Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10]([NH2:24])=[N:11][C:12](=[O:23])[N:13]([CH:22]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)=[O:4].N1C=CN=C1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C>[Si:36]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:26])[C:10]([NH2:24])=[N:11][C:12]2=[O:23])[CH2:15][C@@H:16]1[OH:17])([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37]
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCNC(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(N)nc2=O)C[C@@H]1O
Reaction time: 2 h

Procedure:
To a solution of the starting material (7) (1.0 g, 2.66 mmol) and imidazole (200 mg, 2.93 mmol) in DMF (3.0 ml) at 0° C., was slowly added TBDMSCl (442 mg, 2.93 mmol) in four portions over 1 h. After 2 h, the volatiles were evaporated under reduced pressure and the residue was adsorbed on silica gel and purified by flash chromatography (EtOAc, EtOAc:MeOH 9.5:0.5). The expected product (8) was isolated as a crystalline solid (826 mg, 64%). 1H NMR (d6 DMSO) δ 0.00 (s, 1H, CH3); 0.01 (s, 1H, CH3), 0.79 (s, 9H, tBu), 1.87-1.80 (m, 1H, H-2′), 2.12 (ddd, J=13.0, 5.8 and 3.0 Hz, 1H, H-2′), 3.65 (dd, J=11.5, 2.9 Hz, 1H, H-5′), 3.74 (dd, J=11.5, 2.5 Hz, 1H, H-5′), 3.81-3.80 (m, 1H, H-4′), 4.10-4.09 (m, 1H, H-3′), 4.17 (d, 2H, J=5.1 Hz, NCH2), 5.19 (d, 1H, J=4.0 Hz, 3′-OH), 6.04 (t, J=6.6 Hz, 1H, H-1′), 6.83 (br s, 1H, NHH), 7.78 (br s, 1H, NHH), 7.90 (s, 1H, H-6), 9.86 (t, J=5.1 Hz, 1H, —H2CNH); MS (ES): m/z (%) (MH)+491 (40%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:31]([CH2:30][Cl:29])(=[O:33])=[O:32])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Reactant: O=S(=O)(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)CCl)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (2.5 g) and triethylamine (1.7 g) in dichloromethane (35 ml) was added at 0° C. a solution of chloromethanesulfonyl chloride (1.26 g) in dichloromethane (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with water, 10% citric acid solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless syrup of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(chloromethanesulfonyl)-2-piperazinone (2.47 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([Br:24])[C:18]=3[NH2:25])[CH2:12][CH2:11]2)=[O:8])[CH2:3][CH2:2]1.[C:26]([Cl:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(OC(C)C)(C)C>N1C=CC=CC=1>[ClH:34].[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([Br:24])[C:18]=3[NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH2:11]2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1c(Br)cc(Br)cc1CN1CCN(CC(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: O=C(Nc1c(Br)cc(Br)cc1CN1CCN(CC(=O)N2CCOCC2)CC1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.423 part of N1 -(morpholinocarbonylmethyl)-N4 -(2-amino-3,5-dibromobenzyl)piperazine in 4 volume parts of pyridine is added 0.25 part of benzoylchloride, and the mixture is kept standing overnight at room temperature. The solvent is distilled off, and residue is chromatographed over alumina. Ethyl acetate eluates gives oily substance. The resultant oily substance is treated with ethanolic hydrochloric acid, and to the resultant is added isopropyl ether to give N1 -morpholinocarbonylmethyl-N4 -(2-monobenzoylamino-3,5-dibromobenzyl)piperazine hydrochloride melting at 162° to 164° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C[O-].[Na+].Cl.C[CH2:24][O:25]C(C)=O>CN(C=O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][C:10]3[C:2]([O:25][CH3:24])=[CH:3][C:4]([OH:18])=[CH:5][C:6]=3[CH:7]=2)=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: Oc1ccc(-c2cc3cc(O)cc(Br)c3o2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 160 °C

