Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([C@H:16]2[CH2:20][C@@H:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[NH:18][CH2:17]2)[C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[O:10])[CH2:4][CH2:3]1.[C:30]([N:37]1[CH2:41][C@@H:40]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@H:39]([C:49](O)=[O:50])[CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[C:30]([N:37]1[CH2:38][C@@H:39]([C:49]([N:18]2[CH2:17][C@@H:16]([N:8]([C@H:5]3[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4]3)[C:9]([C@@H:11]3[CH2:15][CH2:14][CH2:13][O:12]3)=[O:10])[CH2:20][C@H:19]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])=[O:50])[C@H:40]([C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH2:41]1)([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2)CC1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)cc2)CC1

Procedure:
(2S)—N-(cis-4-methylcyclohexyl)-N-{(3S,5S)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidin-3-yl}tetrahydrofuran-2-carboxamide (0.76 g, 1.87 mmol) obtained in Step E of Example 16 and (3S,4R)-1-BOC-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid obtained in Preparation 14 were reacted according to the same procedure as in the Step F of Example 1 to give the title compound (1.18 g, 88%).
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([OH:4])=[O:3].[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][O:18][C@@H:17]1Cl)(=[O:14])[CH3:13]>CN(C)C=O>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][O:18][C@H:17]1[S:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]([OH:4])=[O:3])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@@H]1Cl
Reactant: O=C(O)c1ccc(S)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C(=O)O)cc2)OC[C@H]1OC(C)=O
Reaction time: 8 h

Procedure:
To 19.8 g. of sodium salt of paracarboxythiophenol in dimethylformamide solution was added 29.5 g of tri-O-acetyl-α-D-xylosylchloride (4). After the resulting reaction mixture was allowed to stand overnight, the dimethylformamide was distilled away and the resulting residue was extracted with ethyl acetate. The obtained organic layer was washed with water, followed by drying over anhydrous magnesium sulfate. When the solvent was distilled away, white powdery paracarboxyphenyl 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside (10) was obtained. To 144 ml. of anhydrous methanol were added 12.0 g. of the obtained paracarboxyphenyl 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside (10) and 720 mg. of lithium hydroxide, and the mixture was allowed to stand overnight at room temperature. Then, the reaction mixture was diluted with water and was passed through an acidic resin in the usual way. The solution which has thus been passed was adjusted to pH 7.0 by adding sodium hydroxide. The so neutralized solution was concentrated to yield 8 g. of the desired para(sodiumoxycarbonyl)phenyl 1-thio-β-D-xylopyranoside in the state of white powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: BrC1CCCC1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C(c1cccc(Cl)c1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of diisopropylamine (1.80 mL, 12.9 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.4 M in hexanes, 5.4 mL, 12.9 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (1.0 g, 5.9 mmol) in tetrahydrofuran (6 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. Cyclopentyl bromide (0.76 mL, 7.1 mmol) was then added via syringe, and the resulting mixture was stirred at −78° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×15 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×15 mL), and the combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 40% EtOAc/hexane) to yield 1.08 g (79%) (3-chlorophenyl)(cyclopentyl)acetic acid as a clear oil. HRMS: calcd for C13H15ClO2−H, 237.06823; found (ESI, [M−H]−), 237.0682
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:14](O)[CH3:15].OS(O)(=O)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH:5][CH2:6][C:7]([O:9][CH2:14][CH3:15])=[O:8]
Reactant: O=C(O)CNc1ccc(Cl)c(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CNc1ccc(Cl)c(Cl)c1
Yield: 78 %

Procedure:
A solution of 27.5 g (0.125 mol) of 3,4-dichloroanilinoacetic acid, 190 ml of dichloroethane, 15 ml (0.2 mol) of ethanol and 1.5 ml of concentrated H2SO4 is heated for 4 hours under reflux. It is washed with water and with dilute sodium bicarbonate, dried and evaporated to dryness in vacuo. The ester is recrystallised from ethanol and is obtained in a yield of 78%. It melts at 103°-104° C.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])C=CN=[CH:2]1.NC[CH:33]1[CH2:35][CH2:34]1>>[CH:33]1([CH2:2][NH:1][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:12][CH:13]=2)[CH2:35][CH2:34]1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)NCC3CC3)cc2)o1
Yield: 44 %

Procedure:
As described for example 78c, imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) was converted using aminomethylcyclopropane instead of cyclopropylamine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 88 mg, 44%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(OC(=O)C)(=O)C.Cl[C:24](Cl)([F:29])[C:25]([O:27][CH3:28])=[O:26]>[Zn].[Cu]Cl.O1CCCC1>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=CC1(c2ccc(OC(F)F)cc2)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Yield: 28 %

