Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23]([OH:25])=O)[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=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.[NH2:72][C@@H:73]1[C:76](=[O:77])[NH:75][C@@H:74]1[CH2:78][N:79]1[CH2:83][C@@H:82]([CH2:84][NH:85][C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[O:81][C:80]1=[O:93]>CN(C=O)C.C(Cl)Cl.CN(C=O)C>[C:88]([O:87][C:86]([NH:85][CH2:84][C@H:82]1[O:81][C:80](=[O:93])[N:79]([CH2:78][C@@H:74]2[C@H:73]([NH:72][C:23](=[O:25])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:18][CH2:19]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[S:29][CH:30]=3)[C:76](=[O:77])[NH:75]2)[CH2:83]1)=[O:92])([CH3:91])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CN(C[C@H]2NC(=O)[C@H]2N)C(=O)O1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H]1CN(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)O1
Yield: 71.4 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (1.29 g, 2.28 mmol) and HATU (909 mg, 2.39 mmol) in DMF:DCM (3:1, 9.0 mL) at 0° C. was added DIPEA (1.0 mL, 5.72 mmol). After 15 min of stirring at 0° C. tert-butyl (((R)-3-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2-oxooxazolidin-5-yl)methyl)carbamate (715 mg, 2.28 mmol) was added as a solution in DMF:DCM (1:1, 9 mL) followed by a DMF (1.5 mL) wash. After 1.2 h at rt it was diluted with EtOAc and washed with LiCl (5% aq). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with LiCl (5% aq), NaHCO3 (aq satd), brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 5-90%) to afford the title compound (1.357 g, 72%) as a white solid. LCMS: Rt=1.04 min, m/z=834.4 (M+1) Method 2m_acidic.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([C:31]([CH3:34])([CH3:33])[CH3:32])[N:29]=[C:28]([CH:35]=O)[CH:27]=2)=[CH:22][CH:21]=1>>[C:31]([N:30]1[C:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)=[CH:27][C:28]([CH2:35][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:29]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Product: CC(C)(C)n1nc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1-c1ccc(Cl)cc1
Yield: 50.4 %

Procedure:
Compound 57 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)[S:10][CH:11]=2)=[CH:3][CH:2]=1.[ClH:24]>C(Cl)Cl.O1CCOCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([C@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)[S:10][CH:11]=2)=[CH:5][CH:6]=1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc(-c2ccncc2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc(-c2csc([C@H]3CCCN3)n2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 31-mg aliquot of crude product from Step 2 was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL) was added. The mixture was stirred at rt for 2 h and concentrated to leave (R)-4-(pyridin-4-yl)-2-(pyrrolidin-2-yl)thiazole as its HCl salt (35 mg). LC-MS Method 1 tR=0.40 min, m/z=232.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:23]([O:22][C:20]([NH:19][CH2:18][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[CH2:14]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc(OCc3ccccc3)cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1Cc2ccc(O)cc2C1
Yield: 105.9 %

Procedure:
3.53 g (10.0 mmol) of 5-benzyloxy-2-(t-butoxycarbonylaminomethyl)indan was dissolved in 100 ml of methanol and added with 0.3 g of 10% palladium on carbon, followed by stirring for 4 hours in the stream of hydrogen gas. The catalyst was removed by filtration, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 2.79 g of a colorless oil. Yield: 94%
Reaction SMILES: [C@@H:1]1([N:10]2[CH:15]=[C:14]3[CH:16]=[CH:17][C:18](=[O:20])[N:19]=[C:13]3[NH:12][C:11]2=[O:21])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(#N)C=C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C@@H:1]1([N:10]2[CH:15]=[C:14]3[CH:16]=[CH:17][C:18](=[O:20])[N:19]([CH3:22])[C:13]3=[N:12][C:11]2=[O:21])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1ccc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)[nH]c-2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C=CC#N
Solvent: C1COCCO1
Product: Cn1c(=O)ccc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)nc21
Yield: 396.6 %