Procedure:
A solution consisting of 58 (1.5 g, 4.9 mmol) in DMF (25 mL) was treated with CulBr (1.0 g, 6.5 mmol) and NaOMe (6 mL, 4.4 N in MeOH, 27 mmol) and heated to 160° C. for approximately 1 hour. The reaction mixture was allowed to cool and then worked up by adding 2 N HCl and EtOAc. The EtOAc layer was washed with NaHCO3 aq, brine and dried over MgSO4. The solution was concentrated and chromatographed on silica gel (1:4 EtOAc/hexanes to 3:7 EtOAc/hexanes) to yield 0.47 g of pdt: Mp=167–168° C., 1H NMR (DMSO-d6) δ 9.84 (br s, 1 H), 9.18 (br s, 1 H), 7.67 (d, 2 H, J=8.6 Hz), 6.99 (s, 1 H), 6.86 (d, 2 H, J=8.7 Hz), 6.46 (d, 1 H, J=2.1 Hz), 6.34 (d, 1 H, J=2.1 Hz), 3,89 (s, 3 H); MS 257 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8]Cl.[NH4+:19].[OH-].CCO.C(O)(=O)/C=C\C(O)=O>CCOC(C)=O.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][NH2:19]
Reactant: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Reactant: [NH4+]
Agent: O=C(O)/C=C\C(=O)O
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCC[C@@H](Oc1cccc(F)c1)c1ccccc1

Procedure:
A solution of (R)-3-(3-fluorophenoxy)-3-phenylpropyl chloride (0.971 g, 3.96 mmol), conc. NH4OH (30 mL), and EtOH (20 mL) were shaken at 90° C. on a Parr apparatus (50-90 psig) for 18 h. The mixture was then evaporated under vacuum and the residue was dissolved in Et2O (100 mL) and washed with H2O (2×25 mL). The organic layer was dried (anh. Na2SO4), filtered, and evaporated under vacuum to provide a yellow oil. This material was then dissolved in EtOAc (50 mL) and filtered. A solution of 30 maleic acid (0.272 g, 2.6 mmol, 0.93 equiv) dissolved in hot EtOAc (5 mL) was added to precipitate the maleate salt (519 mg, 53.5%) as a white solid: TLC Rf 0.25 (1% MeOH—CHCl3); GC, tr 7.37 min; MS, m/z 245 (M+). The synthesis of Compound 187 was accomplished as follows.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>C(O)C>[OH:23][CH2:1][C:2]([C@H:3]([C@@H:4]([C@@H:5]([CH2:6][OH:8])[OH:20])[OH:21])[OH:22])=[O:7].[C:6](=[O:8])=[O:7]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C=O

Procedure:
It has been calculated from experiments carried out that 1 tonne of sucrose will produce approximately 0.5 tonne of fructose, 0.25 tonne of ethanol and 0.25 tonne of carbon dioxide (CO2).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.N[CH2:32][C:33]1C=NC=C[CH:38]=1>>[N:8]1[CH:38]=[CH:33][CH:32]=[C:11]([CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-(aminomethyl)pyridine instead of 1-BOC-3-aminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.28 (1H, s) 8.73 (1H, t, J=6.05 Hz) 8.55 (1H, d, J=1.76 Hz) 8.45 (1H, dd, J=4.78, 1.66 Hz) 8.02 (1H, d, J=5.47 Hz) 7.81 (1H, d, J=5.47 Hz) 7.67-7.74 (1H, m) 7.50 (1H, d, J=5.47 Hz) 7.28-7.38 (2H, m) 6.84 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.42, 1.85 Hz) 4.48 (2H, d, J=6.05 Hz)
Reaction SMILES: CI.[CH2:3](OC1C=CC(CCl)=CC=1)C1C=CC=CC=1.[C:19]1([S:25]([CH:28]2[C:33](=[O:34])[NH:32][CH2:31][CH2:30][N:29]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([C:28]2([CH3:3])[C:33](=[O:34])[NH:32][CH2:31][CH2:30][N:29]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1S(=O)(=O)c1ccccc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)S(=O)(=O)c1ccccc1

