Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH:29]=O)=[O:8].[CH2:35]([NH2:38])[CH2:36][NH2:37].C1C(=O)N(Br)C(=O)C1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]1[NH:37][CH2:36][CH2:35][N:38]=1)=[O:8]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C=O)n(Cc3ccccn3)c2c1
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C3=NCCN3)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105, 27 mg, 0.058 mmol) in CH2Cl2 (2 ml) was added 1,2-ethylene-diamine (5 μl, 0.070 mmol). The reaction was stirred at room temperature for 1 h and NBS (13 mg, 0.070 mmol) was added. The reaction was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (9:1 EtOAc-Et3N, then 8:2:1 EtOAc-MeOH-Et3N) followed by PTLC eluted with EtOAc to yield the title compound.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C=O)C.[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[N+:17]=[N-:18])[CH3:13].CCOCC>C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15](=[O:19])[C:16](=[N+:17]=[N-:18])[CH:2]=[O:3])[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C=O)=[N+]=[N-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 13.6 %

Procedure:
Oxalyl chloride (4.7 g, 30.1 mL, 37.0 mmol) was added to a cold (0-4° C.) solution of DMF (2.25 g, 2.4 mL, 30.8 mmol) in CHCl3 (20 mL) and stirring was continued for 10 minutes. The reaction mixture was heated at 40° C. for 10 minutes and cooled to −10° C. Diazoacetic acid ethyl ester (3.5 g, 3.5 mL, 30.6 mmol) was then added and stirred at room temperature for 1 hr. The reaction mixture was concentrated ether was then added, the precipite was collected and dissolved in 10% aq Hac (10 mL) and stirring was continued for 1 hr. The reaction mixture was extracted with ether, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 590 mg (21% Yield) of 2-diazo-3-oxo-propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 9.7 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H). Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HOAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. The reaction mixture was concentrated and cold water was then added, the solid was collected to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H). LiOH.H2O (80 mg, 1.9 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (130 mg, 0.6 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure. Cold water was then added and it was acidified with 10% aqueous HCl, the solid was collected to afford 40 mg (35.4% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid. 1H NMR (300 MHz, DMSO-d6): δ 13.4 (bs, 1H), 9.4 (s, 1H), 8.0 (d, 2H), 7.7 (t, 2H), 7.6 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:17].ClN1C2C=CC(C(OC)=O)=CC=2CCC(Cl)(Cl)C1=O.CC([O-])=O.[Na+]>[Pd].C(O)(=O)C>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:17]
Reactant: COC(=O)c1ccc2c(c1)CCC(Cl)(Cl)C(=O)N2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: COC(=O)c1ccc2c(c1)CCC(Cl)(Cl)C(=O)N2Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCC(Cl)C(=O)N2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 10% Pd/C mixture (0.9 g) was added to a mixture of 3,3-dichloro-7-carbomethoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 3 and 1,3,3-trichloro-7-carbomethoxy-2,3,4,5-tetrahydro-1-benzazepin-2-one (9.34 g), NaOAc (5.51 g, 40.5 mmol), and glacial acetic acid (25 mL). After stirring under a hydrogen atmosphere (balloon) at RT for 3.5 h and at 60° C. for an additional 30 min, the reaction mixture was filtered (celite) and concentrated. The resulting material was partitioned between saturated NaHSO4 (aqueous) and CH2Cl2. The organic layer was removed and the aqueous layer was extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4) and concentrated to give 4 (3.6 g). LRMS (ES), [M+H] m/z=254.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15][O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(Br)cc1C=O
Yield: 904.3 %

Procedure:
5-Bromo-2-hydroxy-benzaldehyde (4 g, 2 mmol), 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (5.46 g, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 150° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound 5.7 g.
Reaction SMILES: [O:1]=[C:2]1[NH:5][C@@H:4]([CH2:6]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:3]1[NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N-:29]=[N+:30]=[N-:31].[Na+].CN(C)C=O.C(OCC)(=O)C>C(Cl)Cl>[N:29]([CH2:6][C@H:4]1[C@@H:3]([NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:2](=[O:1])[NH:5]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)COc2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Reaction time: 24 h

