Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][O:17][CH2:20][CH2:19][Br:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: O=CC1c2ccccc2CCc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: BrCCOC=C1c2ccccc2CCc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-carboxaldehyde (11.3 g, 51 mmol, prepared in a similar way as described in Acta Chem. Scand. 1978, B33, 100-103) and tetrabutylammonium bromide (1.64 g, 5.1 mmol) in dichloromethane (100 ml) was added 1,2-dibromoethane (62 ml) and a 12 M sodium hydroxide solution (100 ml). The reaction mixture was stirred vigorously overnight and dichloromethane (100 ml) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic phases were washed with a 0.2 M hydrochloric acid solution (100 ml), brine (25 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give 14.1 g of 2-((10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)methoxy)ethylbromide. TLC: rf=0.48 (SiO2 ; ethyl acetate/n-heptane=1:4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2ccc(CN3CCNCC3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
A 50 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate (1.10 g, 2.85 mmol, 1.00 equiv) and dichloromethane (12 mL). Trifluoroacetic acid (2 mL) was added dropwise at 0° C. The resulting solution was stirred for 5 h at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.700 g (86% yield) of 1-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 286 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>C1COCC1>[N+:6]([C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1

Procedure:
Pyrrolidine (1.5 mL, 18.3 mmol) was added to a stirred solution of 3-nitrophenyl isocyanate (1.5 g, 9.14 mmol) in anhydrous THF (60 mL) and the mixture stirred at reflux for 1 hour. The solvent was evaporated in vacuo. The crude product was then purified by column chromatography (Flashmaster, 40-63 mesh silica gel, 50% isohexane-EtOAc) to provide the title compound as an off white solid (1.85 g, 86%); LC-MS, Rt=2.80 min (MeOH-FA), m/z 236 (MH+).
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH3:34])[CH:31]([OH:33])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH3:34])[CH:31]([OH:33])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC(O)[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1OC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)=NC1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
(5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-ol (410 mg, 0.816 mmol) synthesized in Example (103d) was dissolved in methylene chloride (20 mL), and cooled to −78° C. Boron tribromide (1.0 mol/L methylene chloride solution, 2.04 mL, 2.04 mmol) was added, and stirring was carried out for 2 hours with the temperature being raised gradually to room temperature. A saturated aqueous sodium hydrogencarbonate solution (20 mL) was added, and extraction was carried out twice with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-10%) to afford the desired product (362 mg, yield 91%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[C:16]1([CH:15]=[CH:14][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([CH:9]([CH3:10])[CH3:11])=[C:7]([OH:12])[CH:6]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1C(C)C
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)c1c(O)cc(C=Cc2ccccc2)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To the crude 1-(3,5-dimethoxy-4-i-propylphenyl)-2-phenylethene (18.07 g) in dry CH2Cl2 (100 mL) at −78° C. under N2 was added BBr3 (5.2 mL, 55 mmol) dropwise. After the reaction was stirred at −78° C. for 1 h, the temperature was allowed to rise to room temperature and the reaction mixture was stirred at room temperature for 2 days. Water was added to quench the reaction, followed by 20% NaOH to adjust pH>12. The organic layer was removed and the aqueous layer was washed with hexane (2×100 mL). The aqueous layer was acidified with 6N HCl to pH 1 and extracted with ether (3×200 mL). The organic layer was separated and washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of ether gave a red syrup. Recrystallization with chloroform yielded pure stilbene product 20B (6.92 g) as a white crystal. The mother liquid was concentrated and the residue was recrystallized once more to afford an additional 2.5 g of 20B (total 9.42 g, 67.7% over two steps). 1HNMR (CDCl3, ppm): δ 1.38 (d, J=7.3 Hz, 6H), 3.46 (hept., J=7.3 Hz, 1H), 4.80 (s, 2H), 6.50 (s, 2H), 6.92 (d, J=17.2 Hz, 1H), 6.97 (d, J=17.2 Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10][NH:9]2)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([O:43][CH3:44])=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:38]=1>ClCCl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][CH2:10][N:9]2[S:39]([C:37]1[CH:38]=[C:33]([Cl:32])[CH:34]=[CH:35][C:36]=1[O:43][CH3:44])(=[O:40])=[O:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)NCCN2C(=O)OC(C)(C)C
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester 6-ethyl ester (300 mg, 0.98 mmol) was dissolved in dichloromethane (20 mL) and pyridine (2 mL). N,N-Diisopropylethylamine (127 mg, 0.98 mmol) and 5-chloro-2-methoxy-benzenesulfonyl chloride (300 mg, 1.24 mmol) were added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude compound was purified by flash chromatography, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester 6-ethyl ester as a light yellow gum, 435 mg (87%), H (300 MHz; CDCl3) 8.17 (1H, s), 8.05 (1H, s), 7.82 (1H, d), 7.74 (1H, d), 7.46 (1H, dd), 6.82 (1H, d), 4.35 (2H, q), 3.93 (2H, m), 3.71 (2H, m), 3.56 (3H, s), 1.48 (9H, s), 1.39 (3H, t).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccncc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and pyridine-4 carbaldehyde. MS (ESI) m/z 470.
Reaction SMILES: [CH2:1]([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][O:16]C(=O)CCC(C)=O)[CH:12]=[C:11]([NH:24][C:25]2[C:26]3[C:31]([N:32]=[C:33]4[C:38]=2[CH:37]=[CH:36][CH:35]=[CH:34]4)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=1)=[O:7])[C:2]([CH3:4])=[O:3].C[O-].[Na+]>N1C=CC=CC=1>[CH2:1]([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([NH:24][C:25]2[C:26]3[C:31]([N:32]=[C:33]4[C:38]=2[CH:37]=[CH:36][CH:35]=[CH:34]4)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=1)=[O:7])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CCC(=O)Nc1cc(COC(=O)CCC(C)=O)cc(Nc2c3ccccc3nc3ccccc23)c1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)CCC(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N,O-bis(acetonylacetyl)-3-(9-acridinylamino)-5-hydroxymethylaniline (423 mg, 0.83 mmol) in methanolic sodium methoxide [prepared from sodium (15 mg, 0.65mmol) in MeOH (15 mL)] is stirred at room temperature for 2 days. The mixture is passed through an ion-exchange resin (Dowex 50 in pyridine form). The product is eluted with a mixture of pyridine/H2O (v/v 1:1). The combined eluate is evaporated in vacuo to dryness. The product is purified by chromatography (SiO2, CHCl3 /MeOH, v/v 15:1) to give N-acetonylacety-3-(9-acridinylamino)-5-hydroxymethylaniline, 217 mg (64.0%), mp 197°-199° C. 1H-NMR (DMSO-d6): δ 2.10 (3H, s, COCH3), 4.35 (2H, broad singlet, CH2 --OH), 6.42 (1H, broad singlet, ArH), 6.90 (1H, broad singlet, ArH), 6.89-7.18 (2H, m, ArH), 7.19 (1H, broad singlet, ArH), 7.50-7.76 (4H, m, ArH), 8.30-8.48 (2H, m, ArH, 9.76 (1H, s, NH). Analyses: Calculated for C25H23N3O3 : C, 72.62; H, 5.61; N, 10.16. Found: C, 72.53; H, 5.46; N, 9.99.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[N:8]([CH2:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:24][C:23]=2[F:37])[C:7]1=[O:38].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[O:38]=[C:7]1[N:8]([CH2:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:24][C:23]=2[F:37])[C:9]2[S:15][C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11](=[O:12])[NH:6]1
Reactant: COc1ccc(Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2=O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (1.71 g) and trifluoroacetic acid (20 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (20 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (20 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.3 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1cccnc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4cccnc4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl) oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 3-chloromethylpyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 70 mg (yield 71%) of the title compound.
Reaction SMILES: O[CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-:22].[Li+:23].[P].[S]>>[OH:22][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O-:15])=[O:14].[Li+:23]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Reactant: [OH-]
Agent: [Li+]
Agent: [P]
Agent: [S]
Product: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]