Procedure:
The method of Example 1 was repeated using zinc powder (2.8 g), copper (I) chloride (0.42 g), molecular sieve 4A (2.8 g) tetrahydrofuran (50 ml), 1-(4-difluoromethoxyphenyl)-1-formylcyclopropane, acetic anhydride (1.5 ml) and methyl dichlorofluoroacetate (3.6 g) to yield the title compound (0.79 g, 28%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]3=[O:35])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:38][N:37]=[N:36][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]3=[O:35])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: C(O)[C:2]([NH2:7])([CH2:5]O)CO.Cl.[N+](C1C=CC(SSC2C=CC([N+]([O-])=O)=C(C=2)C(O)=O)=CC=1C(O)=O)([O-])=O.C(SCCN[C:43](=O)[CH2:44][CH2:45][NH:46][C:47](=[O:85])[C@H:48](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)C.NCCCCCN>>[C:47]([NH:46][CH2:45][CH2:44][CH2:43][CH2:5][CH2:2][NH2:7])(=[O:85])[CH3:48]
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: NCCCCCN
Agent: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Product: CC(=O)NCCCCCN

Procedure:
10 mM Tris-HCl (pH 7.8), 0.1 mM DTNB (5,5′-dithiobis-(2-nitrobenzoic acid)), 0.25 mM acetyl CoA, 5 mM cadaverine, enzyme solution
Reaction SMILES: [CH3:1]CCCC.[H-].[Na+].[CH3:8][N:9]([CH3:37])[S:10]([N:13]1[CH:17]=[C:16]([CH:18]([OH:29])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:15]=[C:14]1[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=[O:12])=[O:11].CI>C1COCC1>[CH3:8][N:9]([CH3:37])[S:10]([N:13]1[CH:17]=[C:16]([CH:18]([O:29][CH3:1])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:15]=[C:14]1[Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31])(=[O:11])=[O:12]
Reactant: CCCCC
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccnc3ccccc23)nc1[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To pentane washed sodium hydride (0.048 g, 1.2 mmol) in 5 ml of THF at 0° C., 2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (example 8, step A) (0.375 g, 0.811 mmol) was added slowly over a period of 5 minutes. After stirring at room temperature for 15 minutes, it was, again cooled to 0° C. and methyl iodide (0.1 ml, 1.62 mmol) was added neat. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure and partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 0.32 g (83%) of the product as a syrup.
Reaction SMILES: C[O-].[Na+].CO.[O:6]=[C:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[CH2:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH:39]=O)[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[O:6]=[C:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH2:9][C:8]1=[CH:39][CH:36]1[CH2:35][CH2:34][N:33]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:37]1
Reactant: O=C1CCc2cc(Nc3ncnc4c3CCC4)ccc21
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2cc(Nc3ncnc4c3CCC4)ccc21
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
Under ice cooling, 1.70 g of a 28% sodium methoxide·methanol solution was added to 1.96 g of 4-(1-oxoindan-5-yl)amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in tetrahydrofuran, and then 1.80 g of 1-benzyl-4-formylpiperidine was added dropwise thereto. After the mixture was stirred for 1.5 hours, a saturated saline solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography and then recrystallized from chloroform to obtain 1.35 g of the title compound as pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:42](Cl)(=[O:44])=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:44])=[O:43])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(=O)(=O)Cc3ccccc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, benzylsulfonyl chloride.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:34])[C@@H:23]([CH3:33])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:32])([CH3:31])[CH:28]=[CH:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[OH:36].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:34])[C@@H:23]([CH3:33])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:32])([CH3:31])[C@H:28]5[O:36][C@H:29]5[CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CC[C@H]2C(C)(C)[C@H]3O[C@H]3C[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 70.3 %

Procedure:
To a solution of Compound (41b) (40 mg, 0.08 mmol) in 4 ml of dichloromethane was added 15 mg (0.18 mmol) of sodium hydrogen carbonate under ice-cooling. To the resulting suspension was added 25 mg (0.116 mmol) of 80% m-chloroperbenzoic acid, and the mixture stirred for 18.5 hours at room temperature. To the reaction mixture were added 0.5N aqueous sodium thiosulfate solution and an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; chloroform:methanol=100:1) to give 28 mg (85%) of Compound (43b).
Reaction SMILES: [CH2:1]([O:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC3C=CC=CC=3)=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O1CCCC1>[Pd].CO>[CH2:1]([O:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCOC(C)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 76.6 %

