Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1c(F)cccc1Cl
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3c(F)cccc3Cl)c21
Yield: 57.6 %

Procedure:
The title compound (cis/trans=21/79) was prepared as a pale brown powder in 57.60% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 2-chloro-6-fluorobenzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[O:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)o1
Yield: 14.8 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.3 mg (0.09 mMol) 5-methyl-2-furoic acid, 1.5 mg (87%) of the title compound were recovered.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([F:34])[CH:31]=1)[CH2:27][NH:26][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]=1[CH:22]([CH3:24])[CH3:23])=[O:36]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3cc(F)cc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)NCc2cc(F)cc(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccn1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
Following General Procedure F, ethyl3-(3,5-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 48, 92 mg, 0.187 mmol) in EtOH (10 ml) was added NaOH (40 mg, 0.94 mmol) and H2O (1 ml). The reaction was stirred at 55° C. for 4 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:38]1[N:42]=[C:41]([NH2:43])[S:40][N:39]=1)[C:5]([NH:7][CH:8]1[C:36](=[O:37])[N:10]2[C:11]([C:33]([OH:35])=[O:34])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]>C(O)=O>[CH3:1][O:2][N:3]=[C:4]([C:38]1[N:42]=[C:41]([NH2:43])[S:40][N:39]=1)[C:5]([NH:7][CH:8]1[C:36](=[O:37])[N:10]2[C:11]([C:33]([OH:35])=[O:34])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH2:23][CH2:24][NH2:25])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCCNC(=O)OC(C)(C)C)CS[C@H]12)c1nsc(N)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCCN)CS[C@H]12)c1nsc(N)n1
Yield: 46.5 %

Procedure:
A solution of 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.22 g) in formic acid (22 ml) was stirred for 2.5 hours at ambient temperature. The reaction mixture was post-treated in a conventional manner to give 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.875 g), mp. 185° to 190° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:12]([O:19][NH:20][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)c1ccc(O)cc1
Yield: 45.3 %

Procedure:
To a mixture of 4-hydroxybenzoic acid (E18) (0.424 g, 3.07 mmol), O-benzylhydroxylamine hydrochloride (E19) (0.490 g, 3.07 mmol), and 4-dimethylaminopyridine (0.414 g, 3.39 mmol) in dichloromethane (30 ml) under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.643 g, 3.35 mmol) was added and the resultant mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into a mixture of saturated NaH2PO4 (30 ml) and water (70 ml), and extracted with ethyl acetate (2×75 ml). The extract was washed with a mixture of saturated NaH2PO4 (15 ml) and water (35 ml), brine (50 ml), and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silicagel (50 g) with benzene-ethyl acetate-acetic acid (75:25:1, 100 ml) and benzene-ethyl acetate-acetic acid (50:50:1, 300 ml) as eluents to give the title compound (0.338 g, 45%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 4.88 (2H, s); 6.79 (2H, d, J=8.8 Hz); 7.23-7.55 (5H, m); 7.59 (2H, d, J=8.8 Hz); 10.02 (1H, br s); 11.48 (1H, s).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15](Cl)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1cc(F)cc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,5-difluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.40 (tt, J=8.9, 2.4 Hz, 1H), 7.85-7.94 (m, 2H), 8.39 (dd, J=5.4, 2.2 Hz, 1H), 9.46 (dd, J=5.4, 1.4 Hz, 1H), 9.87 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z=261 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCNCC5)cc4C)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC2CCNCC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Yield: 106 %

Procedure:
The crude (S)-methyl 2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 4a (31 mg, 0.06 mmol) was dissolved in 5 mL of methanol, followed by addition of 1M aqueous sodium hydroxide solution (0.6 mL, 0.62 mmol). The reaction solution was reacted for 2 hours. The resulting solution was concentrated under reduced pressure, mixed with 3 mL of water, 1M citric acid was added dropwise to adjust the pH to 5, and the solution was extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5)-2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 4 (31 mg, yield 100%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:20][CH2:21]1
Reactant: ClCc1ccc2ccccc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(Cc3ccc4ccccc4c3)CC2)nc1