Procedure:
A solution was prepared by dissolving 460 mg of 5-iododeoxyuridine (a) in 20 ml of absolute dioxane, to which 22 mg of palladium acetate, 34 mg of triphenylphosphine, 0.3 ml of triethylamine, and 0.13 ml of acrylonitrile were added and the mixture was made to undergo a reaction at 100° C. for 12 hours. After the removal of the precipitate by filtration, a hydrogen sulfide gas bubbled into the filtrate and the resulting precipitate was removed by filtration with Calite. The filtrate was concentrated under reduced pressure and the residue was refined by column chromatography on silica gel to obtain 159 mg of (E)-5-(2-cyanoethenyl)deoxyuridine (b).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.N1CCCCC1>C(O)C>[OH:9][C:8]1[CH:10]=[CH:11][C:3](/[CH:2]=[C:20](/[C:17]2[CH:18]=[N:19][C:14]([C:13]([F:24])([F:12])[F:23])=[CH:15][CH:16]=2)\[C:21]#[N:22])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: COc1cc(C=O)ccc1O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)ccc1O
Temperature: 25 °C

Procedure:
A suspension of vanillin (1.0 g, 6.57 mmol), 2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.222 g, 6.57 mmol) and piperidine (0.71 mL, 7.23 mmol) in absolute ethanol (10 mL) was stirred at reflux for forty-eight hours and then allowed to cool to room temperature. The resulting precipitate was filtered off, washed with water and dried. Recrystallisation from isopropanol afforded (Z)-3-(4-hydroxy-3-methoxyphenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile as white crystals, 0.904 g (43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6](=O)[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:25]([C:24]1[CH:28]=[C:20]([N:19]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=[C:6]2[C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:21]=[CH:22][C:23]=1[OH:29])([OH:27])=[O:26]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: COc1cccc(C(=O)CC2CCCCC2=O)c1
Solvent: CC(=O)O
Product: COc1cccc(-c2cc3c(n2-c2ccc(O)c(C(=O)O)c2)CCCC3)c1

