Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[Cl:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: Cc1ccc(Cl)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 99 %

Procedure:
1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2-chloro-5-methylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 1.1 g of the title compound. Yield 99% ES MS (+) m/z 391.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH:22]=[CH:21]1>C1(C)C=CC=CC=1.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:11]=[CH:12][CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:22]2[CH:21]1[C:20](=[O:26])[NH:24][C:23]2=[O:25])([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)N1
Reactant: O=[N+]([O-])c1ccccc1/C=C/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1NC(=O)C2C(c3ccccc3[N+](=O)[O-])C=CC(c3ccccc3)C12
Temperature: 130 °C

Procedure:
7.5 g (29.8 mmole) (E,E)-1-(2-nitrophenyl)-4-phenyl-1,3-butadiene and 2.9 g (29.9 mmole) maleic acid imide are heated in 10 ml toluene to 130° C. for 12 hours. After addition of 1.5 g (15.5 mmole) maleic acid imide it is heated at 130° C. for a further 24 hours. After cooling, it is diluted with 40 ml dichloromethane, the product filtered off, and crystallized from ethanol. One obtains 1,3,3a,4,7,7a-hexahydro-4-(2-nitrophenyl)-1,3-dioxo-7-phenyl-2H-isoindole in the form of pale yellow crystals, which decompose from 200°-208° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:4]=[CH:5][N:6]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: Cc1nccn1-c1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(-n2ccnc2C)c1
Reaction time: 1 h
Yield: 97 %

Procedure:
3-(2-Methylimidazol-1-yl)aniline (11 g, 63.6 mmol) is added in portions to acetic anhydride (100 ml) at ambient temperature. After stirring for 1 hour the mixture is poured into water (300 ml). The resulting solution is cooled in an ice-bath and rendered alkaline with aqueous sodium hydroxide (12M). The product is filtered off, washed thoroughly with water and dried to yield 2j (12.3 g, 97%). Mp 238-240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30]>C(O)(=O)C.CO>[CH3:27][O:28][C:29]([NH:31][C:32]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[CH:3][C:2]=2[N:1]=1)=[O:30]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc1N
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OCc4ccccc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-benzyloxy-benzenesulfonic acid 3,4-diamino-phenyl ester (134 mg) in acetic acid (0.83 ml) and methanol (2.5 ml) at 80° C. was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (89 mg). The reaction mixture was refluxed for 2 hours then allowed to cool to ambient temperature and stirred at this temperature for 14 hours. The resultant precipitate was filtered, washed with diethyl ether and dried under vacuum to afford 4-benzyloxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester as a beige solid. Mass spectrum: 454 [M+H]+; retention time=11.46 minutes.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH3:46])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH3:46])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.49 g), sodium hydrogen carbonate (2.40 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(1-benzyl-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 49%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=2[F:25])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4F)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (64 mg, 74%), MS (ISP) m/z=347.5 [(M+H)+], mp 238° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](OC)[C:6]([C:11](=[O:13])C)=[C:5](OCC(OC)=O)[C:4]=1CCC(C)C>C(O)C>[CH:11](=[O:13])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(C)=O
Solvent: CCO
Product: COc1ccc(C=O)cc1
Yield: 101.1 %

Procedure:
To a liquid mixture of 11.8 g of the 4',6'-dimethoxy-2'-methoxycarbonylmethoxy-3'-isopentylacetophenone obtained in Production Example 5, 4.8 g of p-anisaldehyde and 50 ml of ethanol was added 150 ml of a saturated solution of potassium hydroxide in ethanol, and the mixture was stirred at room temperature overnight to effect a reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 12.7 g (yield=81.9%) of 2'-carboxymethoxy-4,4',6'-trimethoxy-3'-isopentylchalcone in the form of a yellow prism.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=O.[O:14]1CCN(C2CCCCC=2)CC1.Cl.[CH:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:14]=[C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: c1ccccc1
Reactant: CC(C(=O)O)c1ccc(C=O)cc1
Agent: Cl
Product: CC(C(=O)O)c1ccc(C=C2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A solution of 3.56 g (0.02 mole) of 2-(p-formylphenyl)propionic acid and 10.1 g (0.056 mole) of 1-morpholinocyclohexene in 40 ml of benzene was allowed to stand overnight (12 hours) at room temperature, after which 20 ml of 6N hydrochloric acid were added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then extracted with benzene; the extract was washed with water and dried; and the solvent was removed by evaporation under reduced pressure to give a crystalline substance. This was recrystallized from a mixture of diethyl ether and hexane, to give 4.02 g (yield 77.7%) of the title compound as white crystals melting at 108°-110° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH2:45]([C:26]1[N:25]=[C:24]([CH3:48])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][F:13])=[CH:18][CH:19]=2)[C:28](=[O:29])[C:27]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:3][C:4](=[O:7])[O:5][N:44]=2)=[CH:33][CH:32]=1)[CH2:46][CH3:47]
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OCCF)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCCF)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (11 mL) was stirred at 50° C. for 30 min, 4′-({1-[4-(2-fluoroethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (11 mL), N,N′-carbonyldiimidazole (0.56 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.1 g, 88%) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:2]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 140 °C
Yield: 56.4 %

