Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:15][O:14][C:12]([CH:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[N:6]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:13]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C1CCCC1NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCCC1N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
To an ice cooled solution of 9.56 g (0.045 mole) of (rac)-2-cyclopentylamino-cyclopentanecarboxylic acid, methyl ester and 200 mL of ethyl acetate was added 9.5 g (0.0475 mole) of 2,4-dichloro-5-nitro-pyrimidine and 9.6 g (0.113 mole) of sodium bicarbonate. The mixture was heated overnight at 65 degrees, then cooled and washed with water, extracting the aqueous layer twice with ethyl acetate. The combined ethyl acetate layers were washed successively with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromography, eluting with hexanes-ethyl acetate (100:0-80:20), to give 11.4 g of (rac)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-cyclopentanecarboxylic acid methyl ester (IV-68).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([CH3:23])[O:22][C:18]=2[CH:17]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:23]/[C:21]2[O:22][C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:25]=[CH:24][C:19]=3[N:20]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc2nc(C)oc2c1
Reactant: O=Cc1ccc(OCCCCl)cc1
Product: COc1ccc2nc(/C=C/c3ccc(OCCCCl)cc3)oc2c1
Yield: 69 %

Procedure:
The procedure of Example 8 was followed starting with 4-chloropropoxybenzaldehyde of Example 8 (1.9 g, 10 mmol) and using 6-methoxy-2-methylbenzoxazole in place of 2-methylbenzoxazole (1.6 ml, 10 mmol) to give 2.4 g (69% yield) of (E)-2-[2-(4-chloropropoxyphenyl)ethenyl]-6-methoxybenzoxazole as an amber oil. 1H NMR (CDCl3): δ 8.29-6.99 (m, 9H), 4.22 (t, J=5.4 Hz, 2H), 3.93 (s, 3H), 3.24 (m, 2H), 2.51 (m, 2H).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.CC(=NO)C(=O)CC.[F:29][C:30]([F:40])([F:39])C1C=C(C=CC=1)C=O>>[CH2:8]([C:7]1[O:6][C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:30]([F:40])([F:39])[F:29])[CH:19]=2)=[N:4][C:3]=1[CH2:2][I:1])[CH3:13]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2cccc(C(F)(F)F)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 3-trifluoromethylbenzaldehyde gave 5-ethyl-4-iodomethyl-2-(3-trifluoromethylphenyl)oxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[NH2:14][C@@H:15]([CH2:24][O:25][CH3:26])[C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.[Cl-].[Na+].O>[OH:17][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:15]([NH:14][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:24][O:25][CH3:26]
Reactant: COC[C@H](N)[C@@H](O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](NC(=O)c1cc2cc(Cl)ncc2[nH]1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 223 mg, 1.13 mmol) and commercially available (1S,2S)-(+)-2-amino-3-methoxy-1-phenyl-1-propanol (200 mg, 1.10 mmol) in DMF (5 mL) was added HOBt (173 mg, 1.13 mmol), DIPEA (0.42 mL, 2.41 mmol) and EDCI (260 mg, 1.36 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate (4×25 mL), washing of the combined extracts with diluted hydrochloric acid (1M, 30 ml), diluted aqueous sodium hydroxide solution (1M, 30 ml) and brine (30 mL) followed by drying over magnesium sulphate gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate). The title compound was obtained as colourless solid. δH (CD3OD): 3.37 (3H, s), 3.34 (1H, dd), 3.66 (1H, dd), 4.53 (1H, ddd), 5.03 (1H, d), 7.15 (1H, s), 7.25-7.45 (5H, 3m), 7.68 (1H, s), 8.58 (1H, s); m/z (ES+)=360.22 [M+H]+; RT=3.12 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]1[N:14]=[C:15]2[C:20]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:18]=[N:17][N:16]2[CH:27]=1.Br[C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:33][CH:34]=1.N#N.CC([O-])=O.[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[O:24]1[CH2:23][CH2:22][N:21]([C:20]2[C:15]3[N:16]([C:27]([C:29]4[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:33][CH:34]=4)=[C:13](/[CH:12]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[N:14]=3)[N:17]=[CH:18][CH:19]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)CCc1ccc(Br)cn1
Reactant: C(=C/c1cn2nccc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
A solution of compound 57c (0.90 g, 2.5 mmol) and compound 57b (0.96 g, 3.7 mmol) in DMF (5 mL) was purged with N2. Pd(OAc)2 (67 mg, 0.30 mmol) was added, followed by KOAc (1.1 g, 11 mmol) and PPh3 (73 mg, 0.28 mmol). The resulting mixture was stirred at 105° C. for 1.5 h, and allowed to cool to rt. water (100 mL) was added. The resulting mixture was extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2-2:1 v/v)) to obtain compound 57d as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H30N6O3: 535.2 (M+H). Found: 535.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>C(Cl)Cl.C(OCC)(=O)C>[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([C:19]1[NH:18][CH:22]=[CH:21][CH:20]=1)=[O:9]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Aluminum chloride (2.6 g, 20 mmol) was added to a mixture of 2-chloro-5-nitro-benzoyl chloride (5 g, 20 mmol) and pyrrole (4 g, 30 mmol) in DCM (100 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins. The reaction was diluted with ethyl acetate, washed with brine, water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give 1.5 g (30%) of (2-chloro-5-nitro-phenyl)-(1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16](Br)[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>C(OCCOCCO)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([N:19]=[N+:20]=[N-:21])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N1CCc2cc(CC(C)Br)cc(C#N)c21
Agent: [Na+]
Solvent: O
Solvent: CCOCCOCCO
Product: CC(=O)N1CCc2cc(CC(C)N=[N+]=[N-])cc(C#N)c21
Yield: 88.5 %