Procedure:
A mixture of 24.6 g. (0.1 mole) of 2-(m-methoxyphenacyl)cyclohexanone, 15.3 g. (0.1 mole) of 5-aminosalicylic acid, and 65 ml. of glacial acetic acid was heated for 2 hours under reflux under nitrogen and cooled. The solid which separated was collected, washed with acetic acid and water, dried and recystallized from acetic acid to provide 23.4 g. (65%) of crystals, m.p. 175°-177°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14](=[O:22])[CH2:15]P(=O)([O-])OCC)[CH:2]([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:29]/[C:30](/[CH:37]=O)=[CH:31]\[C:32]([O:34][CH2:35][CH3:36])=[O:33].O>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14](=[O:22])[CH:15]=[CH:29][C:30]([CH3:37])=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOP(=O)([O-])CC(=O)c1cc(OC)ccc1OCC(C)C
Reactant: CCOC(=O)/C=C(\C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)C=CC(=O)c1cc(OC)ccc1OCC(C)C
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
3 g (8.4 mmol) of ethyl [2-(2-isobutoxy-5-methoxyphenyl)-2-oxoethyl]-phosphonate dissolved in 20 ml of tetrahydrofuran are added dropwise to a suspension of 1.41 g (12.6 mmol) of potassium tert-butoxide in 30 ml of tetrahydrofuran, heated to 50° C. Heating is continued for 20 minutes at 50° C., the mixture is then cooled to 0° C. and 1.8 g (12.6 mmol) of ethyl 3-methyl-4-oxocrotonate dissolved in 20 ml of tetrahydrofuran are added dropwise. The reaction mixture is then stirred for 72 hours at 25° C. Water is added and the resulting mixture is extracted with ether. After drying (Na2SO4), the solvent is evaporated off and the residue is purified by flash chromatography (dichloromethane) (2.58 g of yellow oil; 89%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:15](=[O:19])[C:16]([NH2:18])=[O:17])=[C:13]([CH2:20][CH3:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[OH-].[Na+].Cl>CO>[NH2:18][C:16](=[O:17])[C:15]([C:14]1[C:7]2[C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[N:11][CH:10]=[N:9][C:8]=2[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]=1[CH2:20][CH3:21])=[O:19]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)ncnc2n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
A mixture of 215 mg (0.542 mmol) of [[5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 3 mL of methanol were treated with 0.406 mL of 2 M sodium hydroxide and heated to 55° C. for 3 hours. The reaction was cooled to ambient temperature, 1.0 mL of 1 M HCl was added and the resulting slurry was concentrated under vacuum. The crude solid was combined with 20 mL of water and stirred for 20 minutes. The precipitate was collected by filtration, washed with 20 mL of water, and dried in vacuo (40° C., 10 torr) to provide 190 mg (91.7%) of [[5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid. as a white solid. nmr (500 MHz, dmso-d6) δ1.01 (t, J=7.4 Hz, 3H), 2.95 (q, J=7.4 Hz, 2H), 4.93 (s, 2H), 5.60 (s, 2H), 7.13 (d, J=7.2 Hz, 2H), 7.31 (m, 3H), 7.56 (s, 1H), 7.98 (s, 1H), 8.46 (s, 1H) 12.99 (bs, 1H)
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([C@@H:7](O)[CH2:8][C@@H:9]1[CH2:11][O:10]1)C=C.O.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH2:8]([C@H:9]1[O:10][CH2:11][O:17][C@@H:14]([CH2:16][C:1]#[N:2])[CH2:15]1)[CH:7]=[CH2:4]
Reactant: C=CC[C@@H](O)C[C@@H]1CO1
Reactant: CC(C)O
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: C=CC[C@@H]1C[C@H](CC#N)OCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium cyanide, 1.3 g (20 mmol), is added to a room temperature solution of (R*,R*)-α-2-propenyloxiraneethanol, 2.56 g (20 mmol), in 25 mL of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated, and partitioned between ethyl acetate and brine. The aqueous layer is extracted 2× with ethyl acetate and the combined ethyl acetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 mL of dimethoxymethane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuo provides 1.20 g of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.
Reaction SMILES: Br.[NH2:2][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[C:4](O)=O.[CH2:25]=[O:26].C(NCC)C.[OH-:32].[Na+]>C(OCC)(=O)C>[NH2:2][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[CH2:4][C:25]([OH:32])=[O:26]
Reactant: C=O
Reactant: [OH-]
Reactant: NC(CCCCOc1ccc(CC2CCCCC2)cc1)C(=O)O
Agent: Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: NC(CCCCOc1ccc(Cc2ccccc2)cc1)CC(=O)O

Procedure:
The acrylic acids 17 are prepared via the diacids 16 obtained by saponification in 6N sodium hydroxide under reflux, and then a Mannich reaction in the presence of paraformaldehyde, diethylamine in ethyl acetate under reflux.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]2=[O:23].FOBOF.[CH2:29]([N:36]1[CH2:41][CH:40]2[CH2:42][CH:37]1[CH2:38][NH:39]2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>CS(C)=O.CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:39]1[CH2:38][CH:37]3[CH2:42][CH:40]1[CH2:41][N:36]3[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[N:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]2=[O:23]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: FOBOF
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CC4CC3CN4Cc3ccccc3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a solution of 1.5 g (4 m Mol) of the mixed anhydride of 6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with difluoroboronic acid in 10 ml of dimethylsulfoxide was added 0.9 g (4.78 m Mol) 2-benzyl-2.5-diazabicyclo(2.2.1)heptane and 0.4 g (4 m Mol) of triethylamine. After stirring for 4 hrs at room temperature, 150 ml of ether was added and the crystals that formed were collected by filtration. The residue was heated in a mixture of 60 ml dioxane and 90 ml 1.5N NaOH and heated at 100° C. for 1 hr. The hot solution was filtered to removed non-dissolved material. The solution was neutralized with conc HCl and the resultant crystals collected, washed with water and left to dry in the air. After recrystallization from DMF, 1.23 g (63%) of the product was obtained, mp 275° -280° dec.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:11]2[CH2:10][CH2:9][C:8]3[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Product: CN1CCN(C2CCc3ccc([N+](=O)[O-])cc3CC2)CC1