Procedure:
A lithium hydroxystearate grease thickener was prepared by saponification of a mixture containing 12-hydroxystearic acid (50%) and the tri-glyceride thereof (25%) and 25% of C22 fatty acids containing no OH groups with lithium hydroxide in a mineral oil vehicle (ISO 150 viscosity grade of a 70/30 mixture of naphthenic and paraffinic stocks) at about 350° F. in a closed contactor. After depressuring and dehydration of the thickener in an open kettle sufficient mineral oil was added to reduce the thickener content to about 8%. The dropping point of this grease was 407° F. (208° C.). This grease contained no phosphorus or sulfur additives.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]3[N:24]=[C:25]([NH:28][C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:50][C:51]1[C:52]2[N:53]([N:58]=[N:59][N:60]=2)[N:54]=[C:55]([SH:57])[CH:56]=1>C(#N)C>[NH2:50][C:51]1[C:52]2[N:53]([N:58]=[N:59][N:60]=2)[N:54]=[C:55]([S:57][CH2:5][C:6]2[CH2:7][S:8][C@@H:9]3[CH:16]([NH:17][C:18](=[O:48])[C:19]([C:23]4[N:24]=[C:25]([NH:28][C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[S:26][CH:27]=4)=[N:20][O:21][CH3:22])[C:15](=[O:49])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])[CH:56]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Nc1cc(S)nn2nnnc12
Solvent: CC#N
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cc(N)c4nnnn4n3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a stirred solution of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (0.697 g; 0.001 mole) in anhydrous acetonitrile (50 ml), 8-amino-6-mercaptotetrazolo[1,5-b]pyridazine (0.336 g; 0.002 mole) was added and the resulting slurry was refluxed under a slow stream of nitrogen for 24 hours. Another portion of the mercapto compound (0.168 g; 0.001 mole) was added, and after further 16 hours of stirring at the reflux temperature, the mixture was cooled, the undissolved matter (unreacted mercapto compound) filtered off, the acetonitrile solution evaporated to dryness, the resulting foam taken up in warm methylene chloride (5 ml) and diethyl ether added (25 ml). The resulting white precipitate was collected by filtration and washed with a small amount of ethyl acetate and then with diethyl ether, thus giving 0.650 g of 3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer). This material was reacted with 50% aqueous formic acid, as described in Example 1, thus giving the title product, which was shown by T.L.C., I.R. and NMR to be identical to the product prepared in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[SH:8].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1>>[F:11][C:9]([F:12])([F:10])[C:4]1[CH:5]=[CH:6][C:7]2[S:8][C:19]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Product: FC(F)(F)c1ccc2sc(-c3ccncc3)nc2c1
Yield: 89.2 %

