Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[C:22]([C:24]1[CH:29]=[C:28]([CH2:30][CH2:31]OS(C2C=CC=CC=2)(=O)=O)[CH:27]=[CH:26][N:25]=1)#[N:23].C(C1C=C(CCCl)C=CN=1)#N>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:31][CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:22]#[N:23])[CH:29]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(CCOS(=O)(=O)c2ccccc2)ccn1
Agent: N#Cc1cc(CCCl)ccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccnc(C#N)c2)CC1
Temperature: 80 °C
Yield: 70 %

Procedure:
1-Boc-piperazine (6.8 g, 36 mmol), NaI (2.7 g, 18 mmol), K2CO3 (3.0 g, 21.6 mmol) and a mixture of 2-cyano-4-[2-(benzenesulfonyloxy)ethyl]pyridine and 2-cyano-4-(2-chloroethyl)pyridine (2:1, 4.5 g, 18 mmol) was dissolved in DMF (50 mL) and heated to 80° C. overnight. The mixture was allowed to cool to room temperature and diluted with water and ethyl acetate. The layers were separated and the water layer extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried (Na2SO4), filtered and concentrated under vacuum to proved a dark oil (6.0 g). The crude product was purified by chromatography (SiO2, 1000:10:1-200:10:1 CH2Cl2:methanol:concentrated ammonium hydroxide) to provide 1-Boc-4-[2-(2-cyanopyridin-4-yl)ethyl]piperazine (4.0 g, 70%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[C:11]1=[CH:26][N:27]([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)[C@H](n2ccc(=O)[nH]c2=O)O1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
5'-O-(t-Butyldimethylsilyl)-2',3'-dideoxy-2'-oxo-uridine (2.2 g, 6.45 mmol) was dissolved in 25 mL of dry dimethylformamide (DMF) and 0.85 g (7.1 mmol) of N,N-dimethylformamide dimethyl acetal was added. The reaction mixture was heated to 50° C. under a nitrogen atmosphere and stirred for 0.5 h. The solvent was removed in vacuo and the residue (3.2 g) was dissolved in methylene chloride and purified by flash chromatography (5 psi) on a silica gel column (2×25 cm) eluted with 200 mL of methylene chloride, 200 mL of 2% methanol in methylene chloride and 200 mL of 5% methanol in methylene chloride to give 1.78 g (70% yield) of the title compound MS DCI: 396 (M+H)+, 418 (M+Na)+
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][OH:30].O>O1CCCC1.N1C=CC=CC=1>[OH:30][CH2:29][C:28]1[CH:27]=[C:26]([NH:25][C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)=[O:24])[CH:33]=[CH:32][CH:31]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Reactant: Nc1cccc(CO)c1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CO)c2)cc1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a 0° C. solution of 13 g of p-(tetradecyloxy)phenyl isocyanate in 70 ml of tetrahydrofuran and 30 ml of pyridine is added over 10 minutes a solution of 7.24 g of 3-aminobenzyl alcohol in 70 ml of tetrahydrofuran with continued stirring for one hour. The mixture is heated until all the solids dissolve then allowed to stand at ambient temperature overnight. The mixture is poured into water and the solid collected. The solid is washed with dilute hydrochloric acid and water then crystallized from ethyl alcohol to give 13.1 g of the desired product as a light pink solid, m.p. 150°-158° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:20](Cl)(Cl)=[S:21]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]=[C:20]=[S:21])=[N:10]2)[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccn(Cc2cccc(F)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cccc(Cn2ccc(N=C=S)n2)n1
Reaction time: 15 h
Yield: 76.8 %

