Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1)=[CH:7]2
Reactant: Nc1cccc2cc(O)ccc12
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc3c(N)cccc3c2)ccn1
Temperature: 90 °C

Procedure:
To a solution of 5-amino-2-napthol (2.8 g, 17.6 mmol) in DMF (20 mL), NaH (60% in oil, 843 mg, 21.1 mmol) was added and stirred until the bubbling stopped. To the mixture 4-chloro-N-methylpicolinamide (Org. Proc. Res. & Dev., 2002, 6, 777-781)(1 g, 5.86 mmol) was added and the reaction heated to 90° C. for 22 h. The mixture was cooled to RT and diluted with CHCl3 and washed with water. The emulsion was filtered thru a pad of Celite and the layers separated. The water was washed with CHCl3 and the organic portions combined and washed with 1N NaOH and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography using hexanes and EtOAc as the eluent to give the title compound as a rose-colored solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[C:36](=[O:42])[CH:35]=[CH:34]2.C(OC(=O)C)C.[ClH:49]>C(OCC)(=O)C.CN(C=O)C>[ClH:49].[ClH:49].[CH3:41][N:37]1[C:38]2[C:33](=[CH:32][C:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:11]([CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[CH3:7])[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:40][CH:39]=2)[CH:34]=[CH:35][C:36]1=[O:42]
Reactant: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Reactant: Cc1ccccc1CNCCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1CN(CCCCCOc1ccc2c(ccc(=O)n2C)c1)CCc1cccnc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (360 mg) and (2-methylbenzyl)-(2-pyridin-3-ylethyl)amine (591 mg) were added to a DMF solution (6.5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one (650 mg). The mixture was stirred at 60° C. for 8 hours. Ice water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate:methanol:aqueous ammonia=70:20:10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound (270 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[S:4][C:3]=1[CH:17]=[O:18].[BH4-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[S:4][C:3]=1[CH2:17][OH:18]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cn2)sc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cn2)sc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]thiophene-2-carbaldehyde (intermediate 78, 0.144 g) in tetrahydrofuran (10 ml) and water (15 ml) was treated with sodium borohydride (0.03 g). The reaction was stirred at room temperature for 30 minutes, extracted with ethyl acetate and the organic layer washed with water and dried with brine and over magnesium sulfate. The title compound was isolated after removal of the desiccant and evaporation of the solvent.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[C:9]([F:14])[CH:8]=1.[CH2:15]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[CH2:16][CH3:17]>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:21]2([OH:24])[CH2:22][CH2:23][CH:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]2)=[C:9]([F:14])[CH:8]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CCCC1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1CCC(O)(c2ccc(Br)cc2F)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (108.0 mL, 174.0 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (300 mL) solution of 4-bromo-2-fluoro-1-iodobenzene (67) (50.0 g, 166.0 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then 4-propylcyclohexanone (66) (24.5 g, 174.0 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 200 mL of 1N hydrochloric acid aqueous solution, and extracted with 100 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 1-(4-bromo-2-fluorophenyl)-4-propylcyclohexanol (68) (42.0 g, yield 80.2%) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[O:13]1[CH2:16][C:15](=O)[CH2:14]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH3:1][N:2]([CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH:15]1[CH2:16][O:13][CH2:14]1
Reactant: O=C1COC1
Reactant: CNCc1cc([N+](=O)[O-])nn1C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1cc([N+](=O)[O-])nn1C)C1COC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a mixture of 302a (170 mg, 1 mmol) in methanol (4 mL), ZnCl2 (1 mmol/L in diethyl ether) (2 mL, 2 mmol) and oxetan-3-one (150 mg, 2 mmol) were added at room temperature under nitrogen protection, followed by the addition of NaBH3CN (130 mg, 2 mmol). The reaction mixture was warmed to 50° C. and stirred for 3 h. The mixture was then cooled to room temperature and the solvent was removed. The residue was purified on flush column eluting with 50:1 methylene chloride/methanol to afford 302b as a yellow solid (180 mg, 80%, two steps). LCMS: (M+H)+ 227. 1H NMR (500 MHz, DMSO) δ 6.99 (s, 1H), 4.52 (t, J=6.5, 2H), 4.42 (t, J=6, 2H), 3.98 (s, 3H), 3.63 (m, 1H), 3.50 (s, 2H), 2.03 (s, 3H).
Reaction SMILES: [Cl: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.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=3)[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(Cl)cc3c2C1
Reactant: C=Cc1ccc(NC(C)=O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-(5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C([O:3]/[CH:4]=[CH:5]\[C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH2:35][CH3:36])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH2:35]([C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:15]([C:12]2[N:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH:4]=[O:3])=[CH:7][C:8]3=[N:14][CH:13]=2)=[O:16])[N:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:21]=1)[CH3:36]
Reactant: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A solution of (Z)-7-(2-ethoxyvinyl)-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (211 mg, 0.439 mmol) in dioxane (6 mL) was treated at ambient temperature with 2.0 M HCl-ether. The resulting suspension was stirred at ambient temperature for 30 minutes. At that time 3 drops of water were added, so as not to collapse the suspension, and stirring was continued for another 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate, extracted with DCM and EtOAc, and the combined organic extracts dried over anhydrous sodium sulfate. Concentration of the organic extracts afforded 190 mg of a solid which was used directly in next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2].[C:29]1([CH3:35])[CH:34]=CC=C[CH:30]=1.C=C(C)C>CCCCCC>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:29]([CH3:35])([CH3:34])[CH3:30])[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(NC(C)=O)c(O)c1
Reactant: Cc1ccccc1
Agent: C=C(C)C
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1C(C)(C)C
Reaction time: 5 h

