Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9].S(=O)(=O)(O)O.Cl[O-].[Na+].S([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COC1CCCCC1O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1CCCCC1=O
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 500-ml four-mouth flask equipped with a thermometer, dropping funnel, condenser, and stirrer was charged with 13.0 g (0.1 mol) of (RS)-2-methoxycyclohexanol, 7 g of dichloromethane, and 30 g of 10% aqueous solution of sulfuric acid (30 mmol). The reactants were stirred at 20-25° C. The flask was further charged with 60 g of aqueous solution of sodium hypochlorite containing 12.1% effective chlorine over about 1 hour. Stirring was continued for 30 minutes. The reaction solution was analyzed by gas chromatography to confirm that the peak due to (RS)-2-methoxycyclohexanol had disappeared. The reaction solution was given 2 g of sodium hydrogensulfite with stirring. It was confirmed that the reaction solution did not change potassium iodide starch paper into purple any longer. The reaction solution was extracted twice with 50 g of dichloromethane. The dichloromethane layers were combined together and washed with 30 g of saturated aqueous solution of sodium chloride. Upon concentration and distillation, there was obtained 11.5 g (90 mmol) of (RS)-2-methoxycyclohexanone. The chemical purity of this compound was 99.8%. Incidentally, the dichloromethane used in this example has a partition ratio in water (at 20° C.) greater than 1 and has a solubility in water (40° C.) lower than 5 wt %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:56]1([CH2:59][N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH2:58][CH2:57]1>CN(C=O)C>[CH:56]1([CH2:59][N:60]2[CH2:65][CH2:64][N:63]([C:31](=[O:33])[CH2:30][C:26]3[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])[CH2:62][CH2:61]2)[CH2:58][CH2:57]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: C1CN(CC2CC2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (210 mg, 0.4 mmol), HOBt (54 mg, 1 eq.) and EDAC (77 mg, 1 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-cyclopropylmethyl-piperazine (112 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the precipitate was collected by vacuum filtration, washed with water, sodium bicarbonate and water and then dried to give 240 mg (94%) of the titled compound.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([N:13]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:14]1[CH:23]=[CH:22][C:21]2[C:20]3=[CH:24][CH:25]=[N:26][N:19]3[CH2:18][CH:17](O)[C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(Cl)Cl>[C:35]([O:34][C:32]([N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:14]1[CH:23]=[CH:22][C:21]2[C:20]3=[CH:24][CH:25]=[N:26][N:19]3[CH:18]=[CH:17][C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1C(O)Cn1nccc1-2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
Methanesulfonyl chloride (0.5 mL) was added to a solution of methyl 8-[bis-(tert-butoxycarbonyl)amino]-6-hydroxy-5,6-dihydro-pyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 8, 0.290 g) in triethylamine (0.7 mL) and DCM (10 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The resultant mixture was washed with 1M aqueous hydrochloric acid and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.280 g) as a gum.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:8]1[C:12](=[O:13])[CH:11]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[NH:10][C:9]1=[O:24])[CH:5]([CH3:7])[CH3:6]>Cl>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][CH2:14][CH:11]2[C:12](=[O:13])[N:8]([CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:25])=[O:2])[C:9](=[O:24])[NH:10]2)=[CH:18][CH:19]=1
Reactant: COC(=O)C(C(C)C)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Agent: Cl
Product: CC(C)C(C(=O)O)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Yield: 68 %

Procedure:
A mixture of the compound obtained in step e above (623 mg, 1.512 mmol) and 2 N HCl (20 mL) was refluxed for 2 h. The reaction mixture was cooled down and then extracted with EtOAc. The combined organic layers were dried and concentrated; the crude product was purified by silica gel column chromatography which gave the title compound as colourless oil (409 mg, 68%).
Reaction SMILES: [H-].[Na+].[CH:3]1([C@@H:6]2[O:16][CH2:15][C:9]3=[N:10][O:11][C@@H:12]([CH2:13][OH:14])[C@@H:8]3[CH2:7]2)[CH2:5][CH2:4]1.I[CH3:18].O>CN(C)C=O>[CH:3]1([C@@H:6]2[O:16][CH2:15][C:9]3=[N:10][O:11][C@@H:12]([CH2:13][O:14][CH3:18])[C@@H:8]3[CH2:7]2)[CH2:4][CH2:5]1
Reactant: OC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 395 mg, 9.88 mmol) was slurried in N,N-dimethylformamide (30 mL) and cooled in an ice bath. A solution of rel-[(3R,3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazol-3-yl]methanol (C37) (1.30 g, 6.59 mmol) in minimal N,N-dimethylformamide was added drop-wise, and the reaction mixture was stirred at 0° C. for 30 minutes. Iodomethane (0.45 mL, 7.2 mmol) was then added in a drop-wise manner, and the reaction was allowed to proceed for an additional 30 minutes at 0° C. Water was added, and the mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 60% ethyl acetate in heptane) provided the product as an oil. Yield: 1.0 g, 4.7 mmol, 71%. LCMS m/z 212.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]#[N:3].[CH2:4]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[N:22]=[C:21]([C:23](OC)=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:5]>C(OCC)(=O)C>[C:2]([CH2:1][C:23]([C:21]1[N:22]=[C:17]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([C:7]([O:6][CH2:4][CH3:5])=[O:8])[CH2:10][CH2:11]2)[CH:18]=[CH:19][CH:20]=1)=[O:24])#[N:3]
Reactant: CCOC(=O)N1CCC(COc2cccc(C(=O)OC)n2)CC1
Reactant: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(COc2cccc(C(=O)CC#N)n2)CC1

