Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12]B(O)O.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[OH2:9].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 217.6 %

Procedure:
The general procedure described in Example 3 was used with 4-chlorobenzenesulfonic acid (192 mg, 1.00 mmol), methylboronic acid (90 mg, 1.50 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 12 h, 100° C. The product was isolated as a white solid (207 mg, 99%). Mp=104° C. (lit.=106° C.). 1H NMR (400 MHz, d4-MeOH) δ: 7.71 (d, 2H, J=8.4 Hz), 7.24 (d, 2H, J=8.4 Hz), 5.08 (s, H2O), 2.37 (s, 3H)). 13C NMR (125 MHz, d4-MeOH) δ: 143.3, 142.0, 130.0, 127.1, 21.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]1.[O:20]1[C:24]2[CH:25]=[C:26]([C:29](Cl)=[O:30])[CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:29]([C:26]2[CH:27]=[CH:28][C:23]3[NH:22][C:21](=[O:32])[O:20][C:24]=3[CH:25]=2)=[O:30])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Reactant: O=C(Cl)c1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1N1CCN(CCCCNC(=O)c2ccc3[nH]c(=O)oc3c2)CC1
Yield: 71.2 %

Procedure:
According to the method of Example 3, 4-[4-(2-methyloxyphenyl)piperazinyl]butylamine and benzoxazolin-2-one-6-carbonyl chloride were subjected to acylation in the presence of sodium carbonate as deacidficating agent to obtain the product. Yield: 71.2%. mp: 175-177° C. 1HNMR (ppm, DMSO-d6) δ: 1.53 (m, 4H), 2.36 (m, 2H), 2.50 (s, br., 4H), 2.94 (s, br., 4H), 3.28 (m, 2H), 3.76 (s, 3H), 6.86 (m, 2H), 6.93 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 7.70-7.74 (m, 2H), 8.42 (t, J=5.6 Hz, 1H).
Reaction SMILES: [OH:1][N:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]1=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH2:18]([O:1][N:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]1=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1cccc(=O)n1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc(=O)n1OCc1ccccc1
Yield: 90.9 %

Procedure:
1-Hydroxy-6-carboxy-2 (1H)-pyridinone (15.5 g, 0.1 mol) and anhydrous potassium carbonate (27.6 g, 0.2 mol) were mixed with benzyl chloride (15.2 g, 0.12 mol) in methanol (250 mL). The mixture was refluxed for 16 h, filtered, and the filtrate evaporated to dryness. The residue was dissolved in water (50 mL) and acidified with 6 N HCl to pH 2. The white precipitate was isolated by filtration, washed with cold water, and dried in vacuum, to yield 22.3 g (91%) of 1-Benzyloxy-6-carboxy-2 (1H)-pyridinone, mp 176-177° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH:27]5[CH2:29][O:28]5)=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:13][C:8]=2[O:7][C:6]=1[CH3:30])=[O:4].[CH3:31][NH2:32]>C(Cl)Cl.C1COCC1.CO>[OH:28][CH:27]([CH2:29][NH:32][CH3:31])[CH2:26][O:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[C:6]([CH3:30])[O:7][C:8]=4[CH:13]=3)=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCC5CO5)ccc34)ccc12
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CNCC(O)COc1ccc2c(Oc3ccc4c(C(=O)NC)c(C)oc4c3)ccnc2c1
Temperature: 65 °C

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 123-A (1 g, 2.9 mmol), 2-(bromomethyl)oxirane (467 mg, 3.4 mmol) and Cs2CO3 (1.4g, 4.2 mmol( in CH3CN (25 ml) was heated to 65° C. for 3 hours. The solution was extracted with EtOAc. N,2-dimethyl-6-{[7-(oxiran-2-ylmethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 123-B (1.1 g) was isolated by a silica gel column using 1-5% MeOH in CH2Cl2 To a solution of 123-B (150 mg, 0.35 mmol) in THF (5 ml) was added a solution of methylamine in MeOH (1 N, 1 ml). The solution was heated to 65° C. for 2 hours. The crude product was purified by HPLC (10-40% CH3CN/H2O over 30 min.) to give 6-({7-[2-hydroxy-3-(methylamino)propoxy]quinolin-4-yl}oxy)-N,2-dimethyl-1-benzofuran-3-carboxamide 123.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=2)=[C:4]([F:22])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O1CCOCC1.CO>Cl>[Cl:1][C:2]1[C:3]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=2)=[C:4]([F:22])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2c(Cl)cnc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2F)c(C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cnc(-c2c(Cl)cnc(N3CCC(N)CC3)c2F)c(C)c1
Yield: 121.7 %