Procedure:
A mixture containing 7.0 g. of β-chloromethylnaphthalene, 6.56 g. of 2-pyridylpiperazine and 4.4 g. of sodium carbonate in 40 ml. of dimethylformamide is stirred on a steambath for 90 minutes. The reaction mixture is filtered and the filtrate stirred with ice water. The precipitate was filtered and recrystallized from isobutyl alcohol to yield 1-(β-napthylmethyl)-4-(2-pyridyl)piperazine having a melting point of 124°-126° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[C:10]([CH:21]([CH3:23])[CH3:22])[N:9]=[C:8]1[CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH2:27]([O:26][CH2:25][CH2:24][C:8]1[N:7]([CH2:6][CH2:5][OH:4])[C:11]([S:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[C:10]([CH:21]([CH3:23])[CH3:22])[N:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)OCCn1c(CCOCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)c1nc(CCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
In 30 ml of dry diethyl ether was dissolved 3.0 g (5.9 mmol) of the ester compound (130c), followed by addition of 230 mg (6 mmol) of lithium aluminum hydride under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with water, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and further recrystallized from ethyl acetate-n-hexane to give 2.5 g of 2-(2-(2-benzyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-1-yl)ethanol (130d) as crystals (yield 91%). mp 129-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([C:23]([OH:25])=O)[C@@H:20]([CH3:22])[OH:21])=[O:17])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:27]([O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[CH3:28]>C(Cl)(Cl)Cl.CO>[CH2:27]([O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH:32][C:23](=[O:25])[C@H:19]([C@@H:20]([CH3:22])[OH:21])[NH:18][C:16](=[O:17])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:28]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)[C@@H](C)O)C(C)C

Procedure:
Following General Procedure C and using N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine (prepared from N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester (from Example 144 above) using General Procedure AF) and L-valine ethyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 96:4 CHCl3/MeOH) and the product was purified by silica gel chromatography using 96:4 CHCl3/MeOH as the eluent.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:9]=[C:8]([SH:10])[NH:7][N:6]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([S:4][C:5]1[N:9]=[C:8]([SH:10])[NH:7][N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Sc1n[nH]c(S)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Sc1nc(SCc2ccccc2)n[nH]1
Yield: 59.2 %

Procedure:
Sodium methoxide (35.1 g) was added portionwise to 3,5-dimercapto-1,2,4-triazole (86.4 g) in methanol (400 ml) with stirring and cooling to 5° to 15° C. under nitrogen. After stirring for 5 minutes, the formed derivative was treated dropwise with benzyl chloride (79.7 g) at 5° to 10° C. over a period of 1 hour. The mixture was then stirred for about 20 hours at ambient temperature, then filtered. The precipitate was washed with a little ice-cold methanol, and then with water, to give 83.2 g of desired product, mp 199°-201° C.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:15]([NH2:26])=[N:16][NH:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH2:8]CC.[CH3:28][C:29](=O)[CH2:30][C:31](=O)[CH3:32]>Cl>[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:17][N:16]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:28])=[N:26][C:15]=12)[CH3:8]
Reactant: CCCCOC(=O)Cc1c(N)n[nH]c1-c1ccc(Cl)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C(O)C(=O)O
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn2c(C)cc(C)nc12

Procedure:
A solution of 35.5 g (0.089 mole) of 3-amino-5-(4-chlorophenyl)-1H-pyrazole-4-acetic acid butyl ester ethanedioate, 8.9 g (0.089 mole) of pentane-2,4-dione, and 10 ml of concentrated hydrochloric acid was stirred at room temperature for 17 hours under a nitrogen atmosphere.
Reaction SMILES: [Br:1][C:2]1[C:6]2[NH:7]C(C)(C)[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.Cl.C([O-])(O)=O.[Na+]>CO>[NH2:7][C:6]1[C:2]([Br:1])=[C:3]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[S:4][C:5]=1[C:10]([NH2:9])=[O:11]
Reactant: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)c(Br)c2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1sc(-c2cn[nH]c2)c(Br)c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of 7-bromo-2,2-dimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (243 mg, 0.743 mmol), 1 M HCl (2.60 mL, 2.60 mmol) and MeOH (7 mL) was stirred at 50° C. for 2 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound (147 mg, 69%) as a pale yellow solid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].[NH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[N:23]=[C:22]([SH:27])[N:21]=1>O.C(=O)(O)[O-].[Na+]>[OH2:3].[OH2:3].[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:22]3[N:23]=[C:24]([NH2:26])[CH:25]=[C:20]([NH2:19])[N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Nc1cc(N)nc(S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cc(N)nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Temperature: 60 °C
Yield: 82.5 %