Procedure:
A mixture containing 1.131 g (2.8 mmole) of cis-4 -oxo-3-phenoxyacetylamino-2-p-toluenesulfonyloxymethyl-azetidine, 0.961 g (14.8 mmole) of sodium azide and 25 ml of anhydrous N,N-dimethylformamide was heated under argon at 40° for 6 hours then at ambient temperature for 24 hours. The reaction mixture was poured into ethyl acetate and was washed with water. The combined aqueous washes were extracted once with ethyl acetate and the ethyl acetate fractions were combined and extracted with brine. After drying the ethyl acetate solution (MgSO4) and filtering, the solvent was removed in vacuo to afford to a yellow semi-crystalline residue. This residue was slurried in methylene dichloride and chromatographed on 25 g of silica gel (70-230 mesh). The 1:1 ethyl acetate:methylene dichloride fractions afforded the title compound; tlc: ethyl acetate, silica gel GF, Rf = 0.38; mp 142°-143°(dec) (ethyl acetate-hexane).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH2:13][CH2:14][CH3:15])[CH:5]=1.[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8](=[NH:9])[O:18][CH2:16][CH3:17])=[C:6]([O:12][CH2:13][CH2:14][CH3:15])[CH:5]=1
Reactant: CCO
Reactant: CCCOc1cc(OC)ccc1C#N
Agent: Cl
Product: CCCOc1cc(OC)ccc1C(=N)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride gas was passed through a solution of 4-methoxy-2-propoxy-benzonitrile (280 mg, 1.464 mmol) in anhydrous ethanol (20 mL) at 0° C. After 1 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a stopper. After stirring at room temperature for 2 d, the reaction vessel was cooled to 0° C. and the stopper was removed. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford crude ethyl 4-methoxy-2-propoxy-benzimidate hydrochloride. It was dissolved in ethanol (10 mL), and meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (412 mg, 1.464 mmol) and triethylamine (308 μL, 2.194 mmol) were added. The reaction mixture was heated at reflux for 4 h. The solvent was removed and the residue was taken up in methylene chloride (2 mL) and sodium bicarbonate solution (2 mL). The product was extracted with methylene chloride (2×20 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 70% ethyl acetate in hexanes to afford 4,5-bis-(4-chloro-phenyl)-2-(4-methoxy-2-propoxy-phenyl)-4,5-dihydro-1H-imidazole (303 mg, 46%). HR-MS (ES, m/z) calculated for C25H25N2O2Cl2 [(M+H)+] 455.1288, observed 455.1293.
Reaction SMILES: CO.[CH3:3][C:4]([S:37]([CH3:40])(=[O:39])=[O:38])([CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:25][CH:24]=2)=[CH:19][C:18]1=[O:36])[C:5]([NH:7][O:8]C1CCCCO1)=[O:6]>Cl.O1CCOCC1>[OH:8][NH:7][C:5](=[O:6])[C:4]([CH3:3])([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:27][CH:28]=2)=[CH:19][C:18]1=[O:36]
Reactant: CC(CCn1ccc(-c2ccc(Oc3ccccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(CCn1ccc(-c2ccc(Oc3ccccn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Methanol (25 mL) was added to a solution of 2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[4-(pyridin-2-yloxy)phenyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (212 mg, 0.39 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (4.9 mL) at room temperature. After 1 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 10:1 diethyl ether-methanol, filtered, and dried under reduced pressure to provide a white solid (168 mg, 88%). LCMS m/z 458.6 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 1.73 (s, 3H), 2.41 (ddd, J=13, 10.5, 5 Hz, 1H), 2.67 (ddd, J=13, 10.5, 5 Hz, 1H), 3.11 (s, 3H), 4.06 (ddd, J=13, 11.5 Hz, 1H), 4.39 (ddd, J=13, 11, 5 Hz, 1H), 6.97-7.00 (m, 2H), 7.25 (br d, J=8.7 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.56 (ddd, J=7.4, 5.8, 0.9 Hz, 1H), 7.90-7.94 (m, 3H), 8.33 (ddd, J=8.7, 7.4, 1.9 Hz, 1H), 8.47 (ddd, J=5.8, 1.9, 0.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[C:13](=[O:18])[C:14]([O:16]C)=[O:15]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:18])[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)C(=O)Cl
Product: O=C(O)C(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
In a manner similar to that described in Referential Example 242, 4-chloro-3-nitroaniline was condensed with methyl chlorooxoacetate. In a manner similar to that described in Referential Example 359, the condensed compound was hydrolyzed, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(Cl)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(Cl)cc2)n1