Procedure:
A solution of tert-butyl (1-(5′-chloro-3′-fluoro-3,5-dimethyl-[2,4′-bipyridin]-2′-yl)piperidin-4-yl)carbamate (160 mg, 0.368 mmol) in 4 M HCl in dioxane (3.0 mL, 12.0 mmol) and MeOH (1.0 mL) was stirred at rt for 2 h. After concentration, the residue was further dried under vacuum to give 150 mg (100%) of pale yellow solid as a di-HCl salt: LRMS (M+H)+: 335.0; 1H NMR (400 MHz, DMSO-d6) δ 1.50-1.72 (m, 2 H), 1.94-2.03 (m, 2 H), 2.10 (s, 3 H), 2.37 (s, 3 H), 2.89-3.12 (m, 2 H), 3.20-3.33 (m, 1 H), 3.92-4.08 (m, 2 H), 6.62 (br. s., 1 H), 7.77 (s, 1 H), 8.12-8.31 (m, 4 H), 8.44 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O.CN(C)C=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
To 36.0 g (0.15 mole) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid were added 45 ml of toluene, 15 ml of thionyl chloride and 0.2 ml of N,N-dimethylformamide, and the mixture was refluxed by heating for 4 hours. After the reaction, toluene and excess thionyl chloride were removed under reduced pressure to obtain 2,4,5-trifluoro-3-difluoromethoxybenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH:17]([CH3:25])[C:18]([N:20]1[CH2:24][CH2:23][CH2:22][O:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:17]([CH3:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[O:19])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(Cl)C(=O)N1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)N1CCCO1
Reaction time: 5 h
Yield: 95.9 %

Procedure:
A mixture of 4-(4-chlorophenoxy)phenol (22.1 g), N-[(±)-2-chloropropionyl]isoxazolidine (16.4 g) which was prepared as in Example 1, anhydrous potassium carbonate (15.2 g) and acetonitrile (300 ml) was heated under reflux with stirring for 5 hours. After cooling, the reaction mixture was filtered through a suction filter to remove solid matters and the filtrate was concentrated in vacuo. The residue was washed with the addition of water and benzene and the organic layer formed was separated and dried over anhydrous sodium sulfate. The removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(4-chlorophenoxy)phenoxy]propionyl]isoxazolidine (33.4 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 98°-100° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:31])[CH3:30])([CH3:27])[CH3:26])=[CH:21][CH:20]=1>>[ClH:17].[CH3:27][C:25]([NH:28][C:29](=[O:31])[CH3:30])([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:14]2[CH2:13][CH2:12][N:11]([C:5]3[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=3[F:3])[CH2:16][CH2:15]2)=[CH:20][CH:21]=1)[CH3:26]
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3ccc(F)cc3F)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as pale-brown crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].O>CN(C=O)C>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=NNC(=O)OC(C)(C)C)CC(C)(C)C1

Procedure:
3,3,5,5-Tetramethylcyclohexanone (7.7 g, 0.05 moles) was dissolved in DMF (50 mL) and t-butyl carbazate (6.6 g, 0.05 moles) was added to give a clear solution. Left to stand over the weekend. Poured into water and extracted into ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. Evaporated to give a white solid. Triturated with ether and dried in a desiccator to give the product as a white solid. (10.4 g, 78%). 1H NMR (300 MHz DMSO-d6) mixture of isomers 9.5 and 7.95 (brs, 1H), 2.95 (s, 1H), 2.75 (s, 1H), 2.1 (s, 2H), 1.95 (s, 2H), 1.4 (s, 9H), 0.9 (2s, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10](=S)[NH:9]1.CO.[NH3:22]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10]([NH2:22])=[N:9]1
Reactant: Fc1ccccc1C1(C(F)(F)F)CCOCC(=S)N1
Reactant: N
Solvent: CO
Product: NC1=NC(c2ccccc2F)(C(F)(F)F)CCOC1
Temperature: 25 °C

