Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])[CH2:9][CH2:10][C:11]12[CH:21]=[CH:20][CH:19]=[CH:18][CH:12]1[C:13]([NH:15][C:16]2=[O:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].CC(C)=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.ClCCl.C(Cl)(Cl)Cl>[CH2:1]([N:8]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:9][CH2:10][C:11]12[CH:21]=[CH:20][CH:19]=[CH:18][CH:12]1[C:13]([NH:15][C:16]2=[O:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CCN(CCOCCOCCO)Cc3ccccc3)C=CC=CC12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCOCCOCCN(CCC12C=CC=CC1C(=O)NC2=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-[2-(Benzyl-{2-[2-(2-hydroxy-ethoxy)ethoxy]ethyl}amino)ethyl]phthalimide 33 (2.774 g, 6.7 mmol) was dissolved in mixture of pyridine (20 mL) and dichloromethane (100 mL) and cooled in an ice bath. Methanesulfonyl chloride (0.63 mL, 8 mmol) was added and the resulting solution was stirred at 0° C. for 16 h. (The progress of the reaction was followed by TLC using a 1:1 mixture of 40% acetone in hexanes and chloroform as the eluent. The starting material has Rf=0.35, while the product has Rf=0.50.) Saturated aqueous sodium bicarbonate was added, and after 30 min of stirring, the organic phase was washed with 0.5 M hydrochloric acid and again with saturated aqueous sodium bicarbonate. The solution was dried over sodium sulfate and solvent was removed under reduced pressure. The resulting crude oily product 34 (3.152 g, 96%) was used in the next step without further purification. CIMS (M+): 491.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:19])=O.C(=O)([O-])O.[Na+]>O>[Cl:19][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:14]=1
Reactant: OCc1cccc(Oc2ccnc(Cl)c2)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: ClCc1cccc(Oc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 6-[(2-chloro-4-pyridyl)oxy]-2-pyridinemethanol (10.2 g, 0.043 mol) and thionyl chloride (10 mL) is stirred at room temperature for 90 minutes. Excess thionyl chloride is hydrolyzed by adding water to the reaction mixture until no further reaction is observed. The reaction mixture is then neutralized with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product (10.6 g, 97%).
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].[CH2:21](I)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)[CH:22]=[CH2:21]
Reactant: C=CCI
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Yield: 93.6 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (5.2 g, 20 mmol), sodium hydride (55% content, 1.31 g, 30 mmol), allyl iodide (5.03 g, 30 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 5.64 g of the title compound as a colorless oily substance (93%).
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH3:9][C:5]([CH2:4][N+:1]([O-:3])=[O:2])=[CH:6][CH2:7][OH:8].[C:10]1([NH:16][C:17](=[O:2])[O-:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccccc1
Agent: CC(=CCO)C[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=C([O-])Nc1ccccc1

Procedure:
0.1 Mol of 4-nitro-3-methyl-2-butenol and 0.1 Mol of phenylisocyanate were treated at 60°-80° C. for 3 hours. The reaction mixture was left for several hours at room temperature before dissolving it in hot benzene. The benzene solution was filtered and evaporated. The residue was crystallized from hot ligroin. Yellow crystals, m.p. 63°-66°, were obtained.
Reaction SMILES: [CH:1](=[N:8][NH:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C1(C)C=CC=CC=1>[CH:1](=[N:8][N:9]([CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CNN=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CN(C)N=Cc1ccccc1
Yield: 90.5 %