Procedure:
1.03 g (2.8 mmol) of VII-15, 0.1 g of 5% Pd-C, 15 ml of tetrahydrofuran and 5 ml of methanol were mixed and the mixture was subjected to catalytic hydrogenation under normal pressure. When the hydrogen absorption reached 66 ml, the reaction was stopped and the catalyst was filtered away. The filtrate was concentrated and purified by column chromatography to obtain 0.76 g (98% yield) of (+)-4'-(1-octyloxyethyl)-4-biphenylcarboxylic acid. [α]D25 =+67.5° (c=1, CHCl3), m.p.=139°-140° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:24])([F:23])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21]C=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10].[Cl-].[Cl-].[Ca+2]>C(Cl)Cl>[F:24][C:8]([F:7])([F:23])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:1]([C:2]([Cl:4])=[O:3])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(N1CCC(c2ccccc2)CC1)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
To a flask containing A1Cl3 (534 mg, 4.0 mmol) under an N2 atmosphere was added anhydrous CH2Cl2 (0.1 M), and the drop wise addition of oxalyl chloride (523 μL, 6.0 mmol) over a 20 min period at 15° C. Next, a solution of 2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (17) (2.0 mmol) in anhydrous CH2Cl2 (0.1 M) was added drop-wise to the initial solution over a 45 min period at 15° C. When the reaction was complete as judged by TLC, ice was added to the solution in addition to CaCl2 (1.70 g). The product was extract into CH2Cl2, washed with brine and dried over anhydrous Na2SO4 before concentrating under reduced pressure to yield crude 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzoyl chloride (18). (b) To a stirred solution of 18 (2.0 mmol) and DIPEA (697 μL, 4.0 mmol) in EtOAc (0.1 M) was added 10% Pd/C. The flask was then evacuated and filled with H2 gas and allowed to stir for 30 min. After which time the reaction contents were filtered and concentrated under reduced pressure to give crude product which was purified by silica gel column chromatography (hexanes:EtOAc, 2:1) to furnish 19 (320 mg, 59% (yield over 2 steps)) δH (400 MHz, CDCl3) 1.69-1.81 (m, 2H, CH2), 1.98-2.06 (m, 2H, CH2), 2.83-2.97 (m, 2H, CH2), 3.27 (td, J=12.8 and 2.4 Hz, 1H, CH), 4.13-4.21 (m, 1H, CH), 4.70-4.76 (m, 1H, CH2), 7.37 (d, J=8.4 Hz, 2H, CH), 7.85 (d, J=8.4 Hz, 2H, CH), 9.99 (s, 1H, CHO); LRMS (ES+) calcd for [C14H14F3NO2+Na] 308.09 found 308.19 [M+Na].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C>CS(C)=O>[CH:2]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:1]
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)C[C@@H](C=O)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1-Methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-hydroxymethyl-3-methyl-butylcarbamoyl)-cyclohexyl]-amide (0.328 g, 0.82 mmol) was added to 6 mL of dry DMSO. Triethylamine (0.46 mL, 3.28 mmol) was added followed by sulfur trioxide pyridine complex (0.52 g, 3.28 mmol) and the mixture was stirred at room temperature for a half hour. The mixture was poured into 100 mL of ice water and extracted twice with ethyl acetate. The ethyl acetate extracts were rinsed twice with a 10% citric acid solution, twice with water and once with saturated aqueous sodium bicarbonate and dried over sodium sulfate. Concentration in vacuo gave 0.311 g (0.78 mmol) of 1-methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-formyl-3-methyl-butylcarbamoyl)-cyclohexyl]-amide as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:46][O:47][CH3:48])[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:46][O:47][CH3:48])[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 43.3 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1 g) in anisole (2.5 ml) was added trifluoroacetic acid (6 ml) under ice-cooling. The mixture was stirred for 40 minutes at ambient temperature, concentrated in vacuo to about a half volume and poured into diisopropyl ether (120 ml). The resulting precipitate was collected, dissolved in an aqueous solution (150 ml) of sodium bicarbonate (320 mg). The aqueous solution was washed with ethyl acetate and adjusted to pH 4-5 with 1N hydrochloric acid to give a precipitate. The precipitate was collected, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (330 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:25][N:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:27]1=[O:31]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: CN1CCNC1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3)CC2)nc1C
Yield: 90.6 %

Procedure:
Using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 120 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (369 mg) was obtained.
Reaction SMILES: [N:1]1[C:2]([CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:18]N1C(=O)CCC1=O.O>C(#N)C>[I:18][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CN(C)Cc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: COC(=O)CN(C)Cc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
0.107 g (0.459 mmol) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were dissolved in 4 ml of acetonitrile with magnetic stirring, to this solution were added 0.112 g (0.482 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h. The reaction mixture was treated with 10 ml of water and then extracted with 3×10 ml of ethyl acetate. The combined organic phases were washed with 20 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.093 g (yield=46%) of methyl 2-(((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)acetate were obtained as a yellow oil. LC-MS: m/z=360 (MH+); UV purity at 254 nm=82%. 1H NMR (300 MHz, DMSO) δ 8.30 (d, J=6.8 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.41-7.23 (m, 1H), 7.03 (t, J=6.7 Hz, 1H), 3.79 (s, 2H), 3.62 (s, 3H), 3.37 (s, 2H), 2.34 (s, 3H).