Procedure:
A mixture of 30.0 g of 2-acetylamino-5-hexadecyloxyphenol, 20.0 g of Amberlyst 15 (produced by Rohm & Haas Co., U.S.A.) and 300 ml of toluene was stirred while heating at 80°-90° C., during which isobutene was bubbled therethrough for 5 hours. The reaction solution was filtered to remove solids and the filtrate was condensed. On adding 350 ml of n-hexane to the residue, crystals precipitated. The crystals were collected by filtration. 23.5 g of 2-acetylamino-4-tert-butyl-5-hexadecyloxyphenol was obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[O:13][C:14](C)(C)[CH3:15].CSCC(OCC)=O>[Ni].C(N(CC)CC)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:14](=[O:13])[CH2:15]2
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OCl
Agent: [Ni]
Agent: CCOC(=O)CSC
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(F)(F)F)ccc2N1

Procedure:
In analogous fashion, 4-trifluoromethylaniline was reacted with t-butyl hypochlorite, ethyl 2-(methylthio)acetate and triethylamine followed by reduction of the 3-thiomethyl-5-trifluoromethyl-2-oxindole thus obtained with Raney nickel, to give 5-trifluoromethyl-2-oxindole, m.p. 189.5°-190.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:24])[NH:17][CH2:18][CH:19]([CH2:22][OH:23])[CH2:20][CH3:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH:22]([CH:19]([CH2:20][CH3:21])[CH2:18][NH:17][C:16](=[O:24])[O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:23]
Reactant: CCC(CO)CNC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
Oxalyl chloride (141 μL) was dissolved in methylene chloride (1 mL). To the solution, a solution of dimethyl sulfoxide (176 μL) in methylene chloride (1 mL) was added dropwise at −78° C., and the mixture was stirred for 15 minutes. A solution of the compound (168 mg) obtained in Step 5 in methylene chloride (2 mL) was added dropwise thereto at −78° C., and the mixture was stirred for 2 hours. Triethylamine (695 μL) was added thereto, and the mixture was heated to 0° C. and then stirred overnight. To the reaction solution, methylene chloride was added, and the organic layer was washed with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=9/1-7/3) to obtain the title compound (113 mg).
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][C:6]=2[C:5]=1[C:12]([O:14]C)=O)=[C:2]=[S:3].[CH3:16][C:17]1[N:18]=[CH:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:21]=1>>[CH3:16][C:17]1[N:18]=[CH:19][N:20]([CH2:22][CH2:23][CH2:24][N:25]2[C:12](=[O:14])[C:5]3[C:6]4[CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:21]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC2
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCC4)cn1

Procedure:
The compound was synthesized starting from methyl 5,6-dihydro-2-isothiocyanato-4H-cyclopenta[b]thiophene-3-carboxylate (0.100 g. 0.42 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.058 g, 0.42 mmol) as described above.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[C:15]([S:17]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[N+:29]([O-])=O)(=[O:19])=[O:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2]>CC(N(C)C)=O.[Pt]=O>[C:1]([CH2:4][O:5][C:6]1[CH:16]=[C:15]([S:17]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[NH2:29])(=[O:19])=[O:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2]
Reactant: COc1ccc([N+](=O)[O-])c(NS(=O)(=O)c2ccc(OCC(N)=O)c(OCC(N)=O)c2)c1
Agent: O=[Pt]
Solvent: CC(=O)N(C)C
Product: COc1ccc(N)c(NS(=O)(=O)c2ccc(OCC(N)=O)c(OCC(N)=O)c2)c1