Procedure:
258 g (1.92 mol) of N-benzylidene-N′-methylhydrazine and 325 g (1.92 mol) of ethyl ethoxy-methylenecyanoacetate were initially charged in 1000 ml of toluene and heated at the boil for 1 hour. After cooling, the mixture was filtered off with suction, which gave 447 g (89.5% of theory) of ethyl 3-(N′-benzylidene-N-methylhydrazino)-2-cyanoacrylate [logP (pH 2.3)=2.31]. The filtrate was allowed to stand for 16 hours and then again filtered off with suction, which gave another 7.7 g (1.5% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)C(=O)OCc1ccccc1
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and benzyl pyruvate (prepared by following General Procedure AO above using benzyl alcohol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: ClCCCC(OC(=O)C)CCCC(C)C.C([O:19][CH:20]([CH2:40][CH2:41][CH2:42][CH:43](C)[CH3:44])[CH2:21][CH2:22][CH2:23][N:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])(=O)C>>[OH:19][C@H:20]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:21]#[C:22][CH2:23][N:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[S:25]([CH3:28])(=[O:26])=[O:27]
Reactant: CCOC(=O)CCCCCCN(CCCC(CCCC(C)C)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(CCCCl)CCCC(C)C
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxy-8-methylnonane (Example B, Step 3). The product of Step A is thus ethyl 7-[N-(4-acetoxy-8-methylnonyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-8-methylnonyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]2=[C:13]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)=[O:33])=[CH:27][CH:26]=3)[C:14]([CH:23]=[O:24])=[C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=[CH:9][N:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=4)=[O:33])=[CH:29][CH:30]=3)[C:14]([C:23]([CH:1]3[CH2:3][CH2:2]3)=[O:24])=[C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Br[Mg]C1CC1
Reactant: Nc1ncnn2c(CN3CCOCC3)c(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(CN3CCOCC3)c(C(=O)C3CC3)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Yield: 10.8 %

Procedure:
Cyclopropyl magnesium bromide (7.40 mL, 3.70 mmol, 0.5 M in diethyl ether) was added dropwise to a stirring solution of Example 85 (200 mg, 0.37 mmol) in THF (10 mL). This was allowed to stir until the reaction was complete by HPLC (1 hour). Additional amounts of the grinard reagent were added as needed. The reaction was quenched with methanol and was worked up by adding 1 volume of saturated NH4Cl solution and 5 volumes of EtOAc. The organic layer was washed 2× with NH4Cl and 1× with sodium carbonate soln. The organic layer was dried over Na2SO4 and concentrated. The crude intermediate was dissolved in DMSO (3 mL) and treated with Dess-Martin periodinane (174.7 mg, 0.412 mmol). The reaction was allowed to stir until the reaction was complete by HPLC (2 hours). The reaction was diluted with EtOAc (200 mL) and washed 2× with both saturated NaHCO3 and 2M sodium thiosulfate solution. The organic layer was dried over Na2SO4 and concentrated to give a crude solid which was purified by HPLC (10-70% ACN/H2O) to give 26.3 mg of the above compound (0.04 mmol, 12.3% yield). 1H-NMR (DMSO-d6). δ 9.98 (s, 1H), 9.82 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 0.745-7.41 (m, 3H), 4.08 (s, 2H), 3.55-3.52 (m, 4H), 2.46-2.43 (m, 4H), 2.07-1.97 (m, 1H), 0.95-0.91 (m, 2H), 0.74-0.69 (m, 2H). MS [M+H]+=581; LCMS RT=2.68 min.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15](C(OC)=O)[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH-].[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>CO>[N:12]1([C:8]2[CH:7]=[C:6]3[C:11]([C:2](=[S:25])[CH:3]=[CH:4][NH:5]3)=[CH:10][CH:9]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)N1CCN(c2ccc3c(O)ccnc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: S=c1cc[nH]c2cc(N3CCNCC3)ccc12
Yield: 7.8 %

Procedure:
4-Hydroxy-7-(4-methoxycarbonyl-1-piperazinyl)quinoline (0.32 g, 1.1 mmol) dissolved in methanol (5 ml) was added with 2N sodium hydroxide (1.6 ml) and stirred with heating for 12 hours. After allowing to cool, methanol was removed under reduced pressure. The residue was added with water (10 ml) and adjusted by 5% hydrochloric acid to pH 7 and the water was removed under reduced pressure. This residue was siispended in pyridine (5 ml), added with phosphorus pentasulfide (0.25 g, 1.1 mmol) and stirred at 100° C. for 1.5 hours. After allowing to cool, pyridine was removed under reduced pressure and the residue was purified by preparative TLC (Merck Art. 13895, methylene chloride : methanol : ammonia water=50 : 10 : 1) to obtain 21 mg (8%) of the titled compound.
Reaction SMILES: [CH3:1]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O:21][CH2:22][CH2:23][C:24]1([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:28][CH2:27][CH2:26][C:25]1=[O:29])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:29][C:25]12[CH2:26][CH2:27][CH2:28][C:24]1([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:23][CH2:22][O:21]2
Reactant: C=CCOC(=O)C1(CCOC(C)=O)CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C=CCOC(=O)C12CCCC1(OC)OCC2
Temperature: 25 °C
Yield: 80 %

