=[CH:50][CH:51]=[CH:52][C:53]=3[O:54][C:55]3[C:60]2=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:19][CH:18]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCC1c2ccccc2Oc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCC2c3ccccc3Oc3ccccc32)cc1)OCC
Reaction time: 0.25 h

Procedure:
Diethyl azodicarboxylate (40% solution in toluene, 1.61 g, 9.3 mmol) was added dropwise, under argon, over 10 min to a solution of ethyl 3-(4-hydroxyphenyl)-2-ethoxypropionate (2.23 g, 9.3 mmol) and triphenylphosphine (2.43 g, 9.3 mmol) in THF (45 ml). The mixture was stirred for 15 min, then a solution of 2-(9H-xanthen-9-yl)ethanol (2.0 g, 9.3 mmol) in THF (10 ml) was added dropwise over 10 min. The resulting mixture was stirred at room temperature for 60 h. The solvent was evaporated, the residue stirred with benzene (20 ml) and the resulting crystalline solid filtered off. The filtrate was evaporated and the residue purified by column chromatography on silica gel (benzene eluent) to give the title compound as an oil: (1.9 g, 45.8%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:13]CCC[CH2:9]2)=[CH:4][CH:3]=1.[N-]=C=O.CC1C=C(C(C2C=C(C)C(O)=C(C)C=2)(C)C)C=C(C)C=1O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:13])[CH3:9])=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Agent: Cc1cc(C(C)(C)c2cc(C)c(O)c(C)c2)cc(C)c1O
Agent: [N-]=C=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
1,1-bis(4-hydroxyphenyl)-cyclohexane, at a molar ratio of (1):(2) of from 100 mol %:0 mol % to 10 mol %:90 mol %,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])cn3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Reaction of tert-butyl 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate and 2-(2-aminoethylamino)-5-nitropyridine gave tert-butyl 4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))-amino]ethyl}amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH:38]C=O)[S:36][CH:37]=1)[C:7]([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[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH2:2][CH3:3].Cl>>[CH2:1]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:7]([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[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH2:2][CH3:3]
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(N)n1
Yield: 52.4 %

Procedure:
7-[2-n-Propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.20 g.) was treated with conc. hydrochloric acid (0.56 g.) according to a similar manner to that of Example 12 to give 7-[2-n-propoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.10 g.).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([SH:10])=[CH:5][C:3]=1[NH2:4].[F:11][C:12]([F:16])([F:15])[CH2:13]I.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+]>O.CN(C)C=O>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH2:13][C:12]([F:16])([F:15])[F:11])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1cc(F)c(N)cc1S
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)c(N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To 1,000 ml of a N,N-dimethylformamide solution of 129 g of 2-fluoro-4-methyl-5-mercaptoaniline, 250 g of 2,2,2-trifluoroethyl iodide and 125 g of potassium carbonate were added, and 10 g of Rongalit was further added, followed by stirring at room temperature for 8 hours. The reaction liquid was poured into water, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 182 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)aniline.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>>[C:1]1([C:7]([C:18]2[CH:19]=[CH:20][C:15]([OH:21])=[CH:16][CH:17]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(c1ccccc1)(c1ccccc1)c1ccc(O)cc1

Procedure:
1,1-Diphenylethylene and phenol in an excess amount were heated in an oil bath at 140° to 150° C. for 1 hour in the presence of p-toluenesulfonic acid. After being allowed to cool, p-toluenesulfonic acid was neutralized using sodium hydrogencarbonate and the excess phenol was then removed by steam distillation to obtain p-(1,1-diphenylethyl)phenol. The resulting phenol was then subjected to carboxylation by the Kolbe reaction according to the process described in Synthesis Example 1 to obtain Compound (4) which was then converted into the zinc salt by the same process as that described in Synthesis Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:22]=[CH:21][CH:20]=[C:14]2[C:15]([O:17][C:18](=O)[C:13]=12)=[O:16])([O-:11])=[O:10].O>C(O)(=O)C>[N+:9]([C:12]1[CH:22]=[CH:21][CH:20]=[C:14]2[C:15]([N:1]([C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)[C:18](=[O:17])[C:13]=12)=[O:16])([O-:11])=[O:10]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1ccc(O)cc1
Yield: 78.3 %

