Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])#[N:2].[CH3:15][N:16]([CH3:27])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.N1CCCCC1>N1C=CC=CC=1>[C:1]([C:3](=[CH:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([N:16]([CH3:27])[CH3:15])[CH:18]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])#[N:2]
Reactant: N#CCC(=O)NCCCCCC(=O)O
Reactant: COc1ccc(C=O)cc1N(C)C
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=C(C#N)C(=O)NCCCCCC(=O)O)cc1N(C)C
Reaction time: 20 h

Procedure:
3.96 g (20 mMol 6-(2-cyan-acetylamino)hexanoic acid was dissolved in 27 ml pyridine. 3.64 g (20 mMol) 3-dimethylamino-4-methoxybenzaldehyde and 0.6 mL piperidine were added to the solution and the reaction mixture was stirred for 20 hours. After evaporation of the reaction mixture the residue was solved in 150 ml ethyl acetate and 150 ml water and the pH was adjusted with pure acetic acid to 4.2. The aqueous phase was extracted with ethyl acetate. The collected ethyl acetate phases were washed with NaCl-Solution, dried and evaporated. The residue was chromatographed on SiO2 with ethyl acetate under low pressure. The product was crystallized from little ethyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1
Yield: 93.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 3-dimethylaminophenol (0.82 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (1.72 g), sodium hydride (55 wt. %, 0.26 g) and anhydrous N,N-dimethylformamide (50 ml) and the reaction mixture was purified to give the title compound (2.17 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.[CH3:26][O:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([O-])=O.[NH2:35][C:36]1[CH:37]=[C:38]([C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[C:45]#[N:46])[CH:39]=[CH:40][C:41]=1[NH2:42]>CN(C=O)C>[C:45]([C:44]1[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=1[C:38]1[CH:39]=[CH:40][C:41]2[NH:42][C:31]([CH2:30][CH2:29][C:28]([O:27][CH3:26])=[O:34])=[N:35][C:36]=2[CH:37]=1)#[N:46]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
Dicyclohexylcarbodiimide (0.11 moles, 2.26 g), hydroxybenzotriazole (0.011 moles, 1.48 g) and monomethylsuccinate (0.011 moles, 1.45 g) were dissolved in 75 ml of DMF. 2-(3,4-Diaminophenyl)benzonitrile (0.01 moles, 2.0 g) was added. The reaction was stirred at room temperature for 48 hours The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed thoroughly with brine. The ethyl acetate solution was dried over sodium sulfate and filtered. The solvent was removed. The residue was purified by HPLC on silica gel eluted with ethyl acetate. The material was dissolved in 400 ml toluene with 5 mg of p-toluenesulfonic acid and refluxed for 8 hours. The solvent was removed. The residue was purified by HPLC on silica gel eluted with ethyl acetate to yield 2.3 g of methyl 3-[5-(2-cyanophenyl)-1H-benzimidazole-2-yl]propionate. (MS).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([NH:41]O)=[NH:40])[CH:37]=2)[N:32]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]=1>CN(C=O)C>[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]3[N:40]=[C:5]([C:4]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH3:14])=[C:2]([Cl:1])[CH:3]=4)[O:7][N:41]=3)[CH:37]=2)[N:32]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]=1
Reactant: CCCOc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCOc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)OCC)no2)cc1Cl
Temperature: 80 °C

Procedure:
3-Chloro-4-(propyloxy)benzoic acid (D100) (150 mg, 0.70 mmol) stirring in DMF was treated with EDC (146 mg, 0.76 mmol) followed by HOBt (104 mg, 0.76 mmol). The resultant solution was stirred and ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (216 mg, 0.70 mmol) added. Heated mixture at 80° C. until reaction was complete. Work up obtained the title compound as 160 mg of pale cream solid. δH (400 MHz, d6-DMSO) 1.03 (3H, t), 1.10 (3H, t), 1.77-1.86 (2H, m), 2.90 (2H, t), 4.05 (2H, q), 4.18 (2H, t), 4.49 (2H, t), 7.40 (1H, d), 7.74 (1H, s), 7.81 (1H, d), 7.91 (1H, dd), 8.15 (1H, dd), 8.22-8.23 (2H, m). MS (ES) C24H2335Cl2N3O4 requires 487; found 488 (MH+).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=O)[CH2:12]2)=[CH:7][CH:6]=1>CCOCC.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: CN
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCCCC
Product: CNC1=Cc2cc(OC)ccc2CC1
Reaction time: 0.5 h