Procedure:
A reaction vessel was charged with 1,580 parts of methanol, 25 parts of PPTS, 254 parts of 2-(2-acetoxyethyl)-2-(2-propenyloxycarbonyl)cyclopentanone (14) obtained in Preparation Example 3 at room temperature. The mixture was refluxed for three hours with stirring. After cooling the reaction solution to room temperature, 30 parts of potassium carbonate was added and the mixture was stirred for one hour at room temperature. Insoluble matters were removed by filtration, the filtrate was washed with saturated brine, and the solvent was evaporated. The residue was distilled under reduced pressure to obtain 146 parts of the target compound (15) (yield: 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([OH:11])[CH:5]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Reaction time: 1.5 h

Procedure:
4-Fluoro-3-hydroxybenzoic acid methyl ester (1.70 g, 10.0 mmol) was dissolved in dimethylformamide (9 mL) under nitrogen at room temperature. Sodium hydride (60% oil dispersion, 0.48 g, 12 mmol) was added in portions over 30 min. The reaction was stirred for 90 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (1.58 g, 10.0 mmol) was added in small portions over 50 min. The reaction was stirred at room temperature for 17.5 h. Water (200 ml) was added and the mixture stirred until a brown lump formed. The water was decanted and the residue dissolved in EtOAc (150 mL). The solution was washed with brine, dried (MgSO4), filtered and evaporated to give 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester. Yield: 3.10 g.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@@H]([C@H]([C@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@H](CO)O)O)O.S(=O)(=O)(O)O>[O-][Mo]([O-])(=O)=O.[Na+].[Na+]>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=[Mo](=O)([O-])[O-]
Agent: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To 20 mL of an aqueous feedstock containing 12.6 wt. % L-mannose, 0.07 wt. % L-glucose, and 0.5 wt. % L-arabinose was added sodium molybdate in an amount calculated to afford the desired concentration of Mo. Solutions were adjusted to their desired pH by addition of 10% sulfuric acid and epimerization was followed with time. From the resulting plots of time glucose yield the time for conversion to a 60:40 glucose:mannose mixture (60% yield) was determined. The times as a function of temperature, Mo concentration, and pH are summarized in Table 2.
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:18][N:19]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]1[CH2:25][C:26]([O:28][CH3:29])=[O:27].[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31]>C(O)C.CCOCC>[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31].[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:23]2[N:19]([CH3:18])[C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][C:22]=2[CH3:24])=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: CN=C(Cl)c1ccc(OC)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: CCO
Product: CN=C(c1ccc(OC)cc1)c1c(C)cc(CC(=O)OC)n1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
N-Methyl 4-methoxybenzimidoyl chloride (6.67 g, 36.4 mmole) was placed in a dry 50 ml round bottom flask and treated with alcohol free chloroform (13 ml) and chlorosulfonic acid (0.42 g, 3.6 mmole). The reaction was blanketed with nitrogen and stirred while methyl 1,4-dimethyl-1H-pyrrole-2-acetate (6.03 g., 36.1 mmole) was added dropwise over a period of about five minutes. The reaction was stirred overnight, then heated at 40° C. for two hours. The reaction was quenched with saturated aqueous sodium bicarbonate. The phases were separated, and the organic phase was washed with saturated aqueous sodium bicarbonate and water, then dried over sodium sulfate. The chloroform was removed under reduced pressure to yield a red viscous liquid. The crude product was dissolved in absolute ethanol and treated with 70% perchloric acid (5.7 g, 40 mmole). The solution was cooled and treated with ether to induce crystallization. The yellow solid was isolated by filtration and washed with cold ethanol to yield 10.5 g (64%) of the title compound, m.p. 123°-129° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45]C(=O)C)/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[OH:45])/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4ccncc4)CS[C@H]23)cs1
Reaction time: 2 h
Yield: 17.7 %