Procedure:
1-Methyl-4-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-piperazine was prepared from 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one and 1-methyl piperazine in a similar manner to Example 178a. Product was isolated as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.ClC[C:33]([N:35]=C=O)=[O:34].C(=O)(O)[O-].[Na+]>O1CCCC1.CO.[Zn]>[C:33]([O:1][CH2:2][C:3]1[N:4]([CH2:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1)(=[O:34])[NH2:35]
Reactant: CC(C)c1nc(CO)n(Cc2cnc3ccccc3c2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nc(COC(N)=O)n(Cc2cnc3ccccc3c2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 77.8 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 223 mg (0.50 mmol)of 2-hydroxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (109), followed by dropwise addition of 72 mg (0.60 mmol)of chloroacetylisocyanate with stirring at 0° C., and the mixture was stirred at room temperature for 30 minutes. After the reaction completion, the mixture was worked up. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, extracted with methylene chloride, the extract was washed with water and dried. The-solvent was distilled off under reduced pressure, and 2-chloroacetyl-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (110)suited to the next step of the reaction was obtained. mp 167-170° C. The crystals were dissolved in 20 ml of aqueous methanol, 40 mg of Zn powder was added, and the mixture was stirred at room temperature for 5 hours. After the reaction completion, the mixture was worked up. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the insoluble material was removed by filtration under reduced pressure through Celite. The filtrate was concentrated, extracted with methylene chloride, the extract was washed with water and dried, and the solvent was distilled off. The residual crystals were washed with ethyl acetate and ether to give 195 mg of Compound I-128 (yield 78%). mp 214-216° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1(O)[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:6]([C:17]([O:19][CH3:20])=[O:18])[C:5]([C:22]([F:25])([F:24])[F:23])([OH:21])[O:4]1.[NH3:29]>O1CCCC1>[F:1][C:2]([F:27])([F:28])[C:3](=[O:4])[CH2:8][C:9]([O:11][CH3:12])=[O:10].[F:1][C:2]([F:28])([F:27])[C:3]1([OH:4])[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:6]([C:17]([O:19][CH3:20])=[O:18])[C:5]([C:22]([F:25])([F:24])[F:23])([OH:21])[NH:29]1
Reactant: N
Reactant: COC(=O)C1C(CC(C)C)C(C(=O)OC)C(O)(C(F)(F)F)OC1(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)C1C(CC(C)C)C(C(=O)OC)C(O)(C(F)(F)F)NC1(O)C(F)(F)F
Product: COC(=O)CC(=O)C(F)(F)F

Procedure:
To a solution of 344 g (0.920 mole) crude product from Step 1 in 500 ml of tetrahydrofuran (THF) is passed 58 g (3.41 mole) of gaseous ammonia for 3 hours. The reaction mixture is concentrated and the residue (332 g) is recrystallized from hexane-ether to give 53.7 g (13% yield from methyl trifluoroacetoacetate) of the desired product as a white solid, m.p. 102°-106° C.
Reaction SMILES: [OH-].[Na+].CC(O[CH2:7][C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12]([NH2:15])[C:13](=[O:14])[N:10]2[C:9]=1[C:18]([OH:20])=[O:19])=O.[Na].[Na].[C:23]([CH2:26][C:27]1[N:31]=[C:30]([SH:32])[NH:29][N:28]=1)([OH:25])=[O:24].C(CC1N=C(S)NN=1)(O)=O>C(O)C>[NH2:15][CH:12]1[C:13](=[O:14])[N:10]2[C:9]([C:18]([OH:20])=[O:19])=[C:8]([CH2:7][S:32][C:30]3[N:31]=[C:27]([CH2:26][C:23]([OH:25])=[O:24])[NH:28][N:29]=3)[CH2:17][S:16][C@H:11]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)Cc1n[nH]c(S)n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3n[nH]c(CC(=O)O)n3)CS[C@H]12