Procedure:
This compound was prepared according to the procedure described by Evans, et al., J. Org. Chem. 35, 4122 (1970) as follows. Into a dry, nitrogen purged, 500 ml, 3-neck flask fitted with mechanical stirrer, dropping funnel and nitrogen inlet tube was added a solution of 14.3 g (460 mmole) methylamine in anhydrous ether (100 ml) and a solution of 20.0 g (113.5 mmole) 7-methoxy-2-tetralone in same solvent (100 ml) and the solution was placed under a slow stream of nitrogen and cooled to -18° (ice-methanol). A solution of 11.56 g (61 mmole) titanium tetrachloride in pentane (50 ml) was added dropwise with stirring over 30 min period. After the addition, the reaction mixture was stirred at room temperature for 1 hr and then fast filtered. The solid residue was washed with ether (50 ml) and the filtrate and washings were combined. Removal of the solvent in vacuo gave 20.6 g (96%) of XIId as an oxygen-sensitive oil which crystallized on standing; IR (neat), 3430 (NH), 1630 cm-1 (C=C--N); NMR δ, 2.15 (m, 2, benzylic), 2.55 (m, 2, allylic), 2.70 (s, 3, NCH3), 3.15 (broad, NH), 3.70 (s, 3, OCH3), 5.13 (s, 1, C-1H), 6.25-6.90 (m, 3, ArH).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]2[N:19]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:18]=[CH:17][CH:16]=2)=[C:11]([CH3:28])[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:9]1=[O:39].C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48].C(=O)([O-])O.[Na+]>ClCCl>[C:24]([C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:15]([C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:47](=[O:49])[CH3:48])[C:9](=[O:39])[N:10]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=4)[C:11]=3[CH3:28])=[CH:16][CH:17]=[N:18]2)=[CH:27][CH:26]=1)#[N:25]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCCCCN)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCCn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
To a solution of 4-[5-[3-(5-aminopentyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile hydrochloride (prepared in Example 85) (6.4 mg) and triethylamine (10 μl) in dichloromethane (1.0 ml) was added acetyl chloride (0.7 mg) in ice-cooling and the resulting mixture was stirred for five minutes and stirred at room temperature for thirty minutes. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution (10 ml) and the resulting mixture was extracted with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-[5-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentyl]acetamide (3.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][CH2:10][CH2:11][OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][O-:17].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([O:17][CH3:16])[CH:5]=[C:4]([NH:9][CH2:10][CH2:11][OH:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: C[O-]
Reactant: Nc1cc(Cl)cc(NCCO)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])c(NCCO)c1

Procedure:
0.172 mole (40 g) of 2-amino-6-(β-hydroxyethyl)amino-4-chloronitrobenzene in 160 ml of a 30% solution of sodium methylate in methanol was heated for 21/2 hours over a boiling water bath. The desired product precipitated out after dilution with 350 ml of ice water. After recrystallizing from boiling isopropanol to eliminate an insoluble impurity, the desired product melted at 148° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[CH2:14][CH2:15][CH3:16])[CH:2]=C.[O:17]=[O+][O-].CSC>CO>[O:11]=[C:8]1[C:7]2[CH:12]=[CH:13][C:4]([CH2:1][CH:2]=[O:17])=[C:5]([CH2:14][CH2:15][CH3:16])[C:6]=2[CH2:10][O:9]1
Reactant: C=CCc1ccc2c(c1CCC)COC2=O
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: CCCc1c(CC=O)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
To the flask charged with 5-allyl-4-propyl-2-benzofuran-1(3H)-one (60 mg) was added methanol (10 mL). The solution was chilled to −78° C. before ozone was bubbled through. Ozone was stopped when the solution turned light blue. Excess ozone was removed by bubbling nitrogen through the solution, which was followed by addition of dimethyl sulfide (170 mg, 2.8 mmol). The mixture was allowed to warm to RT. The desired product, (1-oxo-4-propyl-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde, was purified by silica gel chromatography.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=O.[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][N:3]2[C:4]3[C:9](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cccc2c1ccc(=O)n2CC=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1 mL of a chloroform solution containing methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate, 26.5 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 6.9 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 24.2 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 9.3 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26](I)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:26][CH3:27])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC(C(=O)OC)c1ccc(C(C)(C)C)cc1
Yield: 115.2 %

Procedure:
4 g (19 mmol) of methyl 4-tert-butylphenylacetate, 19.5 mL (1.0 M, 19 mmol) of lithium bis(trimethylsilyl)amide and 3.12 g (20 mmol) of ethyl iodide were reacted as described in Preparation 11 to yield 5.13 g of a brown oil. Chromatography, eluting with a gradient solvent of hexanes to hexanes/ethyl acetate 19:1 gave the title compound 2.35 g (53%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN(C)C(=O)N1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C(=Nc1ccccc1N1CCOCC1)N1CCOCC1