Procedure:
To a suspension of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (2.37 g, 3.51 m mol) in a mixture of dichloromethane (12 ml) and anisole (2.4 ml) was added trifluoroacetic acid (4.8 ml) at 5° C. and the mixture was stirred at the same temperature for 2 hours. The mixture was poured into IPE (300 ml) and the precipitates were collected by filtration, washed with IPE and dried in vacuo. The powder was suspended in a mixture of water (150 ml) and methanol (7.5 ml), and ammonium chloride (563 mg, 10.5 m mol) was added thereto. The mixture was stirred at room temperature with keeping the pH to 8 by addition of saturated NaHCO3 aqueous solution. The mixture was adjusted to pH ca. 6 by addition of 6N HCl and by evaporated in vacuo. The residue was adjusted to pH 3.5 by addition of 6N HCl and chromatographed on HP-20 (80 ml) and eluted with 5% aqueous IPA. The eluent was lyophilized and the crude product was purified by preparative HPLC to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylic acid (295 mg).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[C:16](Cl)=[N:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Cl:10][C:11]1[C:16]([O:9][CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)=[N:15][CH:14]=[CH:13][N:12]=1
Reactant: OC1CCOCC1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccnc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.22 g, 5.39 mmol) was added to a solution of tetrahydro-4H-pyran-4-ol (0.47 mL, 4.90 mmol) in THF (10 mL) and the mixture was stirred for 30 mins, during which time a suspension formed. This mixture was added dropwise to a solution of 2,3-dichloropyrazine (0.73 g, 4.90 mmol) in THF (10 mL) at −78° C. under argon. The cooling bath was removed and the mixture was stirred for 3 h with warming to RT. Ethyl acetate and saturated aqueous ammonium chloride were added, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 2-chloro-3-(tetrahydro-2H-pyran-4-yloxy)pyrazine (0.75 g, 3.49 mmol, 71% yield) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][C@H:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])[C:22](=[O:23])[NH:24][CH3:25]
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=424.6 [M+H]+.
Reaction SMILES: Br[C:2]#[N:3].CC([O-])=O.[K+].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[C:10]1([NH:9][C:2]#[N:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: N#CNc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of BrCN (0.11 g, 1.1 mmo) in MeOH (10 mL) at 0° C. was added solid KOAc (0.32 g, 3.3 mmol) and a solution of aniline (0.1 mL, 1.1 mmol) in MeOH (1 mL). The reaction was stirred for 3 hours then partitioned with water (15 mL) and dichloromethane (25 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and reduced to dryness to afford N-phenylcyanamide, which was immediately used without purification.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([N:9]([CH3:19])[CH2:10][CH:11]2[CH2:18][CH2:17][C:14]3([CH2:16][CH2:15]3)[CH2:13][CH2:12]2)[C:6]([C:20](O)=[O:21])=[CH:5][N:4]=1)#[N:2].[C:23]1([CH2:29][C@@H:30]([NH2:37])[CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]1([CH2:29][C@@H:30]([NH:37][C:20]([C:6]2[C:7]([N:9]([CH3:19])[CH2:10][CH:11]3[CH2:18][CH2:17][C:14]4([CH2:15][CH2:16]4)[CH2:13][CH2:12]3)=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:21])[CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@H](Cc1ccccc1)CN1CCCC1
Reactant: CN(CC1CCC2(CC1)CC2)c1nc(C#N)ncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CN(CC1CCC2(CC1)CC2)c1nc(C#N)ncc1C(=O)N[C@H](Cc1ccccc1)CN1CCCC1
Reaction time: 24 h

Procedure:
To a solution of the crude 2-cyano-4-(methylspiro[2.5]oct-6-ylmethylamino)pyrimidine-5-carboxylic acid (82 mg, step 73.4) in DMF (1.5 mL) are added (R)-2-phenyl-1-pyrrolidin-1-ylmethylethylamine (0.3 mmol), EDCI-HCl (0.4 mmol), and HOAt (0.4 mmol) at room temperature. The reaction mixture is stirred for 24 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt and the organic extracts are dried over Na2SO4, filtered, concentrated in vacuo. The resulting residue is purified by RP-HPLC to give the title compound; MS (M+1)+ 488, Rf (solvent) 0.13 (CH2Cl2:MeOH=10:1).