Procedure:
10% Aqueous sodium hydroxide (8 ml.) was added to a suspension of 5.4 g. (20 mmol.) of 7-aminocephalosporanic acid and 5.5 g. (27 mmol.) of 3-carboxymethyl-1,2,4-triazole-5-thiol disodium salt, prepared by addition of a sodium hydroxide solution to a solution of 3-carboxymethyl-1,2,4-triazole-5-thiol in aqueous ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH-].[K+].[CH2:14](Br)[CH3:15]>C(O)C.O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH3:15]
Reactant: CCBr
Reactant: COc1ccc(C=O)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C=O)ccc1OC
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 100 g of 3-hydroxy-4-methoxybenzaldehyde in 200 ml ethanol was added to solution of 44 g KOH in 44 ml H2O. The mixture dissolved upon heating to reflux and 56 ml ethyl bromide was then added slowly. A yellow solid began to precipitate after 15 min and heating of the mixture at reflux was continued overnight. Excess ethyl bromide and solvent were removed in vacuo and the residue was distributed between water and CHCl3. The CHCl3 layer was dried and evaporated to give a pale yellow oil which crystallized from ethanol to give 112 g (93%) of 3-ethoxy-4-methoxybenzaldehyde, mp 49.5°-50.5°(Lit.12 mp 50° -51°).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[C:10](CCCl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=O)C.FC1C=CC(C(C2C=CC(F)=CC=2)=C2CCNCC2)=CC=1>>[CH3:13][C:11]1[S:12][C:6]2[CH2:5][NH:4][CH2:9][CH2:8][C:7]=2[CH:10]=1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Agent: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Product: Cc1cc2c(s1)CNCC2

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.6 g of 4-(bis(4-fluorophenyl)-methylene)piperidine to give 0.5 g of 6-acetyl-3-(2-(4-bis(4-fluorophenyl)methylene)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 209°-211° C. as axalate thereof.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([Br:21])=[C:16]([CH3:22])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([O:13][CH2:12][CH:10]2[CH2:11][NH:8][CH2:9]2)=[CH:15][C:16]=1[CH3:22]
Reactant: Cc1cc(OCC2CN(C(=O)OC(C)(C)C)C2)cc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC2CNC2)cc(C)c1Br
Temperature: 0 °C
Yield: 76.1 %

Procedure:
3-(4-Bromo-3,5-dimethyl-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (3.9 g, 6.32 mmol) is dissolved in 30 mL of dichloromethane and stirred at 0° C. Trifluoroacetic acid (1.45 g, 12.64 mmol) is added and the reaction mixture is stirred at 0° C. for 6 h. 15 mL of saturated aqueous NaHCO3 is added, the organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound (Yield: 1.30 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:14])[CH2:9][CH:10](C)[CH:11]=[CH2:12])[CH2:3]1.CC1(C)CC=C[C:19]([C:23](=[O:29])CC(C)C=C)=C1>>[CH3:15][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2([O:14][CH2:19][CH2:23][O:29]2)[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:3]1
Reactant: C=CC(C)CC(=O)C1=CC=CC(C)(C)C1
Reactant: C=CC(C)CC(=O)C1=CC(C)(C)CC=C1
Product: C=CCCC1(C2=CCCC(C)(C)C2)OCCO1

Procedure:
##STR8## 1-(3,3-Dimethyl-cyclohexa-4,6-dien-1-yl)-3-methyl-pent-4-en-1-one and 1-(3,3-dimethyl-cyclohexa-1,5-dien-1-yl)-3-methyl-pent-4-en-1-one were thus prepared.