Procedure:
CH3CN addition to methyl 6-((1-(ethoxycarbonyl)piperidin-4-yl)methoxy)picolinate following the method described in Example 6 gave ethyl 4-(((6-(2-cyanoacetyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate in ethyl acetate solution which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18]>C(#N)C>[CH3:20][O:19][C:17]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)=[O:18]
Reactant: COC(=O)Cl
Reactant: O=C1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)N1CC2CC(=O)CC2C1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (0.559 g, 2.34 mmol) was dissolved in 20 mL of acetonitrile, and potassium carbonate (0.646 g, 4.68 mmol) and methyl chloroformate (0.22 mL, 2.8 mmol) were then added to the solution in an ice-water bath successively. Upon completion of the addition, the reaction mixture was allowed to increase to room temperature, and stilled overnight. The solvent was evaporated, and 50 mL of water was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine and 50 mL of water successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester 2a (0.25 g, yield 58.4%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cccc(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (157 mg, 0.39 mmol) (from example 30, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.115 mL, 0.39 mmol) dissolved in water (0.200 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.024 mL, 0.39 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (2.014 mL, 12.09 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (128 mg, 88%) as a white solid. MS m/z 371 (M+H)+
Reaction SMILES: [F:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[NH2:8][C:9]1[C:10]([Cl:18])=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:12][NH2:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[NH2:8][C:9]1[C:10]([Cl:18])=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:12][NH:13][C:3](=[O:4])[C:2]([CH3:7])([F:1])[CH3:6]
Reactant: CC(C)(F)C(=O)O
Reactant: NCc1ccc(Cl)c(N)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoroisobutyric acid (555 mg, 5.2 mmol), 3-amino-2,4-dichloro-benzylamine (1.00 g, 5.2 mmol), TBTU (1.85 g, 5.8 mmol), TEA (1.82 mL, 13 mmol) and THF is stirred at rt overnight. The mixture is concentrated, stirred with sat. aq NaHCO3-solution and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]([C:18]#[C:19][CH:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]2)[C:3]=1[OH:29].CN(CCN(C)C)C.C([Zn]CC)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]2[CH:18]=[C:19]([CH:20]3[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]3)[O:29][C:3]=12
Reactant: CCCCCC1CCc2c(C#CC3CCC(CCC)CC3)c(O)c(F)c(F)c2O1
Agent: CC[Zn]CC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCC1CCc2c(c(F)c(F)c3oc(C4CCC(CCC)CC4)cc23)O1

Procedure:
3.00 g (7.41 mmol) of 7,8-difluoro-2-pentyl-5-(4-propylcyclohexylethynyl)chroman-6-ol are initially introduced together with 0.11 ml (0.74 mmol) of TMEDA, and 4.1 ml (4.1 mmol) of diethylzinc (1 M soln. in heptane) are added to the mixture at 3° C. When the evolution of gas has subsided, 11 ml of toluene are added, and the batch is refluxed for 40 h. The solution is added to sat. ammonium chloride soln., and the mixture is extracted with toluene. The combined organic phases are washed with water and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, 1-chlorobutane:pentane=2:1). Further purification is carried out by repeated recrystallisation from ethanol at reduced temperature, giving 4,5-difluoro-7-pentyl-2-(4-propylcyclohexyl)-8,9-dihydro-7H-furo[3,2-f]chromene as a colourless solid having the phase sequence C 56° C. N 62° C. I (Δ∈=−6.8).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH2:9][CH2:8]1)=[O:6].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:21]([NH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:14]([Cl:20])=[CH:15][N:16]=[CH:17][C:18]=2[Cl:19])[CH2:11][CH2:12]1)=[O:6])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1)c1ccccc1
Yield: 36 %

Procedure:
To a solution of N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E13 (50 mg, 0.16 mmol), benzoic acid (23 mg, 0.19 mmol) and HATU (72 mg, 0.19 mmol) in DMF (1 mL) was added DIPEA (82 μL, 0.47 mmol). After 16 h the mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (50 mL), a saturated solution of citric acid (50 mL) water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a white solid (24 mg, 36%), m.p. 209-211° C.; umax (CHCl3)/cm−1 3029, 3006, 1656, 1523, 1385, 1228, 1017; m/z (ESI) C20H22Cl2N4NaO2 requires 443.1012, found [M+Na]+ 443.1013.
Reaction SMILES: CO[C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].CO[C:15]1[CH2:16][CH2:17][CH2:18][N:19]=1>C(N(CC)CC)C>[OH:7][C:6]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:18]2[N:19]([CH2:15][CH2:16][CH2:17]2)[C:3](=[O:4])[CH:5]=1
Reactant: COC1=NCCC1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: CCN(CC)CC
Product: COC(=O)c1c(O)cc(=O)n2c1CCC2
Reaction time: 72 h
Yield: 74.8 %

