Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[NH+]=[C:4]1[C:36]2C(=CC=C[CH:35]=2)[C:7](=[C:8](C2C=CC(N(CC)CC)=CC=2)[C:9]2C=[CH:13][C:12](N(CC)CC)=[CH:11][CH:10]=2)[CH:6]=[CH:5]1.[Cl-].C([O:50][S:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)(=[O:53])=[O:52])CCCCCCCCCCC.[Na]>O>[CH2:13]([C:59]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:51]([OH:50])(=[O:52])=[O:53])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:36][CH3:35]
Reactant: CC[NH+]=C1C=CC(=C(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccccc21
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O

Procedure:
Into a solution prepared by dissolving 20 g of C.I. Basic Blue 7 (commercial name: Aizen Victoria Pure Blue, BOH, made by HODOGAYA CHEMICAL CO., LTD.) into 1.5 l of distilled water was added a solution prepared by dissolving 13 g of sodium dodecylbenzenesulfonate into 500 ml of distilled water. The formed precipitate was recovered and washed with water and dried to give a dodecylbenzenesulfonic acid salt of the dye.
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][C@H:7]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+:4]=[N-:5].[CH3:25]I>CN(C=O)C>[N:3]([CH2:6][C@H:7]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[N+:4]=[N-:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])COCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN=[N+]=[N-])COCc1ccccc1
Reaction time: 0.5 h
Yield: 114.7 %

Procedure:
To a solution NaH (0.29 g, 7.35 mmol) in DMF (10 mL) was added a solution of (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-ylcarbamate (1.5 g, 4.9 mmol) in DMF (10.0 mL). The mixture was stirred for 30 min. MeI (1.0 mL, 9.8 mmol) was then added. The mixture was stirred for another 2 h. LCMS indicated the completion of the reaction. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (200 mL×2). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-yl(methyl)carbamate (1.8 g), which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:28])[CH3:29]
Reactant: O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Yield: 89.4 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(3-fluorophenyl)methyl]-1-indanol (98% trans, 2% cis) and 0.93 g (0.004 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.55 g of trans-3-[(3-fluorophenyl)methyl]-1-indanyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[S-2:11].[Na+].[Na+]>C(O)C>[CH2:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][S:11]1
Reactant: Cc1ccccc1C(Br)Br
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Product: c1ccc2c(c1)CSC2

Procedure:
The compounds of formula 4 where n is 0, 1 or 2 are prepared by a modification of the procedure of ##STR13## Oliver, et al., in Chem. and Ind., 1024 (1965). α,α-Dibromo-o-xylene is reacted with sodium sulfide in ethanol to form 1,3-dihydrobenzo[c]thiophene. The thiophene compound is oxidized to the corresponding dioxide by means of hydrogen peroxide, m-chloroperzenxoic acid or other suitable oxidants or to the monoxide (Can. J. Chem., 51, 4082 (1973) using sodium metaperoidate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.C[O:11][C:12](=[O:30])[C@@H:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][N:14]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O>CO>[C:23]([N:14]1[CH2:15][C@@H:16]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:17][C@H:13]1[C:12]([OH:30])=[O:11])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: SCc1ccc(Br)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](SCc2ccc(Br)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of Na (0.25 g) (0.011 mol) in 3 mL of MeOH was added 4-bromobenzyl mercaptan (2.2 g) (0.011 mol). The reaction mixture was stirred for 1 h. Trans-N-Boc-4-methanesulfonyloxy-L-proline methyl ester (1.2 g) (0.0037 mol) (Preparation 9) was added and the mixture refluxed for 18 hrs. Upon cooling to RT, 40 mL of water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and the solvent evaporated in vacuo to afford cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g). NMR (CDCl3, 200 MHz): 10.65 (1H, COOH), 7.4 (2H, d), 7.15 (2H, d), 4.15-4.35 (1H, m), 3.65 (2H, s), 2.95-3.35 (2H, m), 2.4-2.6 (1H, m), 1.85-2.2 (1H, m), 1.3-1.5 (9H). To a solution of cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g) in 10 mL of MeOH was added dropwise SOCl2 (0.2 mL), and the mixture was stirred for 72 hrs at RT. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with dilute aqueous NaHCO3, water, and dried over MgSO4. The solvent was evaporated in vacuo to afford cis-4-(4-bromo-benzylthio)-L-proline methyl ester (0.6 g).
Reaction SMILES: [Na+].C([NH:12][C@H:13]([C:19]([O-:21])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])(OCC1C=CC=CC=1)=O.[H-].[Na+].Br[CH:25]([S:27]([O-:30])(=[O:29])=[O:28])[CH3:26].[Na+]>CN(C)C=O>[NH2:12][C@H:13]([C:19]([OH:21])=[O:20])[CH2:14][CH2:15][C:16]([NH:17][CH2:26][CH2:25][S:27]([OH:30])(=[O:29])=[O:28])=[O:18]
Reactant: CC(Br)S(=O)(=O)[O-]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)NCCS(=O)(=O)O)C(=O)O