Procedure:
When in the procedure of Example 3a, methyl iodide is substituted for p-benzyloxybenzyl chloride, and 27c is substituted for 2, the title compound is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5](=[O:20])(=[O:19])[C@@H:6]2[C@@H:16]([Cl:17])[C:15](=[O:18])[N:7]2[C:8]=1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10].C(N(CC)CC)C.[SH:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1>C(#N)C>[C:11]([C:9]([C:8]1[N:7]2[C:15](=[O:18])[C@H:16]([Cl:17])[C@H:6]2[S:5](=[O:20])(=[O:19])[CH2:4][C:3]=1[CH2:2][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)C1=C(CBr)CS(=O)(=O)[C@@H]2[C@@H](Cl)C(=O)N12
Reactant: Cn1nnnc1S
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)C(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Yield: 49.3 %

Procedure:
A solution of 3-bromomethyl-4-tert-butylcarbonyl-7α-chloro-3-cephem 1,1-dioxide (65 mg), prepared as in Example 6, in dry acetonitrile (5 ml) was treated with triethylamine (0.025 ml) and 5-mercapto-1-methyl-1,2,3,4-tetrazole (26 mg). An immediate reaction took place (TLC monitoring). The solvent was removed in vacuo and the residue purified by flash-chromatography, thereby obtaining the title product as a white powder (35 mg)
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:26][C:22]1[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(N)n1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 60° and 66° C., to a solution of 2-amino-6-picoline (2.2 g) and triethylamine (4.05 g) in dioxane (130 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc) and the solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (5.6 g) is thereby obtained, which is dissolved in boiling acetonitrile (60 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 2 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (20 cc in total) and then twice with diethyl ether (50 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(6-methyl-2-pyridyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.5 g) in the form of beige-coloured crystals, m.p. 162° C., is thereby obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.C(N(CC)CC)C>ClCCl>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:7](=[O:8])[C:6]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:31][C:32]=1[C:38]([F:39])([F:40])[F:41])#[N:35]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-isopropoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.P1(Cl)(=O)OC2C=CC=CC=2O1.[C:19]1([CH:25]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[O:26][C:27]([CH:29]([N:63]2[C:67](=[O:68])[C:66]3=[CH:69][CH:70]=[CH:71][CH:72]=[C:65]3[C:64]2=[O:73])[CH2:30][CH2:31][CH2:32][C:33]([NH:35][C@@H:36]2[C:61](=[O:62])[N:38]3[C:39]([C:45]([O:47][CH:48]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])=[C:40]([CH2:43]O)[CH2:41][S:42][C@H:37]23)=[O:34])=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:19]1([CH:25]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[O:26][C:27]([CH:29]([N:63]2[C:67](=[O:68])[C:66]3=[CH:69][CH:70]=[CH:71][CH:72]=[C:65]3[C:64]2=[O:73])[CH2:30][CH2:31][CH2:32][C:33]([NH:35][C@@H:36]2[C:61](=[O:62])[N:38]3[C:39]([C:45]([O:47][CH:48]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[O:46])=[C:40]([CH2:43][S:1][C:2]4[N:6]([CH3:7])[N:5]=[N:4][N:3]=4)[CH2:41][S:42][C@H:37]23)=[O:34])=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCCC(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)c2ccccc2C1=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: O=P1(Cl)Oc2ccccc2O1
Solvent: O
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)CCCC(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
In 5 ml of methylene chloride was dissolved 0.195 g of 5-mercapto-1-methyl-1H-tetrazole and the solution was cooled to -10° C. Then, a solution of 0.268 g of o-phenylene phosphorochloridate in 5 ml of methylene chloride was added and, under cooling at -20° to -25° C., a solution of 1.170 g of diphenylmethyl 7β-(5-diphenylmethyloxycarbonyl-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylate in 8 ml of methylene chloride was added dropwise. The mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added 10 ml of water and, then, the mixture was allowed to stand at room temperature for phase separation. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated and poured into 80 ml of ether. The powdery precipitate was collected by filtration and subjected to silica gel column chromatography (silica gel: 30 g, column height: 36 cm), elution being carried out with ethyl acetate-n-hexane (4:1). The fractions were checked by TLC (developing solvent: the same as the above eluent) and the fractions (Rf : about 0.71) containing the desired product were collected and concentrated. To the concentrate was added ether to give diphenylmethyl 7β-(5-diphenylmethyloxycarbonyl-5-phthalimidovaleramido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.O1CCCC1>O>[CH2:1]([S:5]([NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH:11]=1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Yield: 46.6 %