Procedure:
Triethylamine (0.5 mL, 3.6 mmol) was added to a mixture of dimethyl 1,3-acetonedicarboxylate (16.3 mL, 111 mmol) and 5-methoxy-3,4-dihydro-2H-pyrrole (10 g, 101 mmol), and the reaction stirred for 72 h. The white solid was collected by filtration, rinsed with ether, and dried under vacuum to give 15.8 g (75%) of compound 1a. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 5.54 (s, 1H), 3.94 (t, 2H, J=7.6 Hz), 3.80 (s, 3H), 3.36 (t, 2H, J=7.6 Hz), 2.02-2.11 (m, 2H). MS (ES) [m+H] calc'd for C10H11NO4, 210. found 210.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:41]=[O:42])(C)(C)C.C1C=CC=CC=1.[Pb](=O)=O>CO.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:42][CH3:41])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=[Pb]=O
Solvent: c1ccccc1
Solvent: CO
Solvent: ClCCCl
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCC(=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.19 g. (2.4 mmol.) of 7-amino-3-[1-(2-t-butoxycarbonylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g. (2.4 mmol.) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml. of dry benzene was refluxed for 4 hours under a Dean-Stark trap. The solution was evaporated under reduced pressure to leave a residue which was dissolved in 100 ml. of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide was added in portions over 20 minutes until the starting material was completely consumed. The mixture was filtered through Celite and the filter cake was washed with two 20 ml. portions of cold, 1,2-dichloroethane. The filtrate was treated with 25 ml. of methanol (distilled from magnesium) and the reaction mixture was allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product was shown by thin layer chromatography (ca. 3 hours). The mixture was evaporated to yield a brown semi-solid which was dissolved in 30 ml. of methanol and treated with 2.5 g. of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture was stirred at room temperature for 3 hours, then evaporated to give a solid residue which was partitioned between 100 ml. of ethyl acetate and 100 ml. of 20% sodium chloride solution. The organic phase was washed with three 100 ml. portions of 10% sodium chloride solution, two 100 ml. portions of water and 100 ml. of a saturated sodium chloride solution. The organic phase was dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-t-butoxycarbonylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:22])[CH:13]([CH:20]=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]>>[CH2:9]([O:11][C:12](=[O:22])[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][NH:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:10]
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Reactant: Cc1cccnc1N
Product: CCOC(=O)CC(=CNc1ncccc1C)C(=O)OCC
Reaction time: 8 h
Yield: 65 %

Procedure:
10.8 g. (0.1 mole) of 3-methyl-2-amino-pyridine are admixed with 20.2 g. (0.1 mole) of 2-formyl-succinic acid diethyl ester. The reaction mixture warms up to 40°-50° C. The mixture is stirred for an hour, whereupon it is allowed to stand at room temperature overnight. The α-(ethoxycarbonyl-methyl)-β-(3-methyl-2-pyridyl-amino)-acrylic acid ethyl ester thus obtained is recrystallized from 50% aqueous ethanol. Yield: 65-70%, m.p.: 62° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11]Br.[Mg]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4](=[O:5])[CH3:11]
Reactant: O=Cc1cc(F)ccc1F
Reactant: CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 2,5-difluorobenzaldehyde (24.6 g) in tetrahydrofuran (100 ml) was added dropwise to an ice-cooled solution (207 ml) of 0.92N magnesium methylbromide in tetrahydrofuran. The resulting solution was stirred at room temperature for 1.5 hours, and the organic phase was washed in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to subsequently distill off the solvents under reduced pressure. To the residue were added anhydrous dichloromethane (500 ml), sodium acetate (14.2 g) and pyridinium chlorochromate (55.94 g), prior to stirring at room temperature for 10 hours. To the resulting mixture was added an aqueous saturated sodium hydrogen carbonate solution, prior to extraction in ethyl acetate three times. The organic phase was washed in water and in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=85:15), to recover 2′,5′-difluoroacetophenone (22.73 g; yield of 84%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:32])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:33]I>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:32])[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:33])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][C:18]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC)cc3C)CC2)c(C)c1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-4-hydroxymethyloxazolidin-2-one (150 mg) described in Example 222 and methyl iodide (21 μL), (R)-3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-4-methoxymethyloxazolidin-2-one was obtained. The obtained compound was dissolved in a mixture of ethyl acetate and methanol, 4N hydrogen chloride/ethyl acetate was added, and the solvent was evaporated. To the obtained residue was added diisopropyl ether, and the mixture was filtered to give the title compound (140 mg).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with pyridine-3-yl-boronic acid to give the title compound as light yellow amorphous solid. MS: 484.3 (MH+).