Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl.[OH2:6].[N+]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-])=O>>[C:12]([C:10]1[CH:15]=[CH:14][C:13]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:12][CH:11]=1)(=[O:6])[CH2:11][CH2:10][CH2:15][CH3:14]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
560 Gram of granular anhydrous aluminum chloride and 1 l of nitrobenzene were introduced into a 5 l three neck flask, and stirred under water-cooling to give a solution. A solution of 600 g of diphenyl and 482.5 g of n-valeric acid chloride dissolved in 1 l of nitrobenzene (prepared in advance) was dropwise added into said three neck flask over 2 hours. After the addition, the resulting mixture was stirred for one hour as it was. Thereafter it was stirred at 40°-45° C for 2 hours, cooled to room temperature, poured cautiously into a mixed solution of 1.3 l of conc. hydrochloric acid and 1.5 l of water for decomposing the catalyst, and cooled to 20° C. Precipitated crystal was separated by filtration. Nitrobenzene was distilled off from nitrobenzene layer by distillation under a reduced pressure to give an additional crystal. Both the crystals were recrystallized from ethanol to give 881 g of crystal of 4-n-pentanoylbiphenyl (m.p. 79°-79.5° C) (yield: 95% based on biphenyl).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[F:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=1[NH2:26]>C(OCCO)C>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:24]([F:23])[CH:30]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc12
Temperature: 100 °C
Yield: 87.7 %

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 240.0 mg (1.7 mmol) of 2-fluoro-4-chloro-aniline in 15 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. After the work up, 431.3 mg (87.9%) of the product was obtained as an off white solid, m.p. 127° C. (dec.), mass spectrum (electrospray, m/e): M+H 327.8, 329.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[O:14].[H-].[Na+].[NH4+].[Cl-]>COCCOC>[F:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(=O)c1cccc(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: O=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Temperature: 42.5 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A reaction vessel was charged with 2-chloro-5-trifluoromethylpyridine (8 g, 44 mmol), 3-fluoroacetophenone (6.4 g, 46 mmol) and DME (56 ml). Sodium hydride (as a 60% oil dispersion, 5.8 g, 145 mmol) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at 40-45° C. overnight. Upon the completion of the reaction, aqueous NH4Cl solution (240 ml) was added to the reaction mixture at room temperature. The mixture was stirred for 0.5 hr and filtered. The cake was washed with water, slurried in hexanes (32 ml) and dried in a vacuum oven to give 10.44 g (84%) of the title compound (a mixture of ketone and enol isomers) as a solid with purity 99% AUC by HPLC (Phenomenex Luna 3μ cyano, 100 mm×4.6 mm. Flow rate: 1 ml/min. UV detection: 220 nm. Eluent: 75% A, 25% B. A: 80/20/0.05 water/acetonitrile/TFA. B: 20/80/0.05 water/acetonitrile/TFA ).
Reaction SMILES: [CH:1](/[N:6]=[C:7]=[O:8])=[CH:2]\[CH:3]=[CH:4]\[CH3:5].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1](/[NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])=[CH:2]\[CH:3]=[CH:4]\[CH3:5]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C/C=C/C=C/N=C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C/C=C/C=C/NC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of trans,trans-1,3-pentadienyl isocyanate was added a solution of 5-fluorouracil (2.6 g.) in N,N-dimethylacetamide (15 ml.) at 80° C. and stirred for 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (100 ml.), washed with water (4 times), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 1-[N-(trans,trans-1,3-pentadienyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: Nc1ccc(CC(=O)O)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(N)cc1C(F)(F)F

Procedure:
A solution of (4-amino-2-trifluoromethyl-phenyl)-acetic acid (0.082 g) in methanol (10 ml) containing concentrated sulphuric acid (0.1 ml) was heated under reflux for 2 h. The solution was cooled, concentrated, and partitioned between ethyl acetate and aqueous sodium carbonate solution. The organic phase was separated, dried, and concentrated to give the title compound as a yellow solid (0.089 g)
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>>[CH3:6][Si:7]([CH3:9])([CH3:8])[O:5][CH:2]([C:3]#[CH:4])[CH3:1]
Reactant: C#CC(C)O
Reactant: C[Si](C)(C)Cl
Product: C#CC(C)O[Si](C)(C)C
Yield: 60 %