Procedure:
3-Amino-4-mercaptobenzotrifluoride (8.5 g, 0.04 mol) and 4-pyridine carboxaldehyde (4.2 ml, 0.04 mol) were reacted as exemplified in Example 7 step 1, to afford the title compound as a brown solid (10 g, 89%). δH (CDCl3), 7.69 (1H, d of d, J 8.4Hz, J 1.7Hz, ArH), 7.93 (2H, m, ArH), 8.06 (1H, d, J 8.4Hz, ArH), 8.40 (1H, d, J 0.7Hz, ArH), 8.81 (2H, m, ArH). m/z (ES+) 281 (M+1)+.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[C:7]=1[CH2:13][CH:14]=[O:15].Cl>C1COCC1>[CH3:5][C:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[C:7]=1[CH2:13][CH:14]([OH:15])[C:1]#[CH:2]
Reactant: C#C[Mg]Br
Reactant: CC1=C(CC=O)C2CCC1C2
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)CC1=C(C)C2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Ethynylmagnesium bromide in THF (0.5 M, 210.0 ml, 105.0 mmol) was placed in a reactor under a nitrogen atmosphere at room temperature and (3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetaldehyde (12.15 g, 80.9 mmol) in THF (200 ml) was introduced over a 90 minutes period and the mixture turned orange. The mixture was further stirred at room temperature for 30 minutes and was hydrolyzed with aqueous HCl 5% at room temperature. The mixture was extracted twice with Et2O and the combined organic layers were washed twice with a saturated aqueous solution of NaHCO3, H2O, and brine and dried over Na2SO4. Solvents were removed under vacuum to give a crude which was purified by flash chromatography with cyclohexane/AcOEt (95/5) as eluent to afford the title compound (11.32 g) in 79% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCCCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCCO

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 4-amino-1-butanol (21 ul) according to Method A to give a material which was re-purified by reversed phase C-18 HPLC in absence of trifluoroacetic acid to give the title compound (19 mg). 1H-NMR (400 MHz, CD3OD) d 7.75 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.28-7.18 (m, 5H), 7.04 (d, J=8.8 Hz, 1H), 4.79 (s, 2H), 4.51 (m, 1H), 4.24 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 3.52 (m, 1H), 3.18 (m, 1H), 3.09-2.92 (m, 4H), 2.75 (m, 1H), 1.45 (m, 4H), 1.36 (s, 9H); HRMS m/z 601.2616 (calc. of monoisotopic mass for C30H39N3O10 gives 601.2635).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Product: O=C(c1ccccc1)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
3-Nitro-4-chloro-benzophenone is reacted with morpholine as described in Example 7 to obtain 3-nitro-4-morpholino-benzophenone with a yield of 98 %. The product melts at 103 °C.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=1)(=[O:3])[CH3:2].[Br-:24]>C(OCC)(=O)C>[Br:24][CH2:2][C:1]([C:4]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: COC(=O)COc1c(C(C)(C)C)cc(C(C)=O)cc1C(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)COc1c(C(C)(C)C)cc(C(=O)CBr)cc1C(C)(C)C

Procedure:
A mixture of the product from step (i) above (4.91 g) and cuptic bromide (6.82 g) in ethyl acetate (45 ml) was heated at reflux temperature for 24 hours. On cooling, the mixture was filtered and the liltrate concentrated in vacuo. The residue on purification by flash chromatography on silica, eluting with 5% v/v ethyl acetate/hexane, gave methyl 4-bromoacetyl-2,6-di-tert-butylphenoxyacetate, 4.98 g, as an oil: NMR (d6DMSO) δ7.90 (2H, s), 4.92 (2H, s), 4.40 (2H, s), 3.76 (3H, s), 1.41 (18H, s).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C(C)=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[S:21]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cccc(I)c1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(I)c1
Yield: 84.5 %

Procedure:
52.5 g (0.2 mol) of methyl 3-iodobenzoate were heated to reflux for 18 hours with 81 g (0.2 mol) of Lawesson reagent in 330 ml of xylene. By working-up in an analogous manner to that described in Example 1(B) there were obtained 47 g (84.4%) of O-methyl 3-iodothiobenzoate as a yellow evil-smelling oil which was used without further purification.