Procedure:
Intermediate 48 (48 mg, 0.250 mmol) was dissolved in 2 mL of DCM. 2 mL of sodium bicarbonate solution (aqueous, saturated) were added to the mixture and finally thiocarbonyl dichloride (ALDRICH, 0.019 mL, 0.250 mmol) was added dropwise. The reaction was stirred for 15 h. The crude was dissolved in 5 mL of DCM and washed with 5 mL of distilled water. Organic layer was dried over MgSO4 (anh), filtered and concentrated to dryness to give the title compound as a brown oil (45 mg, 0.192 mmol, 77%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.78 (q, 1H), 7.49 (d, 1H), 6.98 (dd, 1H), 6.89 (dd, 1H), 6.22 (d, 1H); 5.26 (s, 2H). [ES+MS] m/z 235 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[N:12][N:11]3[CH2:21][CH2:22][CH2:23][C:10]=23)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:20][C:16]1[N:15]=[C:14]([C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[C:10]3[CH2:23][CH2:22][CH2:21][N:11]3[N:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2c(-c3cccc(C)n3)nn3c2CCC3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(-c2nn3c(c2-c2ccc(O)cc2)CCC3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To a solution of 3-(4-methoxy-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (72 mg, 0.24 mmol) in methylene chloride (1 mL) is added boron tribromide (0.3 mL). The solution is stirred at ambient temperature for 3 h, then quenched with methanol. The mixture is concentrated in vacuo to a reddish solid. The solid is passed through a silica gel cartridge (methylene chloride, ethyl acetate, then acetone). The appropriate methylene chloride fractions are concentrated in vacuo to yield 4 mg (5.8%) of the title compound. The more polar fractions are concentrated in vacuo then treated with aqueous ammonium chloride and methanol. The mixture is concentrated in vacuo and the residue purified on a silica cartridge eluting as above. Appropriate fractions are combined and concentrated in vacuo to yield an additional 49 mg (71%) of the title compound.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([C@@:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2cccs2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2cccs2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 72.9 %

Procedure:
Pd(PPh3)2Cl2 (100 mg) was added to the solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (1.0 g, 2.5 mmol), 4-fluorophenylboronic acid (420 mg, 3.0 mmol) in 1,4-dioxane. Cs2CO3 (5 mL) was slowly added. The mixture was heated to reflux for 2 h. The mixture was quenched with water and separated, extracted with EtOAc twice, dried over anhydrous Na2SO4 and concentrated to afford the residue, which was purified by TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (768 mg, 73%).
Reaction SMILES: C([O:8][C@@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][CH:10]1[N:31]1[CH:35]=[C:34]([I:36])[CH:33]=[C:32]1[CH:37]=[O:38])C1C=CC=CC=1.CO.[NH4+].[OH-].O>ClCCl.B(Br)(Br)Br>[C@@H:10]1([N:31]2[CH:35]=[C:34]([I:36])[CH:33]=[C:32]2[CH:37]=[O:38])[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@H:9]1[OH:8]
Reactant: O=Cc1cc(I)cn1C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cc(I)cn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
To 1-(2,3,5-tri-O-benzyl-D-ribofuranosyl)-4-iodopyrrole-2-carbaldehyde in dichloromethane (15 ml), BBr3 (1 M, 8.5 ml) was added at −78° C. The reaction mixture was stirred for 2 hours, followed by addition of 50% methanol in CH2Cl2 (30 ml). After this solution was stirred at −78° C. for 10 minutes, 28% NH4OH (4 ml) was added and the reaction mixture was stirred until it reached room temperature. The solution was added to CH2Cl2 and H2O. The aqueous layer was partitioned and washed three times with CH2Cl2, and the residue was concentrated under reduced pressure. The product was purified by reversed-phase C18 HPLC to give 1-(β-D-ribofuranosyl)-4-iodopyrrole-2-carbaldehyde (330 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.S(Cl)([Cl:16])(=O)=O.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:16][C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C1CCCNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cl)CCCNC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of ethyl 2-oxopiperidine-3-carboxylate (30 g) in THF (300 mL) was added dropwise sulfuryl chloride (14.2 mL) at 0° C-5° C., and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (300 mL) at 0° C., and the mixture was stirred at room temperature for 30 min and extracted with ethyl acetate (300 mL×3). The extract was washed with saturated brine (300 mL), and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane/ethyl acetate (5/1, 60 mL×2) to give the title compound (32.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH2:8][OH:9]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(CO)c1
Reaction time: 2 h