Procedure:
The above compound was prepared in a 60% yield from 35 g of but-3-yn-2-ol and 50.4 g of trimethylsilyl chloride according to the method given in Can. J. Chem. 43, 2004 (1965); b.p. 117°/760 Torr.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH:14]([OH:35])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:14]([OH:35])[CH2:13][S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][CH:2]=[N:1]4)[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Sc1cccc2ncccc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: OC(CSc1cccc2ncccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 20.3 %

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 220 mg of 5-quinolinethiol and 1.2 g of 4-(3-chloro-2-hydroxypropyl)-1-(diphenylmethyl)piperazine, in order to obtain 130 mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropylthio]quinoline.
Reaction SMILES: [CH2:1]([C:3]1[S:25][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[CH2:1]([C:3]1[S:25][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:26](=[O:28])[CH3:27])[CH2:20]4)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1cc2c(N3CCN(C(=O)C4CCCNC4)CC3)ncnc2s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2c(N3CCN(C(=O)C4CCCN(C(C)=O)C4)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
[4-(6-Ethyl-thieno[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-piperidin-3-yl-methanone (Example 294, 17.0 mg) was dissolved in methylene chloride (1.00 mL) and diisopropylethylamine (12.4 μL). Acetylchloride (3.7 μL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction was applied to silica gel and the product was isolated by eluting from 0% to 4% methanol/methylene chloride over 45 minutes then 10% methanol/methylene chloride for 15 minutes. Yield=53%, ES-MS: (M+H)+ 402
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:31]1[CH:36]=[C:35]([N:37]([CH3:61])[C:38]([N:40]([C:49]2[C:54]([Cl:55])=[C:53]([O:56][CH3:57])[CH:52]=[C:51]([O:58][CH3:59])[C:50]=2[Cl:60])[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:39])[N:34]=[CH:33][N:32]=1)[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni].O>[NH2:28][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:31]1[CH:36]=[C:35]([N:37]([CH3:61])[C:38]([N:40]([C:49]2[C:50]([Cl:60])=[C:51]([O:58][CH3:59])[CH:52]=[C:53]([O:56][CH3:57])[C:54]=2[Cl:55])[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:46])[CH3:47])=[O:39])[N:34]=[CH:33][N:32]=1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-(4-((tert-butoxycarbonyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)-3-nitrophenyl)piperazine-1-carboxylate (149 g, 0.164 mmol) was stirred in THF (1.5 ml) and MeOH (1.5 ml). Five drops of Raney Nickel suspension in water was added. The solution was stirred under hydrogen atmosphere at room temperature overnight. The reaction was filtered through a pad of Celite®. and filtrate was concentrated to give crude title compound which was taken to the next step without further purification. ESI-MS: 877 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:17][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCC1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CC3CCC3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=266.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromomethyl-cyclobutane.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[CH3:11][S:12][CH2:13][C:5]1[C:6]([F:10])=[C:7]([F:9])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: CSC
Reactant: Nc1cc(F)c(F)cc1F
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1c(N)c(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,4,5-trifluoroaniline (35.0 g) are added anhydrous dichloromethane (530 ml) and dimethyl sulfide (24.6 ml) and the mixture is cooled to 0° C. Thereto N-chlorosuccinimide (38.2 g) is gradually added below 5° C. After the mixture is stirred at the same temperature for 15 minutes, triethylamine (47.7 ml) is gradually added. After reflux for 12 hours, the resultant is made alkaline with 5 % aqueous sodium hydroxide solution, extracted with dichloromethane, and the extract is dried over sodium sulfate and concentrated. The residue is purified with column chlomatography (silica-gel, dichloromethane: n-hexane=1:4) to give 2-methylthiomethyl-3,4,6-trifluoroaniline (22.3 g).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:10])[NH:5][C:6](=[NH:9])[S:7][CH3:8])[CH3:2].[C:11]1([CH3:20])[C:12]([N:17]=[C:18]=[O:19])=[CH:13][CH:14]=[CH:15][CH:16]=1>C1C=CC=CC=1>[CH2:1]([NH:3][C:4]([N:5]=[C:6]([S:7][CH3:8])[NH:9][C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:20])=[O:19])=[O:10])[CH3:2]
Reactant: CCNC(=O)NC(=N)SC
Reactant: Cc1ccccc1N=C=O
Solvent: c1ccccc1
Product: CCNC(=O)N=C(NC(=O)Nc1ccccc1C)SC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 5 parts of methyl 4-ethylthioallophanimidate (a compound of formula II) in 30 ml benzene was added 4.1 parts o-tolylisocyanate in 15 ml benzene. After stirring for 15 minutes at room temperature, the resulting solids were filtered off and recrystallized from benzene to give methyl N-ethylcarbamoyl-4-(o-tolyl)-thioallophanimidate (a compound of formula I), m.p. 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCN1CCc2ccc(S(=O)(=O)Nc3ccc(Cl)cc3)cc2C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCN1CCc2ccc(S(=O)(=O)Nc3ccc(Cl)cc3)cc2C1