Procedure:
A mixture of 1.11 g of 2-fluoro-4-(trifluoromethyl)benzaldehyde, 739 mg of methyl thioglycolate, 1.3 g of potassium carbonate and 20 ml of DMF was stirred at 140° C. for hours, and then the reaction mixture was cooled to room temperature. To the reaction mixture was added water, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with water, followed by saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 848 mg of methyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][C:9]([O:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)([CH3:11])[CH3:10])C(=O)C2=CC=CC=C12.[OH-].[Na+]>O>[NH2:15][CH2:14][CH2:13][O:12][C:9]([O:8][CH2:7][CH2:6][NH2:5])([CH3:10])[CH3:11]
Reactant: CC(C)(OCCN1C(=O)c2ccccc2C1=O)OCCN1C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(OCCN)OCCN
Yield: 70 %

Procedure:
2,2-Di-(2-phthalimidoethoxy)propane (46.2 gm, 0.11 mole), sodium hydroxide (43.7 gm, 1.10 mole) and 100 mL of H2O were combined and refluxed for 20 hours. After cooling this solution was extracted with p-dioxane in a liquid-liquid extractor for 20 hours. The p-dioxane was removed by rotary evaporation to give a yellow oil. The oil was distilled under reduced pressure yielding 12.5 gm of a clear colourless oil: 0.077 mole, 71%. bp 107°-110° C./0.18 mm Hg. NMR δ(CDCl3)3.41(tr, 4 H, J=6 Hz, CH2O), 2.78(tr, 4 H, J=6 Hz, NCH2), 1.33 (s, 6 H, geminal (CH3)2), 1.20(s, 4 H, NH2).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>CN(C=O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
11 g of hydroquinone (100 mmol) in 100 ml of DMF is placed at 80° C. for 2 h. This mixture is cooled at ambient temperature then a solution of ethyl bromoisobutyrate (14.7 ml, 100 mmol) in 30 ml of DMF is added dropwise. The mixture is stirred for 3 h then the reaction medium is dry concentrated. The residue obtained is taken up in a 1 N HCl solution then extracted with AcOEt. The organic phases are washed with water, dried on MgSO4, then dry concentrated. The residue obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 80:20). 9 g of oil corresponding to intermediate 10c are thus isolated (40% yield). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 70:30, Rf=0.50.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[C:6]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25](=O)[CH2:26][S:27][C:28]#[N:29])[C:20](=[O:32])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[NH2:7].C(OCC)(=O)C.P(=O)(O)(O)O>P([O-])([O-])([O-])=O>[C:6]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[NH:29][C:28](=[O:2])[S:27][CH:26]=3)[C:20](=[O:32])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[NH2:7]
Reactant: O=C([O-])O
Reactant: N#CSCC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)[nH]3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 30.3 %