Procedure:
3.02 g. (10 mmoles) of carbobenzyloxy-L-glutamine sodium salt (Liebig's Ann. 640, 145 /1961/) are dissolved in 50 ml. of dimethyl formamide, 12 mmoles of sodium hydride are added in the form of an oily dispersion, and the mixture is heated for 2 hours under exclusion of air humidity. Thereafter a solution of 2.11 g. (10 mmoles) of sodium bromoethanesulfonate in 50 ml. of dimethyl formamide is added dropwise, and the mixture is heated for additional 2 hours. The mixture is evaporated in vacuo. The residue is extracted with ether, then the dry substance is dissolved in water, and the solution is passed through a column filled with Dowex 50 ion exchanger. The column is eluted with water. The eluate is evaporated in vacuo, and the residue is dried over solid potassium hydroxide. The obtained substance is subjected to catalytic hydrogenation as described in Example 5. The product is recrystallized from a mixture of ethanol and water. 1.55 g. of gamma-L-glutamyl-taurine are obtained.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(#N)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OCc2ccccc2)cc1)OCC
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of ethyl(2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (23.8 g, 100 mmol, prepared as described in WO99/62872) in acetonitrile (200 mL) was added anhydrous potassium carbonate (31.9 g, 231 mmol) followed by benzyl bromoacetate (17.4 mL, 110 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was allowed to cool to room temperature, insoluble salts were filtered off and the solution was concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), and the organic phase was washed with aqueous NaHCO3 (3×100 mL) and brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification on silica gel with methylene chloride as the eluent and collection of pure fractions yielded 22.4 g (58%) of a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].O[Li].O.O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:23][C:24]([F:25])([F:26])[F:27])[CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:5][C:4]=1[C:28]([F:29])([F:30])[F:31])#[N:2]
Reactant: COC(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(N(CCOc2ccc(C(=O)O)cc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.8 %

Procedure:
To a solution of methyl 4-({2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl}oxy)benzoate (0.0863 g, 0.193 mmol, Example 32) in THF (3 mL) at rt was added LiOH.H2O (0.041 g, 0.97 mmol) and water (0.30 mL). The mixture was stirred 19 h at rt, then 8 h at reflux, cooled and partitioned between 1 N NaOH/Et2O. Layers were separated, and the aqueous layer extracted with Et2O (×1). The aqueous layer was then acidified to approximately pH 1 by addition of 2N HCl and extracted with EtOAc (×3). Combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo yielding 0.0816 g of the title compound as a colorless film which crystallized when triturated with CDCl3: 1H NMR (400 MHz, CD3OD) δ 7.97-7.90 (m, 2H), 7.75 (d, J=8.9 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.28 (dd, J=8.9, 2.5 Hz, 1H), 6.97-6.92 (m, 2H), 4.45 (q, J=8.8 Hz, 2H), 4.31 (t, J=5.2 Hz, 2H), 4.08 (t, J=5.2 Hz, 2H); MS (ESI) m/z 431 (M−1).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:23]C(=O)C)=[N:10][C:11]2[CH:12]=[CH:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[NH2:23][C:9]1[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:17][C:16]2[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(=O)Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Solvent: CO
Product: Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A solution of the obtained crude product of N-(2-benzyl-8-hydroxybenzo[f]quinoxalin-3-yl)acetamide (13) in methanol (20 mL) was heated to 65° C. and stirred overnight (14 hours). After cooling to room temperature, the solution was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=1/1→1/10) to give 3-amino-2-benzylbenzo[f]quinoxalin-8-ol (14, v-coelenteramine) (51.3 mg, 170 mmol, quant., two steps) as an ocherous solid. TLC Rf=0.34 (n-hexane/ethyl acetate=1/1); 1H NMR (500 MHz, CD3OD) δ 4.33 (s, 2H), 7.16-7.20 (m, 2H), 7.21-7.26 (m, 1H), 7.30-7.38 (m, 5H), 7.50 (d, 1H, J=9.0 Hz), 7.76 (d, 1H, J=9.0 Hz), 8.77 (d, 1H, J=9.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[CH2:12][NH:13][C:7]=2[CH:6]=1)=[O:4].[F:19][C:20]([F:38])([F:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]=1[CH3:36].C(N(CC)CC)C>ClCCCl>[CH3:36][C:28]1[CH:29]=[C:30]([C:31]([N:13]2[C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:18]=[CH:17][C:8]=3[CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[CH2:12]2)=[O:32])[CH:34]=[CH:35][C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([F:19])([F:37])[F:38]
Reactant: Cc1cc(C(=O)Cl)ccc1-c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid methyl ester of Step B (1.64 g) in 1,2-dichloroethane (25 mL) was added 4-(2-trifluoromethylphenyl)-3-methylbenzoyl chloride (2.0 g, 1.1 eq) prepared in the manner of Example 1, Step D and triethylamine (1.0 g) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with 10% ethyl acetate in petroleum ether to provide the title compound as a white crystalline solid, m.p. 180–182° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].[CH2:10]([Mg]Br)[C:11]#[CH:12]>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1])[CH2:12][C:11]#[CH:10]
Reactant: C#CC[Mg]Br
Reactant: CC(=O)C=CC=C(C)C
Product: C#CCC(C)(O)CCC=C(C)C