Procedure:
A solution of 5-methoxy-2-nitrobenzaldehyde (2.3 g.) in ethanol (100 ml.) was stirred at ambient temperature, sodium borohydride (0.6 g.) was added and stirring was continued for 2 hours. Water (100 ml.) was added, and the solution was acidified with 2 N hydrochloric acid and extracted with ether (3×100 ml.). The extracts were combined and dried and the solvent was evaporated to give 5-methoxy-2-nitrobenzyl alcohol.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][N:9]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:13])=[O:12])[CH3:10].C(N(S(C1C=CC=CC=1S(N)(=O)=O)(=O)=O)CC)C.C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[CH2:1]([NH:5][C:6]([NH:23][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([N:9]([CH3:10])[CH3:8])(=[O:12])=[O:13])(=[O:21])=[O:22])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)S(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: CCN(CC)S(=O)(=O)c1ccccc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1S(=O)(=O)N(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
18.6 g (0.18 mol) of n-butyl isocyanate were added dropwise at 25° C. to a suspension of 44.2 g (0.17 mol) of 2-[(N,N-dimethylamino)sulfonyl]benzenesulfonamide (prepared similarly to 2-[(N,N-diethylamino)sulfonyl]benzenesulfonamide in U.S. Pat. No. 4,310,346) in 450 ml of acetonitrile. After the addition of 25.4 g (0.18 mol) of potassium carbonate, the refluxed mixture was stirred for 3 hours. It was cooled to 0° C., after which 400 ml of ice/water were added, the pH was brought to 1 by adding concentrated hydrochloric acid and the precipitate formed was filtered off under suction, washed neutral with water and dried at 40° C. under reduced pressure from a water pump. 60.0 g of the title compound (99% of theory) were obtained in this manner as a pale yellow powder.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N-]>CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh].C(Cl)Cl>[O:23]=[C:4]1[CH2:3][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCCOC(=O)Cc1c(CCC(=O)C=[N+]=[N-])[nH]c2ccccc12
Agent: [Rh]
Solvent: CCCCCCCC(=O)O
Solvent: ClCCl
Product: CCCOC(=O)Cc1c2n(c3ccccc13)CC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Rhodium (II) octanoate dimer (0.1 equiv.) was added to a CH2Cl2 solution (0.02 M) of propyl [2-(4-diazo-3-oxobutyl)-1H-indo1-3-yl]acetate from Step 4. The reaction mixture was stirred overnight at rt and then concentrated. The residue was purified by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (2:98 to 10:90) to give the title compound (64%) as a yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:20]([F:31])[CH:19]=2)[CH2:13]1)=[N+:9]=[N-:10]>C(Cl)Cl>[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[C:20]([F:31])[CH:19]=2)[CH2:13]1)=[N+:9]=[N-:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
60% TFA in DCM (5 mL) was added to 5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one (0.336 g, 1 mmol), and the solution kept at r.t. for 1 h. Solvents were removed in vacuo to afford 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (0.280 g, 99%). A mixture of 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one well stirred mixture of (0.080 g, 0.286 mmol) and thiosemicarbazide (0.0957 g, 0.286 mmol) in dioxane (2 mL) was heated until the mixture was homogeneous. Phosphorous oxychloride (0.027 ml, 0.29 mmol) was added, and the mixture heated at reflux for 1 h. The mixture was allowed to cool to r.t., and the white precipitate filtered, washed with dioxane, suspended in saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. Combined organic extracts were washed with brine, and dried (MgSO4) Solvent was removed under vacuum, and the crude product purified by PTLC (10% MeOH in DCM) to give product as a white solid (0.038 g, 40%); MS (m/z): [M+H]+=336.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25]O)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[SH:39][C:40]1[N:44]([CH3:45])[N:43]=[N:42][N:41]=1.CNC(N1C2C(=CC=CC=2)C(=O)C1=O)=O>C(#N)C>[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][S:39][C:40]4[N:44]([CH3:45])[N:43]=[N:42][N:41]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: CNC(=O)N1C(=O)C(=O)c2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
In acetonitrile (14 ml) is dissolved 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (900 mg), followed by the addition of triethylamine (200 mg), 5-mercapto-1-methyl-1H-tetrazole (464 mg) and N-(methylcarbamoyl)isatin (916 mg). The mixture is stirred at 30° C. overnight. The solvent is then distilled off and the residue is dissolved by the addition of water and ethyl acetate. After separation, the water layer is taken, rinsed once with ethyl acetate and rendered acidic with hydrochloric acid. Following the addition of ethyl acetate, the mixture is stirred for 30 minutes. After separation , the organic layer is taken and rinsed with an aqueous solution of sodium chloride. It is extracted with an aqueous solution of sodium hdyrogen carbonate. The water layer is purified by column chromatography on Sephadex LH-20 . The fractions rich in the contemplated compound are pooled, concentrated, rendered acidic with phosphoric acid and extracted with ethyl acetate. After drying, the extract is concentrated, followed by addition of ether to the residue. The procedure provides 7β-phenylacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The NMR spectrum of this product is in good agreement with that of the compound obtained in Example 6.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[OH:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: OCc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 2-bromobenzyl alcohol (187 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 153 mg (83%) of the title compound.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=O)=O)=CC=1.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [I-]
Reactant: O=S(=O)(OCCOCc1ccccc1)c1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of (benzyloxy)ethyl 4-bromobenzenesulfonate (Preparation 89, 6.92 g, 19.5 mmol) in acetone (60 ml) was added sodium iodide (5.84 g, 39.0 mmol) and the reaction mixture was left to stir at room temperature for 16 h. The resulting precipitate was filtered and the filtrate was concentrated in vacuo. The crude residue was dissolved in dichloromethane and washed with aqueous sodium thiosulphate solution and then with water (2×60 ml). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale brown oil (4.5 g, 88%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([NH:14]C(=O)C)=[C:7]([CH3:18])[CH:6]=1)(=O)C>Cl>[NH2:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[CH3:18]
Reactant: CC(=O)Nc1c(C)cc(OC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cc(O)cc([N+](=O)[O-])c1N