Procedure:
Reaction of 4-dimethylcarbamoylmorpholine (3.8 g) in benzene (25 ml) with 4-(2-aminophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride (2.1 ml) for 40 hours at 80°-85° C. gave N,N-dimethyl-N'-(2-morpholinophenyl)morpholine-4-carboxamidine (m.p. 126°-128° C.) which was recrystallised from hexane.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]([NH:8][C:9](=S)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:41][OH:42]>O>[Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)[C:5]([NH:8][C:9](=[N:41][OH:42])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1c(Br)cnc(NC(=S)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(Br)cnc(NC(Cc2ccc(S(C)(=O)=O)cc2)=NO)c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of N-[5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-2-(4-methanesulfonyl-phenyl)-thioacetamide (Int. 11, 190 mg, 0.35 mmol) in IMS (3 mL) was added triethylamine (63 μL, 0.45 mmol) followed by hydroxylamine hydrochloride (29 mg, 0.42 mmol). After stirring at room temperature for 30 mins, water (10 mL) was added and the resultant orange solid was collected by filtration then dried at 50° C. under vacuum to give the title compound (165 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[CH3:21][S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:33][CH:32]=2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: CS(=O)(=O)c1ccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 4-(methylsulphonyl)benzoic acid (0.063 g). Title compound obtained as white solid (0.038 g).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1([CH3:33])[C@H:7](/[CH:8]=[C:9](/[F:13])\[C:10](=[O:12])[OH:11])[C@H:6]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]>C(Cl)Cl.C(O)(=O)C>[CH3:4][C:5]1([CH3:33])[C@H:7](/[CH:8]=[C:9](/[F:13])\[C:10](=[O:11])[O:12][CH3:3])[C@H:6]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: CC1(C)[C@H](/C=C(/F)C(=O)O)[C@H]1C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A slight excess of diazomethane in methylene chloride solution was added at 5° to 10° C. to a solution of 860 mg of the product of Step A in 2 ml of methylene chloride and the mixture was stirred at 5° C. for 15 minutes and at room temperature for 30 minutes. A few drops of acetic acid were added to the mixture which was then evaporated to dryness to obtain 950 mg of an oil residue. The latter was chromatographed over silica gel and was eluted with an 85-15 hexane-ethyl acetate mixture to obtain 700 mg of (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-31°±2.5° (c=0.25% in chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15]2)=[O:13])=[N:8][CH:7]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[Cl:31][C:27]1[CH:26]=[C:25]2[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:9]3[S:10][C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])=[CH:7][N:8]=3)[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Reactant: O=C(Cl)C1CC1
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCNC(=O)C3CC3)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that methyl 1-((5-((3-aminopropyl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that cyclopropanecarbonyl chloride was used instead of acetyl chloride.
Reaction SMILES: C(O)C.O.NN.[CH2:7]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:10]1=2)[CH3:8]>[Pd].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:10]2[N:9]([CH2:7][CH3:8])[C:15](=[O:16])[CH2:14][CH2:13][C:12]([CH3:17])([CH3:18])[C:11]=2[CH:19]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Yield: 73 %

Procedure:
Added 30 mL of ethanol, 10% Palladium on activated carbon, 50% wet with water for safety (273 mg), and hydrazine monohydrate (400 ul) to 1-Ethyl-5,5-dimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (537 mg, 2.047 mmol). Heated reaction to 60° C. for 24 hours. Filtered reaction through Celite, and concentrated under reduced pressure. Purified with normal phase silica gel chromatography eluting with 40% to 60% ethyl acetate in hexane to obtain a yellow sticky solid, 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (347 mg, 73%). LCMS: m/z=233.07 (M+H+), 1H NMR (400 MHz, DMSO-d6) δ 6.98 (d, 1H, J=8.9 Hz), 6.59 (d, 1H, J=1.8 Hz), 6.48 (dd, 1H, J=8.3, 1.5 Hz), 5.08 (s, 2H), 3.58 (m, 2H), 1.96 (m, 4H), 1.17 (m, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([Br:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[Na].[C:17](OCC)(=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Br:14][C:6]1[C:5]2[O:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:2][C:1](=[O:3])[C:4]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc2c(c(Br)c1O)CCCC2
Agent: [Na]
Product: CCOC(=O)c1cc(=O)c2cc3c(c(Br)c2o1)CCCC3
Yield: 72.3 %

Procedure:
The product of step (a) (5.3 g) was treated with sodium (2.3 g) and diethyl oxalate (7.3 g) under the conditions of Example 1(d) to give the title ester (5.0 g; 72%), mp 130°-132°.
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:24]([O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[C:19]([Cl:23])[CH2:20][S:21](=O)[C@H:16]23)=[O:13])[N:10]=1.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:24]([O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[C:19]([Cl:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS(=O)[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Reaction time: 0.83 h
Yield: 27.1 %

Procedure:
Phosphorus trichloride (210 mg.) was added to a solution of n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate-1-oxide (syn-isomer: 570 mg.) in dry dimethylformamide (10 ml.) at -30° C., and stirred at -20° to -30° C. for 50 minutes. 10% Aqueous solution (50 ml.) of sodium chloride was added to the resultant solution, adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue (560 mg.) was purified with column chromatography on silica gel (20 g.) (eluent:ethyl acetate), and the resultant residue (180 mg.) was pulverized with n-hexane (10 ml.) and diethyl ether (5 ml.) to give n-hexanoyloxymethyl 7-[2-(2-amino-4 -thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn-isomer: 150 mg.)
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[OH:7][C@@:6]1([C:19]([F:21])([F:20])[F:18])[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:2]1[CH3:1]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution (10 mL) of benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (1.0 g) in THF were added trifluoromethyltrimethylsilane (0.95 mL) and 1 mol/L tetrabutylammonium fluoride—THF solution (0.43 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. A 1 mol/L tetrabutylammonium fluoride—THF solution (8.56 mL) was added to the reaction mixture, and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as colorless oil (yield: 1.06 g, yield: 81%).