Procedure:
Reaction of this ketone with propargyl magnesium bromide provides 4,8-dimethyl-4-hydroxy-non-7-ene-1-yne. This alcohol is protected with trimethylsilyl chloride and converted to the trans vinyl tin derivative of 4,7-dimethyl-4-trimethylsiloxy-non-8-ene-1-yne which is converted to the corresponding prostagladin by the methods described in U.S. Pat. Nos. 4,322,543 and 4,271,314 to provide methyl 7-[3α-hydroxy-2β-(4-hydroxy-4,8-dimethyl-1,5,7-trans,trans,trans-nonatrienyl)-5-oxocyclopent ane]-1α-hept-4Z-enoate having the formula ##STR16##
Reaction SMILES: [Cl:1][C:2]1[C:6](Cl)=[C:5]([CH:8]=[O:9])[S:4][N:3]=1.[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O>O>[C:11]1([S:17]([C:6]2[C:2]([Cl:1])=[N:3][S:4][C:5]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1snc(Cl)c1Cl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1snc(Cl)c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
A mixture of 3,4-dichloroisothiazole-5-carbaldehyde (0.087 g), benzenesulfinic acid sodium salt (0.078 g) and dimethyl sulfoxide (3.0 mL) was stirred at room temperature for 3.5 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a colourless oil (0.093 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][CH2:16][C:17]([NH2:19])=[O:18].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:17]([CH2:16][NH:15][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])(=[O:18])[NH2:19]
Reactant: O=C(O)c1cccc2cccnc12
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of quinoline-8-carboxylic acid (3.45 mmol), glycinamide hydrochloride (3.45 mmol), NMM (41.43 mmol) and HOAt (4.14 mmol) in DMF (17 mL) at room temperature was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (4.14 mmol). After stirring at room temperature overnight, the reaction mixture was purified by HPLC to afford the title compound as a white solid. MH+230.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][C:13](=O)OC(C)(C)C)(=[O:11])=[O:10])([O-:3])=[O:2].[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][CH2:13][CH3:23])(=[O:11])=[O:10])([O-:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CCNS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude tert-butyl N-(3-nitrobenzylsulfamoyl)carbamate, triphenylphosphine (2 g) and diisopropyl azodicarboxylate (DIAD, 1.6 g) were dissolved in THF (20 mL) and ethanol (0.47 ml). The solution was stirred at ambient temperature overnight. The reaction solution was evaporated to dryness. The residue was dissolved in methanol (10 mL) and treated with 4.0 M HCl in dioxane (10 mL). It was stirred at rt overnight and then evaporated. The residue was diluted with ethyl acetate (100 mL) and washed with NaHCO3 aq. (2×100 mL). The organic solution was evaporated and purified by flash column chromatography (EtOAc/hexane=1/2, 1/1) to give N-(3-nitrobenzyl)-N′-ethylsulfamide. 1H NMR (DMSO-d6): δ 1.02 (t, J=7.2 Hz, 3H), 2.82 (p, J=6.9 Hz, 2H), 4.14 (d, J=6.6 Hz, 2H), 6.93 (t, J=5.4 Hz, 1H), 7.54 (t, J=6.3 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.20 (s, 1H); LCMS: purity: 1.2 g, 88.4%; MS (m/e): 260.16 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.CCCCCC.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:19][C:18]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(B(O)O)cc1
Solvent: CCCCCC
Product: CCOC(=O)Cc1ccc(OC)cc1