Procedure:
1-Acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (1.42 g) and sodium azide (0.30 g) were dissolved in diethylene glycol monoethyl ether (1.4 ml) and water (3.2 ml), and the mixture was stirred at 90° C. for 9.5 hours.-To the reaction mixture was added water, and the mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of ethyl acetate and hexane (3/1) as eluent to give 1.10 g of 1-acetyl-5-(2-azidopropyl)indoline-7-carbonitrile as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH:14]=1)[CH:12]=[O:13].[OH-].[Na+].S(OC)(O[CH3:32])(=O)=O.Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:32])=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C=O
Yield: 68.8 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (0.500 g, 1.45 mmol) was dissolved in ethanol (15 ml) and after adding thereto in sequence sodium hydroxide (0.064 g, 1.59 mmol) and dimethyl sulfate (0.200 g, 1.59 mmol), the solution was stirred at room temperature for 12 hours. After the completion of reaction, the reaction solution was poured into a cold diluted hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with water and then dried, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (0.359 g, 0.998 mmol, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][N:39]=[CH:38]2)[CH:32]=1)CCC>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:38]=[N:39][N:40]=[CH:41]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid butyl ester (Example H11) (345 mg, 1.2 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (207 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:3]=1[O:21][CH3:22].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([C:31]([S:34]([CH3:37])(=[O:36])=[O:35])([CH3:33])[CH3:32])[N:25]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:21][C:3]1[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][C:2]=1[NH:30][C:29]1[C:24]([CH3:23])=[N:25][C:26]([C:31]([S:34]([CH3:37])(=[O:36])=[O:35])([CH3:32])[CH3:33])=[CH:27][CH:28]=1
Reactant: Cc1nc(C(C)(C)S(C)(=O)=O)ccc1N
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1c(Nc2ccc(C(C)(C)S(C)(=O)=O)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 100 °C
Yield: 3.7 %