Procedure:
2-Carbamoylmethoxy-4-{(5-methoxy-2-nitrophenyl)aminosulfonyl}phenoxyacetamide (Intermediate A67, 14 g, 0.031 mol) in 100 mL of dimethylacetamide was hydrogenated with platinum oxide (0.50 g, 0.0022 mol) as catalyst. After the catalyst was filtered off, the mixture was concentrated under high vacuum. The residue was triturated successively with 1:1 hexanes:ethyl acetate and 2:1 dichloromethane:hexanes. The collected solid, title compound, weighed 12.8 g (97%) after air-drying.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.O.[CH3:10][N:11](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:10]#[N:11]
Reactant: Nc1cc(Br)ccn1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccnc(N)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A mixture of 4-bromopyridin-2-amine (4.9 g, 28.5 mmol), Zn(CN)2 (5.0 g, 42.5 mmol), Pd2(dba)3 (1.3 g, 1.4 mmol) and dppf (1.6 g, 2.8 mmol) in DMF (150 mL) was stirred at 100° C. under nitrogen atmosphere for 1.5 h. The mixture was cooled to rt and water (500 mL) was added. The mixture was extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10:1 to 2:1 petroleum ether/EtOAc to afford 2-aminoisonicotinonitrile as a light yellow solid (2.7 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.19 (d, J=5.1 Hz, 1H), 6.82 (d, J=4.8 Hz, 1H), 6.69 (d, J=0.9 Hz, 1H), 4.72 (br s, 2H). LCMS (ESI) m/z 120 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14](=O)[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O:22][C:23]1[CH:24]=[C:25]([CH:33]([O:50][NH2:51])[C:34]([O:36][CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:26]=[CH:27][C:28]=1[O:29][C:30](=[O:32])[CH3:31])(=[O:21])[CH3:20]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:51]/[O:50][CH:33]([C:34]([O:36][CH:37]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[C:25]2[CH:26]=[CH:27][C:28]([O:29][C:30](=[O:32])[CH3:31])=[C:23]([O:22][C:19](=[O:21])[CH3:20])[CH:24]=2)/[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)ns1
Solvent: CO
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2nsc(NC(=O)OC(C)(C)C)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reaction time: 3 h
Yield: 100 %

Procedure:
2-(5-Tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1.49 g) was dissolved in methanol (60 ml), and to this solution a solution of diphenylmethyl (3,4-diacetoxyphenyl)-2-aminooxyacetate (2.45 g) in methanol (25 ml) was added dropwise. The mixture was stirred for 3 hrs. at the room temperature, and the solvent was evaporated to obtain (Z)-2-(5-tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-[[(diphenylmethyloxycarbonyl)(3,4-diacetoxyphenyl)methoxy]imino]acetic acid (3.84 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=2[C:16]1=[O:21]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in acetic acid (3.0 ml) was stirred for 3 hours under refluxing. Water (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was dried, and the solvent was distilled off under reduced pressure. The resulting pale yellow oily substance was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=8/1) to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a colorless transparent oily substance (0.513 g, 1.41 mmol, 65% yield). Ethanol (1.0 ml) was added thereto for recrystallization to obtain the product as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[N:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[N:13]=[CH:12][C:11]([CH:14]([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
1-[6-(4-Trifluoromethyl-phenoxy)-pyridin-3-yl]-heptan-1-one (1.45 g, 4.13 mmol) is dissolved into denatured ethanol (20 mL) at room temperature then cooled to 0° C. in an ice bath. Sodium borohydride (0.132 g, 4.13 mmol) is then carefully added in small portions. The reaction is allowed to warm slowly to room temperature and is monitored by HPLC. Upon complete consumption of starting material, the reaction is carefully quenched with water and diluted with ethyl acetate. The ethanol is removed and the residue is extracted with ethyl acetate, washed, dried, and concentrated. The 1-[6-(4-trifluoromethyl-phenoxy)-pyridin-3-yl]-heptan-1-ol (1.29 g, 3.65 mmol, 88%), is obtained in purified form after flash column chromatography.
Reaction SMILES: [Cl-].[Li+].[C:3]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:4]=1.[CH3:22][C:23]1[C:24](OS(C(F)(F)F)(=O)=O)=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32].C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>CN1CCCC1=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].C(OCC)(=O)C.O>[CH3:22][C:23]1[C:24]([CH:3]=[CH2:4])=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 55 °C

Procedure:
A mixture of lithium chloride (4.8 g), tris(dibenzylideneacetone)dipalladium (O) chloroform adduct (0.65 g), triphenylarsine (1.6 g) and methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (24.2 g) in N-methylpyrrolidinone (220 ml) was heated to 55° C. Vinyltributyltin (15 g) was added. After 3 hours the mixture was added to water (500 ml), potassium fluoride (16 g) and ethyl acetate. The organic solution was dried, filtered through celite and evaporated to afford methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][OH:20])[CH:15]=2)[CH2:10]1)[CH2:2][CH3:3].C(N(CC)CC)C.O>CS(C)=O>[CH2:21]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:19]=[O:20])[CH:15]=2)[CH2:10]1)[CH2:22][CH3:23]
Reactant: CCCN(CCC)CCCCN1CCc2cc(CO)ccc2C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCN(CCC)CCCCN1CCc2cc(C=O)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of the compound 21 (2.28 g) and triethylamine (4.99 mL) in dimethyl sulfoxide (30 mL), a sulfur trioxide-pyridine complex (2.28 g) was slowly added. The reaction mixture was stirred at room temperature for one hour. To the reaction solution, water (100 mL) was added. The aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol:triethylamine=10:1:0→10:1:0.5) to obtain the title compound (2.26 g) having the following physical properties.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.CS(O)(=O)=O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: CS(=O)(=O)O
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 1.96 g of ferric chloride, 0.35 ml of methanesulfonic acid and 1.95 ml of trimethyl borate. The mixture was heated at 30° C. for 5 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.74 g. The yield of the desired product was 58%.