Procedure:
5-(2-Fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepane-3-thione (1.25 g, 4.26 mmol) was dissolved in NH3 solution 7 mol/L in methanol (27 mL, 128 mmol). The sealed reaction vessel was stirred over night at rt. The reaction mixture was evaporated, dissolved in TBME and extracted with 1N HCl. The layers were separated, washed with water and TBME. The aqueous layers were combined, basified by addition of solid K2CO3 and extracted with dichloromethane four times. The combined CH2Cl2 layers were dried over MgSO4.H2O and evaporated to give 1.12 g of the title compound as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)C>[Br:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1
Reactant: C1COCCN1
Reactant: BrCc1cccc(CBr)n1
Solvent: CCO
Product: BrCc1cccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
2,6-Bis(bromomethyl)pyridine (265 mg) was suspended in 2 mL of ethanol, thereto 87 mg of morpholine was added at ice temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (methylene chloride-ethanol-triethylamine=400:20:1 (v/v, the same hereinafter)) to give 90 mg of 4-(6-bromomethylpyridin-2-ylmethyl)morpholine as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[N:11]=[CH:10][C:9]=1[C:23]([NH:25][C:26]1[CH:27]=[N:28][C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:30]([CH3:32])[CH:31]=1)=[O:24].N1C=CC=CC=1.C(N(CC)CC)C>C(O)C.O>[CH3:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][N:14]=2)[N:11]=[CH:10][C:9]=1[C:23]([NH:25][C:26]1[CH:27]=[N:28][C:29]([CH:33]2[CH2:34][CH2:35][N:36]([C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])[CH2:37][CH2:38]2)=[C:30]([CH3:32])[CH:31]=1)=[O:24]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C(=O)C(C)C)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
2-Methylpropanoylchloride (79 μl) was added to a mixture of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (222 mg) described in Reference Example 171 and pyridine (2.5 ml), and stirred at 40° C. for five hours. Triethylamine (350 μl), water and ethanol were added to the reaction solution, and the precipitated solid was washed with water to give the titled compound (220 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.Br[CH2:19][CH2:20][CH:21]=[C:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[N:32][C:27]=2[CH2:26][O:25][C:24]2[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]1=2.[I-].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:19][CH2:20][CH:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[N:32][C:27]=4[CH2:26][O:25][C:24]4[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]3=4)[C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccc(Cl)cc2C2(CCNCC2)O1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1C(=O)OC3(CCNCC3)c3cc(Cl)ccc31)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
A solution of 6-chloro-1,2-dihydro-2-oxo-spiro[4H-3,1-benzoxazin-4,4′-piperidine] (Made by the procedure of Bock, et al. GB2,355,465, 0.25 g, 0.7 mmol) in isopropanol (5 mL) was treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.19 g, 0.50 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 5 hr, and evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC to yield 0.029 g (10%) of the title compound, 1H-NMR (CD3OD) δ: 1.50 (3H, s), 2.18 (2H, brs), 2.95-3.2 (6H, m), 5.30 (2H, brs), 6.18 (1H, t), 6.79 (1H, m), 6.92 (1H, m), 7.12 (1H, m), 7.38 (2H, m), 7.48 (2H, m), 7.81 (2H, m), 8.31 (1H, m), 8.55 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]#[CH:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:38][CH2:39]I)(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(OCC)(=O)C.C(OC(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]#[CH:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:39][O:38][C:31](=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCCCCC(=O)OCI
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=C)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)CCCCC)=C(C=C)CS[C@H]12)c1csc(N)n1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2 g) in N,N-dimethylformamide (20 ml) was added a solution of iodomethyl hexanoate (1.28 g) in N,N-dimethylformamide (4 ml) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added ethyl acetate (80 ml), followed by washing twice with water, three times with 5% aqueous solution of sodium bicarbonate and twice with a saturated aqueous solution of sodium chloride. The resultant solution was dried over anhydrous magnesium sulfate and then evaporated to give a residue, which was pulverized with diisopropyl ether to obtain hexanoyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.85 g), mp 98°-109° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:40]1[CH2:58][CH:41]1[CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][CH2:52][CH2:53][O:54][CH:55]([CH3:57])[CH3:56])=[CH:46][CH:45]=1>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH:30][CH2:58][CH:41]([OH:40])[CH2:42][O:43][C:44]3[CH:49]=[CH:48][C:47]([CH2:50][O:51][CH2:52][CH2:53][O:54][CH:55]([CH3:57])[CH3:56])=[CH:46][CH:45]=3)([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)N)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)NCC(O)COc3ccc(COCCOC(C)C)cc3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 4.6 g (8.5 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-amino-2-methylpropoxy)-phenoxy]-ethyl}-ester 5-methyl ester and 2.95 g (11 mmol) of 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene in 20 ml of isopropanol is heated under reflux for 6 hours while stirring. Working up and chromatographic purification analogously to Example 1 yield 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[[3-[4-(2-isopropoxyethoxymethyl)-phenoxy]-2-hydroxypropylamino]]-2-methylpropoxy}-phenoxy}}-ethyl}}}-ester 5-methyl ester in the form of a vitreous solid having the structure: ##STR38##
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])[C:7](=[O:13])[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1.[OH:19][CH2:20][CH:21]([CH2:23][OH:24])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:19][CH2:20][CH:21]1[CH2:23][O:24][C:7]2([C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]3[O:3][C:2]([CH3:18])([CH3:1])[CH2:11][CH2:10][C:9]=3[C:8]2=[O:12])[O:13]1
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CO)O1)C2=O
Yield: 36 %