Procedure:
To a solution of sodium bicarbonate (0.067 g.) in pH 6.4 phosphate buffer (5 ml.) was gradually added 3-carbamoyloxymethyl-7-(3-oxo-4-thiocyanatobutyramido)-3-cephem-4-carboxylic acid (0.33 g.) with stirring at room temperature, and then the mixture was allowed to stand for 30 hours at room temperature. After the reaction, to the reaction mixture was added ethyl acetate (50 ml.). The reaction mixture was adjusted to pH 2 with 50% phosphoric acid, and then the ethyl acetate layer was separated therefrom. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate, treated with activated carbon and then the solvent was distilled off. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 3-carbamoyloxymethyl-7-(2-oxo-2,3-dihydrothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid (0.1 g.). The IR Spectrum and NMR Spectrum of this object compound were identical as those of the object compound obtained in Example 15.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[O:27]1CCCC1>>[Cl:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][OH:27])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C1c2ccccc2C=Cc2c(Cl)cccc21
Agent: B1C2CCCC1CCC2
Product: OCC1c2ccccc2C=Cc2c(Cl)cccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-chloro-5-methylene-dibenzo[a,d]cycloheptene (9.0 g) in dry tetrahydrofuran (60 ml), under an inert atmosphere was added 9-borabicyclo[3, 3,1]nonane (80.5 ml of a 0.5 molar solution in THF) at ambient temperature and the reaction mixture was then refluxed for 3h. After cooling, the reaction was quenched by the slow addition of 2N sodium hydroxide solution (180 ml) and 30% hydrogen peroxide (36 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a 2h period then extracted into diethyl ether (3×250 ml). The combined organic layers were washed with brine (1×500 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on flash silica with 40% ethyl acetate in hexane as eluent to give the title compound (8.3 g) as a colourless oil. δ (360 MHz, CDCl3) 3.87 (2H, m, CH--CH2OH), 4.21 (1H, t, J=7.9 Hz, CH--CH2OH) 7.02 (1H, d, J=11.9 Hz, CHA =CHB) and 7.17-7.46 (8H, m, CHA =CHB and 7 aromatic protons). m/e 258 and 256 (M+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:19]([CH3:21])[CH3:20])=[CH:10][C:11]=2/[C:13](/[CH3:18])=[C:14](/[F:17])\[CH2:15][OH:16])[C:6]([CH3:23])([CH3:22])[CH2:5][CH2:4]1)[CH3:2].[CH3:24][N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:17]/[C:14](=[C:13](/[C:11]1[CH:10]=[C:9]([CH:19]([CH3:20])[CH3:21])[CH:8]=[C:7]2[C:12]=1[N:3]([CH2:1][CH2:2][CH3:24])[CH2:4][CH2:5][C:6]2([CH3:22])[CH3:23])\[CH3:18])/[CH2:15][OH:16]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)CO)c21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)CO)c21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-but-2-en-1-ol (Intermediate 18, 133 mg, 0.35 mmol) in 2 ml of CH2Cl2 at 0° C. was added 4-methylmorpholine N-oxide (83 mg, 0.71 mmol), tetrapropylammonium perruthenate (18.6 mg, 0.05 mmol), and 4 Å molecular sieve powder (10 mg). The mixture was stirred at 0° C. for 5 min, and the bath was removed. The temperature of reaction mixture was monitored carefully, and as soon as the temperature rose to 25° C., the reaction was re-cooled in an ice bath. The cooled reaction mixture was loaded onto a pre-packed silica gel column, and the product was eluted with 100% hexane followed by 2% ethyl acetate in hexane to yield the title compound as a bright yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[O:20]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:26]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)=[O:27])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=C(O)C1CCOCC1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CCOCC3)ncc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol), tetrahydro-2H-pyran-4-carboxylic acid (1.43 mmol, 185 mg), N,N-diisopropylethylamine (384 mg, 2.98 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (543 mg, 1.43 mmol) were dissolved in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 48 hours. Water (1 mL) was added, and the mixture was concentrated, washed with methanol to give the product (45.2 mg, 21.0%). LCMS (ESI): RT (Min)=1.203, M+H+=365.0, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.15 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.14 (d, J=12.0 Hz, 2H), 3.92-3.88 (m, 2H), 3.36-3.32 (m, 2H), 2.81-2.80 (m, 1H), 2.23 (s, 3H), 1.71-1.66 (m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:21])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:28]1([NH:31][C:32](=[O:50])[C:33]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]([CH3:48])=[C:35]([F:49])[CH:34]=2)[CH2:30][CH2:29]1>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:37]3[CH:38]=[C:33]([C:32](=[O:50])[NH:31][CH:28]4[CH2:29][CH2:30]4)[CH:34]=[C:35]([F:49])[C:36]=3[CH3:48])[CH:14]=2)[C:9]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCn1cc(C=O)c2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc2c1=O

Procedure:
3-(6-Bromo-4-formyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (Example 10c, 0.90 g), potassium carbonate (1.06 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.82 g) and Pd-118 (0.050 g) in DMF (10 ml) were heated under nitrogen at 70° C. for 12 h. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with ethyl acetate) to afford the subtitle compound.