Procedure:
Ethyl 4-[7-(4-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butyrate was hydrolysed with sodium hydroxide solution by the method described in Example 2(b) and the product was recrystallised from ethanol to give the title compound, m.p. 210°-210.5° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH:25][CH3:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([OH:13])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH:25][CH3:26])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6]
Reactant: Br[Mg]c1ccccc1
Reactant: CC=CC=CCOc1ccc(C(=O)c2ccc(OCC=CC=CC)cc2)cc1
Solvent: C1CCOC1
Product: CC=CC=CCOc1ccc(C(O)(c2ccccc2)c2ccc(OCC=CC=CC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Compound 35 (2.0 grams) was dissolved in THF (45 mL) and phenylmagnesium bromide (1.0 M solution in THF; 10.6 mL, 10.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 hours, and evaporated to dryness under vacuum. The residue was redissolved in dichloromethane and washed with a saturated solution of ammonium chloride, followed by water. The organic phase was dried (MgSO4), concentrated in vacuo and purified column chromatography (silica gel; hexane/CH2Cl2, 1/9) to afford 1.84 grams (77%) of compound 36 as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.73 (d, J=6.9 Hz, 6 H), 4.54 (d, J=6.0 Hz, 4 H), 5.68-5.80 (m, 4 H), 6.02, 6.11 (m, 2 H), 6.20-6.37 (m, 2 H), 6.85 (d, J=6.9 Hz, 4 H), 7.05 (d, J=7.0 Hz, 4 H), 7.14-7.32 (m, 5 H); Anal. Calcd for C31H32O3 (452.5920): C, 82.27; H, 7.13; Found: C, 82.30; H, 7.11.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([C:17]([O:19]CCI)=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].C(O)(=O)C.CN(C)C=O>C(OCC)(=O)C.[Zn]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:24])[C:14]([C:17]([OH:19])=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)OCCI)=CS[C@H]12
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)O)=CS[C@H]12

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-(2-iodoethoxycarbonyl)-2-cephem-4-carboxylate (2.79 g., 4.05 mmol.) was dissolved in a mixture of 8 ml. of glacial acetic acid and 48 ml. dimethylformamide at 0° and was reacted with 2.79 g. zinc dust (10.5 eq.) for 1.5 hours. The reaction mixture was diluted with ethyl acetate and filtered through a celite filter. The filtrate was washed successively with sodium bicarbonate solution (3X), water, 1N.HCl, and brine and then dried (Na2SO4). Evaporation to dryness in vacuo gave 1.92 (89%) of benzhydryl 7-(2-thienylacetamido)-3-carboxy-2-cephem-4-carboxylate: nmr (CDCl3) δ3.84 (s, side chain CH2), 4.99 (d, 1, J = 4.0 Hz, C6 --H), 5.45 (m, C4 --H and C7 --H) and 7.80 (s, C2 --H).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:26]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C=Cc1ccc(C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Cc1ccc(/C=C/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 82.3 %