Procedure:
A mixture of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (78.5 mg, 0.238 mmol), 2-methyl-6-(2-(methylsulfonyl)propan-2-yl)pyridin-3-amine (54.3 mg, 0.238 mmol), Pd2(dba)3 (20.0 mg, 0.0218 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (3.0 mg, 0.0101 μmol), and cesium carbonate (160 mg, 0.491 mmol) in 4M dioxane were heated under microwave irradiation at 100° C. Mixture was purified by HPLC; fractions containing product were partly concentrated, and residue was extracted with CH2Cl2 and 1M NaHCO3. Organic phases were dried over MgSO4, filtered, and concentrated to give isopropyl 4-(5-methoxy-6-(2-methyl-6-(2-(methylsulfonyl)propan-2-yl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate (4.6 mg, 4%) as a white solid. 1HNMR (CDCl3, 400 MHz) δ 1.16-1.17 (d, J=6.3 Hz, 6H), 1.80-1.86 (m, 2H), 1.87 (s, 6H), 2.01-2.06 (m, 2H), 2.56 (s, 3H), 2.81 (s, 3H), 3.38-3.44 (m, 2H), 3.77-3.82 (m, 2H), 3.96 (s, 3H), 4.91-4.97 (m, 1H), 5.35-5.39 (m, 1H), 6.98 (s, 1H), 7.51-7.53 (d, J=8.6 Hz, 1H), 8.13 (s, 1H), 8.51-8.53 (d, J=8.6 Hz, 1H). Exact mass calculated for C24H35N5O6S 521.23 found 522.5 (MH+).
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][CH:8]3[C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2cccnc2N2CCCC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1cnc2c(c1)NCC1CCCN21

Procedure:
Following the procedure of Example 3, 6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one is reduced with lithium aluminum hydride to afford the title compound as the hydrochloride salt, m.p. 198°-201° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[H-].[Na+].I[CH3:14]>O1CCCC1>[CH3:14][N:4]1[CH2:5][CH2:6][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: CI
Reactant: c1ccc2c(c1)NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCOc2ccccc21
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 35.51 mmol) in tetrahydrofuran (50 mL). To the above was added NaH (2.3 g, 57.50 mmol) in several batches, while cooling to a temperature of 0-5° C. The mixture was stirred for 30 minutes at 0-5° C. To the above was added iodomethane (9.0 g, 63.41 mmol) dropwise with stirring, white cooling to a temperature of 0-5° C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 3.0 g (50%) of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:25]O)=[N:21][C:22]=3[CH2:23][CH3:24])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:52]1[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:25][N:52]4[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]4)=[N:21][C:22]=3[CH2:23][CH3:24])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)C1CNC1
Reactant: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {5-[5-(3-chloro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-6-ethylpyridin-2-yl}methanol (0.15 g, 0.40 mmol) that was obtained in Example 25 (25c), carbon tetrabromide (0.27 g, 0.80 mmol), triphenylphosphine (0.21 g, 0.80 mmol), methyl 3-azetidinecarboxylate hydrochloride (91 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.21 ml, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1 or 3:1) as the eluent to afford the title compound (0.16 g) in a yield of 83% as a pale yellowish oily product.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)=O)(C)(C)C.[CH3:23][S:24]([OH:27])(=[O:26])=[O:25]>>[CH3:23][S:24]([OH:27])(=[O:26])=[O:25].[N+:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][C@@H:9]1[CH2:10][CH2:11][NH:8]1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccc([N+](=O)[O-])c1
Agent: CS(=O)(=O)O
Product: O=[N+]([O-])c1cccc(OC[C@@H]2CCN2)c1