Procedure:
2.7 g (0.01 mole) of 7-aminocephalosporanic acid are dissolved in 50 ml of water with the required amount of sodium bicarbonate. 1.7 g (0.013 mole) of 4,6-diamino-2-mercapto-pyrimidine and the equivalent amount of sodium bicarbonate are added and the reaction solution is heated to 60° C. for 4 hours, whilst stirring and keeping the pH value constant (pH=7). The mixture is allowed to cool, undissolved material is filtered off and the filtrate is concentrated in vacuo at 30° C. to half its volume. The aqueous solution which remains is extracted several times with ethyl acetate and the aqueous phase is adjusted to a pH of 2 with 2N hydrochloric acid. The precipitate is filtered off, washed with water until free from chloride and dried in vacuo at 37° C. over potassium hydroxide. 1.61 g of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[CH:8](O)=[O:9]>>[CH:8]([NH:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1)=[O:9]
Reactant: O=CO
Reactant: Nc1nc(S)n[nH]1
Product: O=CNc1nc(S)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL, 3-necked flask equipped with a mechanical stirrer, a reflux condenser with nitrogen outlet and a thermometer was charged with 24.4 g (0.2 mole) of 95 percent pure 5-amino-3-mercapto-1,2,4-triazole and 140 mL of formic acid. The mixture was heated to reflux with stirring for 4 hr and allowed to cool to room temperature. The solids present were collected by filtration, washed with water, and dried to obtain 28.2 g (98 percent of theory) of the title compound as a white solid, m.p. 260°-262° C. The infrared spectrum was consistent with the assigned structure, having a carbonyl stretch at 1700 cm-1, as was the mass spectrum, having a parent peak at 144 (M+).
Reaction SMILES: COC(=O)[C:4](=[C:14]1[CH2:18][CH2:17][CH2:16][NH:15]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1>C(Cl)Cl>[N:15]1[CH2:16][CH2:17][CH2:18][C:14]=1[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:12]#[N:13]
Reactant: COC(=O)C(Cc1cccc(C#N)c1)=C1CCCN1
Solvent: ClCCl
Product: N#Cc1cccc(CCC2=NCCC2)c1
Temperature: 180 °C
Yield: 35.8 %

Procedure:
A flask containing 3-(3-Cyano-phenyl)-2-pyrrolidin-2-ylidene-propionic acid methyl ester (0.25 g, 0.977 mmol), and H3BO3 (0.0664 g, 1.07 mmol) is heated to 180° C. for 2 h. The reaction is cooled to RT and treated with H20 (0.8 mL) and CH2Cl2 (2 mL) and the resulting mixture is vigorously stirred. The organic phase is separated, diluted with CH2Cl2 (15 mL) dried over Na2SO4 and concentrated. Purification by flash chromatography (2:1:1/EtOAc:CH2Cl2:hexanes) yields the title compound (0.07 g, 0.35 mmol). 1H NMR (CDCl3, 300 MHz) 7.63-7.35(m, 4H), 4.08-3.95(m, 2H), 3.18-3.01(m, 4H), 2.87-2.73(m, 2H), 2.20-2.06(m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([S:7][C:8]2[CH:9]([CH3:22])[C@@H:10]3[CH:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[CH2:4][NH:3]1.[Na+].[CH:24]1([O:30][C:31]([O:33][CH:34](I)[CH3:35])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[O:1]=[C:2]1[CH2:6][CH:5]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O:15][CH:34]([O:33][C:31]([O:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:32])[CH3:35])=[O:14])[CH2:4][NH:3]1
Reactant: CC1C(SC2CNC(=O)C2)=C(C(=O)[O-])N2C(=O)C([C@@H](C)O)[C@@H]12
Reactant: CC(I)OC(=O)OC1CCCCC1
Agent: [Na+]
Product: CC(OC(=O)OC1CCCCC1)OC(=O)C1=C(SC2CNC(=O)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
Following a procedure similar to that described in Example 39, but using 54 mg of sodium 2-(2-oxo-4-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate obtained by a similar procedure to that described in Example 36 and 50 μl of 1-(cyclohexyloxycarbonyloxy)ethyl iodide, 62 mg of the title compound were obtained as a colorless powder.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 41.6 %