Procedure:
The starting material used in the above example can be prepared as follows: 34.3 g (0.31 mol) of 4-aminophenol and 59.9 g (0.31 mol) of 3-nitrophthalic anhydride in 600 ml of acetic acid are refluxed for 6 hours and the mixture is then stirred into 3,000 ml of water. The product which has precipitated is washed with water and dried for 24 hours at 70° C./30 mm Hg. 69 g (78% of theory) of 4-(3-nitrophthalimidyl)-phenol are obtained; melting point 202° C. IR spectrum (KBr): 1785 cm-1 and 1725 cm-1 (CO--N--CO); 1550 and 1350 cm-1 (NO2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-])=O)=[CH:7][C:8]=1[Br:9])[NH2:5]>C(O)C.[Ni]>[Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:6]([NH2:10])=[C:4]([NH2:5])[CH:3]=1
Reactant: Nc1cc(Br)c(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Br)c(Br)cc1N

Procedure:
Following the procedure of Example 9, 5 g. of 3,4-dibromo-6-nitroaniline were reduced in anhydrous ethanol with Raney nickel to yield 4,5-dibromo-o-phenylenediamine which was not isolated but mixed immediately with 2.47 g. of 2-ketoglutaric acid. One hundred ml. of ethanol were added and the mixture heated to refluxing temperature for 3 hours. 3 gms. of β-(6,7-dibromo-3,4-dihydro-3-oxo-2-quinoxaline)propionic acid were obtained melting at 249°-250° C. The free acid was converted to the corresponding ethyl ester by the procedure of Example 8. Ethyl β-(6,7-dibromo-3,4-dihydro-3-oxo-2-quinoxaline)propionate thus prepared melted at 189°-190° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C([O-])([O-])=O.[K+].[K+].[NH:21]1[CH2:25][CH2:24][N:23]=[C:22]1S(O)(=O)=O>CO>[NH:23]1[CH2:24][CH2:25][N:21]=[C:22]1[N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(O)C1=NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NCCN2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.86 of Boc-piperazine were combined with 25 ml of water, 25 ml of methanol, 2.77 g of K2CO3 and 1.5 g of imidazoline-2-sulphonic acid and stirred for 2 days at RT. After dilution with water the mixture was extracted with EE and chromatographed over silica gel. 0.8 g of 1-(imidazolin-2-yl)-4-Boc-piperazine were obtained. This substance was combined with 6.2 ml of DMF and 136 mg of NaH dispersion (60%). After one hour, 0.214 ml of methyl iodide was added dropwise and the reaction mixture was left for three days at RT. It was combined with water, extracted with EE and chromatographed over silica gel. In this way, 0.47 g of 1-(1-methylimidazolin-2-yl)-4-Boc -piperazine was obtained, which was treated with 5 ml of 4N HCl in dioxane at RT. After one hour, the mixture was concentrated by evaporation, stirred with ether and evaporated to dryness in vacuo. 0.38 g of 1-(1-methyl -imidazolin-2-yl)-piperazine dihydrochloride was thus obtained as a solid substance (yield 15%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39]>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH:12]=[C:13]([NH:39][C:38]2[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:36]([F:35])[CH:37]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(F)cc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 2-(4′-chloro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3-fluoro-5-(trifluoromethyl)aniline under the conditions described in Example 37, step (b). Mass spectrum (ES-, m/z): 560, 562 (M−H);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.O1CCCC1.C([Li])CCC.Cl[Si:21]([CH3:24])([CH3:23])[CH3:22]>CO.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:5]=[C:4]([Br:9])[CH:3]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 1,3,5-tribromobenzene was added to 20 mL of tetrahydrofuran and the temperature was adjusted to −78° C. Subsequently, 1.65 mL of butyllithium was slowly added dropwise. The mixture was stirred for 2 hr while maintaining its temperature, and 0.45 g of chlorotrimethylsilane was slowly added dropwise, after which the temperature of the mixture was raised to room temperature. After completion of the reaction, triethylamine and methanol were added, and the reaction mixture was stirred and extracted, followed by drying the solvent. The resulting solid was filtered and purified, yielding (3,5-dibromophenyl)trimethylsilane as an intermediate.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34]COC)[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([OH:34])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OCOC)c2)c1)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(O)c2)c1)C1CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 46.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-(methoxymethoxy)biphenyl-4-yl)oxy)methyl)phenyl)propanoate (1.84 g) in THF (30 mL) was added 6N hydrochloric acid (3.0 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (788 mg) as a colorless oil.