Procedure:
N-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide (0.505 g) was added to a mixture of 1.32 g of sodium hydrosulfite, 1 ml of ethanol, 1 ml of tetrahydrofuran and 1 ml of water at room temperature. The mixture was heat-refluxed for 40 minutes. The solvent was distilled off under reduced pressure, and water was added to the residue. The solid material precipitated was collected, and was dried. Further, the resulting material was washed with a mixed solution of 10 ml of methanol and 3 ml of water, and was dried to give 0.220 g of N-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[S:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[N:14]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[S:13]1[CH:17]=[C:16]([CH:18]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[N:15]=[N:14]1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: O=Cc1csnn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OC(c2cccs2)=NC1=Cc1csnn1
Temperature: 90 °C
Yield: 38 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,2,3-thiadiazol-4-carboxaldehyde (37 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 30 mg of the above-captioned compound.
Reaction SMILES: [C:1](OO)(=O)C.[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:10][C:9]([CH2:30]SC)=[N:8]1.C([O-])(=O)C.[Na+].[S:38]([O-:41])([O-])=[O:39].[Na+].[Na+]>C(O)(=O)C>[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:10][C:9]([CH2:30][S:38]([CH3:1])(=[O:41])=[O:39])=[N:8]1
Reactant: O=S([O-])[O-]
Reactant: CC(=O)OO
Reactant: CSCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(CS(C)(=O)=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Peracetic acid (1.05 ml of a 6.1M solution) in acetic acid (7 ml) was added to an ice-cooled solution of 1-methyl-3-methylthiomethyl-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-5-amine (0.82 g) in acetic acid (10 ml) with sodium acetate (0.52 g). The mixture was stirred at room temperature for 18 h, sodium sulphite (1.25 g) added and the mixture evaporated to dryness. The residue was basified to pH 8 with sodium bicarbonate solution, washed with ethyl acetate, basified to pH 10 with sodium carbonate and extracted with ethyl acetate to give a foam (0.46 g). This was crystallised from methyl acetate-petroleum ether (b.p. 60°-80°) to give the title compound as a white solid (0.22 g), m.p. 121°-122°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23](=[O:31])[CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.[C:39]1(=O)[CH2:42]C[CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(Cl)CCl>[CH:12]1([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:19]=[CH:20][C:21]([NH:22][C:23](=[O:31])[CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:2]([F:1])[CH:3]=3)[CH2:7][CH2:8]2)[CH2:42][CH2:39][CH2:40]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CN3CCOCC3)c(F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCOCC1)Nc1ccc(OC2CCN(C3CCC3)CC2)cc1F
Yield: 55.5 %

Procedure:
To a stirred solution of tert-Butyl 4-[3-fluoro-4-(2-(morpholin-4-yl)acetylamino) phenoxy]piperidine-1-carboxylate (3.1 g, 0.007 moles, obtained in above step) in dichloromethane (25 mL) was added trifluoroacetic acid (8.1 g, 0.071 moles) and stirred reaction mass overnight at room temperature. After completion of reaction, solvent was evaporated under vacuum and the residue, thus obtained, was basified with 10% caustic lye solution. Extracted the reaction mass with ethyl acetate twice, the combined organic layer dried over sodium sulphate and evaporated under reduced pressure. The crude product, thus obtained, was treated with cyclobutanone (0.6 g, 0.008 moles), in ethylene dichloride (30 mL), and stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (3 g, 0.014 moles) was added to reaction mass in a single lot and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched in water and basified with lye solution. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over sodium sulfate, concentrated under vacuum and the residual mass was further purified by flash chromatography (dichloromethane: triethylamine, 9.5:0.5) to obtain the title compound 1.52 g (Yield: 55%).