Procedure:
A solution of 1 (10.0 mg, 0.0315 mmol) in 0.4 mL of 95% aqueous ethanol was added dropwise to a solution of 4-methylstyrene (9.0 mg, 0.076 mmol) and palladium(II) acetate (0.2 mg, 0.0009 mmol) in 0.12 g of 95% aqueous ethanol. The reaction mixture was heated on an oil bath at 70° C. for 5 h. After cooling, the mixture was filtered through a pad of Celite 545 and purified by SiO2 column chromatography (9:1 hexane/CH2Cl2) to give 2c (8.3 mg, 82% yield) as colorless crystals; m.p. 165.2-166.5° C. IR (ATR): {tilde over (v)}=1593, 1514, 1450, 1416, 1329, 1265, 1098, 972, 962, 841 cm−1. MS (GC, EI): m/z=320 [M+], 193 [M+-F5S], 178 [M+-CH3F5S]. 1H NMR (500 MHz, CDCl3): δ=7.72 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.16 (d, J=16.4 Hz, 1H), 7.04 (d, J=16.4 Hz, 1H), 2.38 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=152.3 (C), 140.8 (C), 138.6 (C), 133.6 (C), 131.9 (CH), 129.5 (2CH), 126.7 (2CH), 126.3 (2CH), 126.2 (2CH), 125.3 (CH), 21.3 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=85.1 (quint, J=150 Hz, 1 F), 63.1 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][N:24]=[CH:10]2
Reactant: Cc1cc(C#N)cc(Cl)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-chloro-5-methylbenzonitrile (3.00 g, 18.0 mmol) in CHCl3 (50 mL) was added acetic anhydride (3.9 mL, 41.4 mmol). The mixture was stirred at room temperature overnight and then heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and potassium acetate (530 mg, 5.40 mmol) and isoamyl nitrite (5.28 mL, 39.6 mmol) were added. The mixture was heated at reflux for 3 days. The reaction mixture was washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. To this was added methanol followed by water (25 mL) and 38% HCl (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the pH was adjusted to about 7. The solids were isolated by filtration and then washed with water (2×30 mL) and heptane (2×30 mL). Purify by Biotage chromatography (CH2Cl2-heptane (1:1)/MeOH gradient to afford 7-chloro-1H-indazole-5-carbonitrile was isolated as a white solid (585 mg, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][NH2:11]>CO>[CH3:10][NH:11][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: CN
Reactant: O=Cc1cccc(O)c1
Solvent: CO
Product: CNCc1cccc(O)c1

Procedure:
10.0 g of 3-hydroxybenzaldehyde and 9.55 g of a 40% methanol solution of methylamine were mixed, and then the solvent was evaporated. The resulting Schiff base was dissolved in 50 ml of ethanol, and with stirring under ice cooling, 10.0 g of sodium borohydride was added. The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium chloride were added to extract it. The organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography Wakogel C-100, 100 g; eluting solvent: methylene chloride/methanol=10/1→5/1) to give 8.88 g (yield Λ%) of N-methyl-3-hydroxybenzylamine as pale yellow crystals, m.p. 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(N(C(C)C)CC)(C)C>C1C=CC=CC=1.O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCCCC2)cc1

Procedure:
2.16 g (13.1 mmol) of ethyl 4-aminobenzoate was dissolved in 20 ml of benzene. 2.97 g (13.0 mmol) of 1,5-dibromopentane and 4.53 ml (26.0 mmol) of diisopropylethylamine were added to the solution, and they were heated under reflux for 48 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with water and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13](O)=O)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[N:35][OH:36])[NH2:34])=[CH:31][CH:30]=1>ClCCl>[F:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]2[N:34]=[C:13]([C:8]34[CH2:11][CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:6][CH2:7]3)[CH2:10][CH2:9]4)[O:36][N:35]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Reactant: NC(=NO)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COC(=O)C12CCC(c3nc(-c4ccc(F)cc4)no3)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (7-A) (0.906 g, 4.27 mmol) in dichloromethane (20 mL) was added 1,1′-carbonyldiimidazole (1.04 g, 6.41 mmol). The reaction turned into a clear solution instantly with evolving of gas. After the mixture was stirred at room temperature for 1 h, 4-fluorobenzamidoxime was added (1.98 g, 12.8 mmol). Stirring was continued overnight. The mixture was then concentrated and the residue was refluxed in toluene for 16 h. The mixture was concentrated and the residue was purified by column chromatography using hexane/ethyl acetate as eluent (7/1) to give methyl 4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octane-1-carboxylate acid (7-B) as a white solid. 1H NMR (500 MHz, CDCl3) δ 1.96-1.99 (m, 6H), 2.08-2.14 (m, 6H), 3.71 (s, 3H), 7.16-7.20 (m, 2H), 8.08-8.10 (m, 2H) ppm. ESI-MS m/z (M+H) 349.2.