Procedure:
To a solution of 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (1.21 g, 5 mmol) in benzene (12 ml) is added glycerol (0.92 g, 10 mmol) and p-toluenesulfonic acid monohydrate (0.28 g, 1.5 mmol). The resulting mixture is refluxed for 6 hours. After removal of the solvent, product is purified by column chromatography on silica gel eluting with 30% ethyl acetate in methylene chloride to provide 0.57 g (36% yield) as a light yellow solid, which is a mixture of diasteromers. M.p. 44-46° C.; 400 MHz 1H NMR (CDCl3) δ: 1.41 (s, 6H), 1.73-1.82 (m, 2H), 2.36-2.42 (m, 1H), 2.48-2.54 (m, 1H), 3.72-3.78 (m, 1H), 4.18 (d, J=2.5 Hz, 1H), 4.20-4.29 (m, 1H), 4.40 (t, J=8.0 Hz, 1H), 4.71-4.74 (m, 1H), 4.85 (d, J=8.8 Hz, 1H), 7.38-7.44 (m, 2H), 7.54-7.56 (m, 1H), 7.75-7.78 (m, 1H); LCMS: Calc. for C18H21O5: 217; Found 217.
Reaction SMILES: C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.[CH2:19]([O:21][C:22]1[C:23]([C:37](=[O:39])[CH3:38])=[CH:24][C:25]2[C:26](C(C)C)=[CH:27][CH2:28][C:29]([CH3:33])([CH3:32])[C:30]=2[CH:31]=1)[CH3:20]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]([O:21][C:22]1[C:23]([C:37](=[O:39])[CH3:38])=[CH:24][C:25]2[CH:26]=[CH:27][CH2:28][C:29]([CH3:32])([CH3:33])[C:30]=2[CH:31]=1)[CH3:20]
Reactant: CCOc1cc2c(cc1C(C)=O)C(C(C)C)=CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1C(C)=O)C=CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of mixture B (2.18 g, 7.21 mmol) in THF (40 mL) was added tributyl(1-ethoxyvinyl)tin (3.66 mL, 10.8 mmol). After the mixture was degassed via bubbling argon for 30 min, dichlorobis(triphenylphosphine)palladium (II) (0.25 g, 0.05 mmol) was added. The reaction mixture was heated to reflux for 48 h. Because the reaction was incomplete via TLC, another 0.5 eq tributyl(1-ethoxyvinyl)tin and 0.05 eq dichlorobis(triphenylphosphine)palladium (II) were added and the mixture was heated at reflux for overnight. The reaction mixture was cooled to room temperature and quenched with water and 10% HCl. After stirring at room temperature for 30 min, the mixture was extracted with ether. The combined ethereal layers were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 1% ethyl acetate in hexanes) gave a separable mixture of 1-(3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-24) and the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[CH:25]=[CH:24]2>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:37]2[CH2:36][CH2:35][N:34]([S:31]([C:26]3[CH:25]=[CH:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([Cl:20])[CH:22]=4)[CH:27]=3)(=[O:33])=[O:32])[CH2:39][CH2:38]2)=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of 3-(1-tert-butoxycarbonylpiperidin-4-yl)propionic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Na]>C(OC(=O)OCC)C>[C:1]([Si:5]([CH3:19])([CH3:20])[O:6][C:7]1[CH:8]=[C:9]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Na]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 160.7 %

Procedure:
To a solution of ethyl 3-(tertbutyldimethylsilyloxy)phenylacetate (10 g) in 25 ml of diethylcarbonate are added portionwise 0.86 g of sodium and the mixture is refluxed for 2 hours. The solvent is evaporated off and the residue is poured into water (90 ml). The pH is adjusted to pH=6 with acetic acid and the mixture is extracted with diethyl ether. The organic phase is dried over sodium sulfate and cocentrated to dryness to give 10 g of an orange oil which is purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 95:5), to give 2.45 of the product.