Procedure:
20.4 g (80.7 mmol) 4-acetylamino-3-methyl-5-nitro-phenyl acetate in 100 mL semi-concentrated aqueous hydrochloric acid were refluxed for 2 h. Then the reaction mixture was evaporated down, the residue was triturated with acetone and suction filtered. After washing with acetone and diethyl ether the precipitate was dried under HV. The mother liquor was evaporated down, the residue was taken up in water and freeze-dried.
Reaction SMILES: Cl.[CH2:2]([NH:6][C:7](=[O:15])[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.O.[Rh]>[CH2:2]([NH:6][C:7](=[O:15])[NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC(=O)Nc1ccncc1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCNC(=O)NC1CCNCC1
Yield: 19.4 %

Procedure:
A solution of 3-n-butyl-1-(4-pyridyl)urea hydrochloride (37.4 g) in ethanol-water (1:1, 400 ml) containing 5% rhodium/alumina catalyst (10 g) was hydrogenated (50°, 750 psi) until no further uptake of hydrogen occurred. The catalyst was then removed by filtration and the solvent evaporated to leave an oil which partially solidified on storage at 0°. The solid was separated, treated with base, extracted with chloroform/n-butanol, the extracts evaporated and the residue recrystallized twice from ethyl acetate to give 3-n-butyl-1-(4-piperidyl)urea, (6.3 g), m.p. 132°-134°.
Reaction SMILES: CCO[CH:4]([O:12]CC)[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.[Li]CCCC.[C:20]1([CH:26]([CH2:42][CH3:43])[C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35]C3CCCCO3)=[CH:31][CH:30]=2)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[OH:35][C:32]1[CH:31]=[CH:30][C:29](/[C:27](/[C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:12])=[CH:10][CH:9]=2)=[C:26](\[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)/[CH2:42][CH3:43])=[CH:34][CH:33]=1
Reactant: CCC(C(=O)c1ccc(OC2CCCCO2)cc1)c1ccccc1
Reactant: CCOC(OCC)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(C=O)cc1)c1ccccc1
Temperature: -65 °C
Yield: 63 %

Procedure:
A three-neck flask equipped with mechanical stirrer, thermometer, and nitrogen inlet was charged with 4-bromobenzaldehydediethyl acetal (800 g, 2.47 mol) and THF (7.2 L). The contents were cooled to −65° C. and treated with a 2.5M solution of n-BuLi in hexanes (1.23, 3.08 mol) at a rate to maintain temperature <−65° C. The solution was then treated with a solution of 9 (800 g, 2.47 mol) in THF (2.4 L) at a rate to maintain temperature <−65° C. The resulting solution was allowed to warm to ambient temperature over a 1 h period. At 20° C. the reaction was quenched by addition of a saturated aqueous NH4Cl solution (4 L) followed by EtOAc (4 L). After mixing well, the lower aqueous layer was separated and the organic layer washed with H2O (2×4 L). The organic layer was evaporated under reduced pressure to approximately 4 L. tert-BuOH (8 L) was added and evaporation continued to a volume of approximately 4 L. The solution was heated to 65° C. and treated with 3 N aqueous HCl (80 mL) and maintained at 65° C. for approximately 1 h. The reaction solution was diluted with heptane (8 L) and then cooled slowly to 5° C. and maintained for 1 h. The solids were collected by filtration, washed with heptane (2×1.5 L), and dried in vacuo at 40° C. to afford 511 g of 10 (63%) as a 98:2 mixture of Z:E isomers. 1HNMR (400 MHz, DMSO-d6): δ 0.83 (t, J=7.3 Hz, 3H), 2.33 (q, J=7.3 Hz, 2H), 6.41 (d, J=8.4 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 7.10-7.20 (m, 5H), 7.40 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 9.25 (s, 1H), 9.98 (s, 1H).