Procedure:
98.4 mg (78.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (80.1 mg, 0.275 mmol), 1-(2-fluorophenyl)piperazine (65 mL, 0.413mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)C>CCOCC>[CH2:10]([O:12][C:13]([CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27](=[O:28])[NH:5][C:4]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=3)=[CH:25][CH:26]=2)[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: Cc1ccc(N)cc1I
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Solvent: CCOCC
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cc2)CC1

Procedure:
1-[4-(3-Iodo-4-methyl-phenylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid ethyl ester was prepared from 3-iodo-4-methyl aniline and 1-(4-carboxy-phenyl)-piperidine-4-carboxylic acid ethyl ester following a procedure similar to the one described in the synthesis of 1-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid ethyl ester above. The product was isolated after a silica gel column with a 20-50% Et2O in hexanes gradient followed by a 50% EtOAc in hexanes elution. HRMS m/z calcd for C22H25N2O3I [M+H]+: 493.0983. Found: 493.0982.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][NH:11][C:10]=1[CH3:22]
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1O
Yield: 84 %

Procedure:
3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.5 g, 1.60 mmol) was dissolved in methanol and hydrogenated over 10% Pd/C for 3 hrs at 50 psi hydrogen on a Parr hydrogenator. The mixture was filtered through CELITE™ and the filtrate was evaporated to give a solid (300 mg, 84.2%).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CC=C(c3c[nH]c4ccccc34)CC2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-yl]ethanone (150 mg, 0.34 mmole) was dissolved in ethyl methyl ketone (3 ml) and chlorotrimethylsilane (0.063 ml, 0.5 mmole) was added. After 1 hour the hydrochloride was isolated as a reddish-brown solid with an m.p. of 177°-182° C. in a yield of 69% (112 mg) (Example 25).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2)[C:10](O)=[O:11])[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:36][CH:37]1[C:47](=[O:48])[N:39]2[C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH2:42][S:43][C@H:38]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:20][CH:21]=2)[C:10]([NH:36][CH:37]2[C:47](=[O:48])[N:39]3[C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH2:42][S:43][C@H:38]23)=[O:11])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CC(C)(C)OC(=O)NCc1ccc(CON=C(C(=O)O)c2csc(NC=O)n2)cc1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cc1
Yield: 70.5 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(4-tert-butoxycarbonylaminomethylbenzyloxyimino)acetic acid (syn isomer, 1.4 g.), N,N-dimethylformamide (0.29 g.), phosphoryl chloride (0.6 g.), 7-amino-3-cephem-4-carboxylic acid (0.65 g.), trimethylsilylacetamide (2.5 g.) and ethyl acetate (18 ml.) were treated in a similar manner to that of Example 11-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(4-tert-butoxycarbonylaminomethylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br>>[N+:14]([C:10]1[CH:9]=[C:8]([C:7]2([C:6]([OH:5])=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: BrCCCCBr
Product: O=C(O)C1(c2cccc([N+](=O)[O-])c2)CCCC1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,4-dibromobutane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclopentanecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=1>CCOC(C)=O.O=[Pt]=O>[C:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH2:14][CH2:13]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(F)c2Cl)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.5 %

Procedure:
A mixture of tert-butyl 4-(2-chloro-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (12, 0.488 g, 1.41 mmol) and PtO2 (0.109 g, 0.48 mmol) in EtOAc (15 mL) was stirred at ambient temperature for 18 h under a balloon of H2. The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (4 mL). To this solution was added HCl (2 N in Et2O, 4.0 mL) and the resulting mixture stirred at ambient temperature for 20 min. The resulting suspension was diluted with Et2O (20 mL) and the solids were collected by filtration to provide tert-butyl-4-(2-chloro-3-fluorophenyl)piperidine-1 carboxylate (13) as a clear semi-solid (0.471 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 7.43-7.19 (m, 3H), 4.17-4.01 (m, 2H), 3.20-3.03 (m, 1H), 2.95-2.68 (m, 2H), 1.79-1.65 (m, 2H), 1.58-1.45 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:17])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=1.[C:18]1([N:24]2[C:28]3[CH:29]=[CH:30][C:31](B4OC(C)(C)C(C)(C)O4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.O>[C:18]1([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:2]4[CH:3]=[CH:4][C:5](=[O:17])[N:6]([CH2:8][CH2:9][CH2:10][N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[CH:7]=4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)OB(c2ccc3c(c2)ncn3-c2ccccc2)OC1(C)C
Reactant: O=c1ccc(I)cn1CCCN1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc(-c2ccc3c(c2)ncn3-c2ccccc2)cn1CCCN1CCCCC1
Temperature: 80 °C
Yield: 70.8 %