Procedure:
A mixture of intermediate 59 (1.0 g, 0.0027 mol), 4-fluorobenzylamine (0.372 mL, 0.00321 mol) and MeOH (0.4 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and partitioned between dichloromethane and water. The organic solution is separated, dried (MgSO4), and concentrated in vacuo. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-40:60) gives 0.50 g of the product 85. 1H NMR (CDCl3) δ 7.60-7.35 (m, 3 H), 7.15-6.90 (m, 10 H), 6.85-6.70 (m, 2 H), 5.50-5.30 (m, 2 H), 5.75-5.55 (m, 2 H), 1.12 (s, 9 H); MS: m/z 446 (M++1).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21][C@@H:20]([C:34](=[O:57])[N:35]([CH:54]4[CH2:56][CH2:55]4)[C:36]4[CH:37]=[CH:38][C:39]5[O:44][C:43]([CH3:46])([CH3:45])[C:42](=[O:47])[N:41]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:40]=5[CH:53]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.CCOC(C)=O.C1(CC(Cl)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C1CCN2C(=NCCC2)CC1>>[CH:54]1([N:35]([C:36]2[CH:37]=[CH:38][C:39]3[O:44][C:43]([CH3:46])([CH3:45])[C:42](=[O:47])[N:41]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:40]=3[CH:53]=2)[C:34]([C@@H:20]2[CH2:21][C@H:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:23][NH:18][CH2:19]2)=[O:57])[CH2:56][CH2:55]1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)Cc4ccccc4)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Agent: Cl
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@H]3CNC[C@@H](NC(=O)Cc4ccccc4)C3)C3CC3)cc21
Reaction time: 0.67 h

Procedure:
(3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-[1,4]oxazin-6-yl]-carbamoyl}-5-phenylacetylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (90 mg, 0.12 mmol) is treated with 4N HCl/AcOEt (2 mL) at r.t. for 1 hr, then evaporated. The evaporated residue is dissolved in CH2Cl2 (1 mL). To the solution is added phenylacetyl chloride (20.4 mg, 0.132 mmol) and diisopropyl ethyl amine (32 mg, 0.264 mmol) at 0° C. and stirred for 40 min. After adding 1N HClaq, the mixture is extracted with CH2Cl2, washed with sat NaHCO3aq, brine and dried (MgSO4). Concentration under vacuum and the evaporated residue is dissolved in THF (1 mL). To the solution is added DBU (9 mg, 0.06 mmol) and N-(2-mercaptoethyl)aminoethyl polystyrene (2.1 mmol/g, 286 mg, 0.6 mmol) and stirred for 1 h at r.t. The reaction mixture is filtered via celite pad and washed with THF. Concentration under vacuum and purification with RP-HPLC gives the title compound. MS: 549 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.78 min.
Reaction SMILES: [CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](OC)([O:22]C)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].COCCOC.O.Cl>C(Cl)Cl>[CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(SC)c1cccc(C(OC)(OC)c2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C)(SC)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.5 %

Procedure:
To 978 mg of methyl α-methylthio-α-[m-(α,α-dimethoxybenzyl)phenyl]propionate were added 2 ml of 1,2-dimethoxyethane and 0.5 ml of water, and 0.2 ml of conc. hydrochloric acid was further added. The mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with 50 ml of methylene chloride, and dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure to afford 874 mg of methyl α-methylthio-α-(m-benzoylphenyl)propionate. The product was found to be substantially pure by its NMR and GLC.