Procedure:
A 278 mg sample of the purified product from step 22a above was treated according to the procedure of Example 1c (except starting with the methanesulfonic acid instead of HCl/ether) to afford 78 mg of the title product. MS: 209 (M+H)+. NMR (D2O) δ: 2.70 (q, 2H, J=8.1 Hz), 2.80(s, 3H), 4.08-4.18 (m, 2H), 4.46 (d, 2H, J=4.0 Hz), 4.90-4.96 (m, 1H), 7.45-7.49 (m, 1H), 7.60 (t, 1H, 8.4 Hz), 7.90 (t, 1H, 2.4), 7.93-7.96 (m, 1H). Anal. Calcd for C10H12ClN2O3.1.16 CH3SO3H: C, 34.60; H, 5.21; N, 5.93; Found: C, 34.25; H, 5.25; N, 6.08.
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([NH:12][CH:13]([C:31]([OH:33])=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=1[OH:30])(=[O:21])=[O:20])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>>[C:5]([O:9][C:10]([NH:12][CH:13]([C:31]([OH:33])=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[C:23]([OH:30])=[C:24]([NH:29][C:43]([NH:42][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([Cl:41])[C:35]=2[Cl:34])=[O:44])[CH:25]=[CH:26][C:27]=1[Cl:28])(=[O:20])=[O:21])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O)C(=O)O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O)C(=O)O
Yield: 30.2 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]-3-amino-6-chloro-2-hydroxybenzenesulfonamide (233 mg, 0.518 mmol) and 2,3-dichlorophenylisocyanate (98 mg, 0.518 mmol) were coupled to form the desired urea (100 mg, 30%). LC-MS (m/z) 641.2 (M+).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[Cl:27][CH:28]([Cl:32])[C:29](Cl)=[O:30].Cl>C(OCC)(=O)C.CC(C)=O.O>[Cl:27][CH:28]([Cl:32])[C:29]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:30]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Yield: 34.2 %

Procedure:
7-Amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g) was suspended in a mixture (60 ml) of water and acetone (1:1) and sodium bicarbonate was added to the suspension little by little to give a solution. Dichloroacetyl chloride (3 g) was added dropwise to the solution at -5° C under stirring and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (50 ml) was added to the reaction mixture and the mixture was adjusted to pH 2 with diluted hydrochloric acid under stirring and filtered. The ethyl acetate layer was separated from the filtrate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then treated with activated charcoal powder. Ethyl acetate was distilled off from the solution under reduced pressure. Ether was added to the residue and the mixture was stirred overnight. Precipitates were collected by filtration to give pale yellow powder of 7-dichloroacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.5 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=2)=[C:7]([OH:9])[CH:8]=1)[CH3:2].C(N(CC)CC)C.[C:25](O)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: CCc1ccc(Oc2cccc(F)n2)c(O)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2cccc(F)n2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of 5-Ethyl-2-(6-fluoro-pyridin-2-yloxy)-phenol (20 mg; 0.09 mmol), under argon, in dimethylformamide (2 mL), cooled to 0° C., was added triethylamine (36 μL; 0.26 mmol) and acetic acid (10 μL; 0.18 mmol). The reaction mixture was allowed to stir overnight, with gradual warming to room temperature. The reaction was concentrated, diluted with saturated NaHCO3 (5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (8 mg; 34%) was obtained as clear oil, after purification on neutral alumina gel (cyclohexane/ethyl acetate: 9/1).
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[C:17]([CH:21]=1)[C:18](Cl)=[O:19]>C(#N)C>[Cl-:9].[Cl:9][C:10]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[C:17]([CH:21]=1)[C:18]([NH:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: N[n+]1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: O=C(N[n+]1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 0.67 h
Yield: 156.1 %

Procedure:
1-Aminopyridinium chloride (2.9 g) was added to 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoyl chloride (7.6 g) in acetonitrile (50 ml). The mixture was stirred and heated to reflux. After 20 minutes a solid precipitated. Reflux was continued for a further 40 minutes. Then the mixture was cooled in ice and the solid filtered off. The solid was washed with cold acetonitrile, then with ether, and was air dried to give 7.4 g of the desired product, mp 234°-237° C.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3,4-dichlorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 325, 327, 329 (MH+).