Procedure:
5-iodo-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (18) (0.096 g, 0.28 mmol), 1-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazole (0.081 g, 0.25 mmol), palladium(II) acetate (0.003 g, 0.013 mmol), triphenylphosphine (0.010 g, 0.038 mmol) and sodium carbonate (0,080 g, 0.75 mmol) were stirred in 1.6 mL of a 3:1 mixture of dioxane/water. The mixture was degassed 3× by alternating vacuum and an argon atmosphere. The reaction was heated to 80° C. for 18 h, cooled and diluted with water. The aqueous phase was extracted 3× with EtOAc and the resulting organic phase was dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (eluted with 85:15 CH2Cl2/MeOH) afforded 0.073 g 5-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (19) (71% yield). 1H NMR (CDCl3) δ9.60 (s, 1H), 7.90 (d, J=1.3 Hz, 1H), 7.74-7.67 (m, 2H), 7.64-7.48 (m, 6H), 7.39 (dd, J=2.5, 9.5 Hz, 1H), 6.68 (d, J=9.5 Hz, 1H), 4.13 (t, J=6.5 Hz, 2H), 2.42 (bs, 6H), 2.10 (t, J=6.5 Hz, 2H), 1.64 (m, 4H), 1.46 (m, 2H). Mass Spectrometry (for C26H28N4O): [M+H]+413.2334, theoretical 413.2336.
Reaction SMILES: Cl[C:2]1C=CC(S(N2[C@H](C)CC(=O)C[C@@H]2C)(=O)=O)=CC=1.CN(C(OC)OC)C.O.NN.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]2[CH2:46][CH2:45]C(=O)[CH2:43][CH:42]2[C:48]2[CH:49]=[N:50]C=[N:52][CH:53]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([N:41]2[C@H:46]([CH3:45])[CH2:2][C:53]3[NH:52][N:50]=[CH:49][C:48]=3[C@@H:42]2[CH3:43])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(Cl)cc2)C(c2cncnc2)C1
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: COC(OC)N(C)C
Agent: NN
Solvent: O
Product: C[C@@H]1Cc2[nH]ncc2[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
cis-1-(4-Chlorophenylsulfonyl)-2,6-dimethylpiperidin-4-one (92) was treated with DMF-DMA followed by hydrazine hydrate as described for compound 71 in Example 4.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:17]([C:30]2[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33](=[O:39])[N:32]([CH3:40])[CH:31]=2)[CH:16]=1)=[O:13].I[CH3:42]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]([CH3:42])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:17]([C:30]2[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33](=[O:39])[N:32]([CH3:40])[CH:31]=2)[CH:16]=1)=[O:13]
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Cc2cc(F)ccc2Cl)ccc1Oc1ccc(F)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)C(C)c2cc(F)ccc2Cl)ccc1Oc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 4 mL vial with stirbar was charged with sodium hydride, dry 95% (2.9 mg, 0.115 mmol), placed in an ice bath and charged with a solution of Example 1H (0.0527 g, 0.097 mmol) in DMF (1 mL). After stirring 10 min at 0° C., iodomethane (8 μL, 0.128 mmol) was added by syringe. After 1 hour, the mixture was partitioned between 25 mL each of ethyl acetate and aqueous ammonium chloride. The organics were dried over anhydrous sodium sulfate. After filtration and solvent removal, the material was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 0-100%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.60 (d, J=2.6 Hz, 1H), 7.58 (s, 1H), 7.54-7.49 (m, 2H), 7.46-7.25 (m, 2H), 7.22-6.92 (m, 3H), 6.87 (d, J=8.8 Hz, 1H), 5.79 (s, 1H), 4.15 (q, J=7.1 Hz, 1H), 3.93 (d, J=7.0 Hz, 2H), 3.34 (s, 3H), 1.47 (d, J=7.1 Hz, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI) 557.1 (M+H)+.