Procedure:
Ethyl 4-methoxyphenylacetate was prepared by the general experimental method from 4-methoxyphenylboronic acid (152 mg, 1.00 mmol). After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 4-methoxyphenylacetate is obtained as a colourless liquid in a yield of 77% of theory. 1H NMR (200 MHz, CDCl3): δ=7.25 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.13-4.26 (m, 2H), 3.82 (s, 3H), 3.59 (s, 2H), 1.24-1.26 (m, 3H) ppm; 13C NMR (50 MHz, CDCl3): δ=172.3, 159.1, 130.7, 126.7, 114.4, 61.1, 55.6, 40.9, 14.6 ppm; MS (70 eV), m/z (%): 194 (24) [M+], 121 (100), 91 (8), 77 (10), 51 (4); IR (NaCl): ν=2981 (m), 2836 (w), 1732 (s), 1513 (s), 1247 (m), 1032 (m) cm−1; elemental analysis: (theor): C=68.02, H=7.27, (exp): C=67.91, H=7.18.
Reaction SMILES: C1(CC(N[C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.[C:30]1(CC(N[C@@H]2C(=O)N3C(C(O)=O)=C(C=CC)CS[C@H]23)=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:30]1([C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH:16]([NH:13][C:28](=[O:29])[CH3:11])[S:17][C@H:12]23)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC=CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: CC=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Product: CC=CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](c3ccccc3)[C@H]2SC1NC(C)=O

Procedure:
To a stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylate in dichloromethane (30 ml.g-1) was added Lewis acid (3-5 equiv., see table for conditions). The formation of (6R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylic acid was monitored either by HPLC or TLC. The results are summarized in the table.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32]C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCOCC1.Cl>CO>[CH2:3]([N:10]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCC(=O)N(Cc1ccccc1)Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccccc1)Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
5 mol/L sodium hydroxide solution (0.3 mL) was added to the compound (45 mg) prepared in Example 6 in a mixed solution of dioxane (2 mL) and methanol (1 mL) and stirred for 2 hours at 80° C. To acidify, 1 mol/L hydrochloric acid was added to the concentrated reaction mixture to be extracted with ethyl acetate. The organic layer was washed with saturated sodium and dried by anhydrous sodium sulfate, and then concentrated to obtain the titled compound (37 mg) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=[O:17])/[C:5]/2=[N:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[C:8]1([N:7]2[C:11]3[C:12](=[CH:13][C:14]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:15][CH:16]=3)/[C:5](=[N:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)/[C:6]2=[O:17])[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1/C(=N\c2cccc(C(F)(F)F)c2)c2cc(Br)ccc2N1c1ccccc1
Reactant: OB(O)c1ccccc1
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: C1CCOC1
Product: O=C1/C(=N\c2cccc(C(F)(F)F)c2)c2cc(-c3ccccc3)ccc2N1c1ccccc1
Temperature: 67 °C
Yield: 18.1 %

Procedure:
A mixture of (3z)-5-bromo-1-phenyl-3-{[3-(trifluoromethyl)phenyl]imino}-1,3-dihydro-2H-indol-2-one (22 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (12.0 mg, 0.01 mmol), benzene boronic acid (10 mg, 0.08 mmol) in THF (5 mL), and aqueous Na2CO3 (2M, 100 μL) was heated at 67° C. for 24 h. The crude product was concentrated in vacuo and the residue was extracted with CH2Cl2 (3×1 ml), concentrated, and purified by preparative TLC using 10% methanol in CHCl3, giving the desired product (4 mg, 18%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:6])[CH3:2].[C:15]([OH:18])(=[S:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][S:17][C:15](=[O:18])[CH3:16])[CH3:2]
Reactant: C=C(Cc1ccccc1)C(=O)OCC
Reactant: CC(O)=S
Product: CCOC(=O)C(CSC(C)=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 576 mg of α-benzylacrylic acid ethyl ester and 0.259 ml of thioacetic acid is stirred for 20 hours at 70° and then concentrated by evaporation in vacuo. The residue is purified by flash chromatography with eluant F. Rf (C)=0.35.