Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[N:49][C:48]([CH3:51])=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[N:49][C:48]([CH3:51])=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cn1cnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)c1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4cn(C)cn4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To solution of 4-[1-phenyl-1-(1-methylimidazol-4-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.0477 g, 0.0775 mmol) in CH2Cl2 (3 mL) was added TFA (0.3 mL) and the solution was allowed to stir at rt for 30 min. The solvent was then removed in vacuo and the material was dissolved in CHCl3. To this solution was added 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0258 g, 0.0764 mmol) and iPrNEt2 (0.024 mL, 1.38 mmol), followed by BOP-Cl (0.0271 g, 0.106 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo and the residue was partitioned with H2O-EtOAc. The aqueous phase was re-extracted with EtOAc (×2) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated. The resulting residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0210 g, 50%) as a colorless solid:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[NH4+:14]>[Ni].CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH2:14])[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: [NH4+]
Agent: [Ni]
Agent: [OH-]
Solvent: CO
Product: CC(N)c1ccc2c(c1)OCO2
Reaction time: 24 h
Yield: 45 %

Procedure:
A suspension of Raney nickel (1 mL) in methanol (5 mL) and ammonium hydroxide (1 mL) was added to a solution of 1-(1,3-benzodioxol-5-yl)acetaldehyde, oxime (Preparation 1, 8.98 g, 50 mmole) in methanol (50 mL). The reaction mixture was hydrogenated (shaken on a Parr hydrogenator under H2 atmosphere at 60 psi) for 24 hours. The reaction mixture was filtered, and the resultant filtrate was concentrated in vacuo to provide the title compound as an oil (3.68 g, 45%).
Reaction SMILES: [S:1]([C:5]1[C:6]([O:8][C:9](=[O:11])[CH:10]=1)=[O:7])([OH:4])(=[O:3])=[O:2].[CH3:12][O-:13].[Na+:14].C[OH:16]>>[CH3:12][O:13][CH:10]([CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[C:6]([O-:16])=[O:7])[C:9]([O-:8])=[O:11].[Na+:14].[Na+:14].[Na+:14]
Reactant: O=C1C=C(S(=O)(=O)O)C(=O)O1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COC(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Temperature: 80 °C

Procedure:
Sulfomaleic anhydride, 3.9 gm, was dissolved in 25 ml of methanol and refluxed for 5 hours. Then, 24 gm of 25% sodium methoxide in methanol was added and the solution was refluxed for 2 hours. The methanol was then evaporated and the residue was dissolved in 100 ml of water and heated for 1 hour at 80° C. The solution was then decolorized with 5 gm of charcoal, filtered and evaporated. The crude residue of trisodium α-methoxy-β-sulfosuccinate was purified by trituration with acetic acid and then filtered, washed with acetone and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(-c2ccccc2)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2ccccc2)ccc1CBr
Yield: 97.2 %

Procedure:
A mixture of 6.00 g of 3-fluoro-4-methylbiphenyl, 5.73 g of N-bromosuccinimide, 0.075 g of 2,2′-azobisisobutylonitrile and 120 ml of carbon tetrachloride was heat-refluxed for 5 hours. The reaction solution was washed with water, and the organic layer was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 9:1) to give 8.30 g of oily 4-bromomethyl-3-fluorobiphenyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[S:57][CH2:58][CH2:59]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:59][CH2:58][S:57][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: OCCCSc1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCSc4ccccn4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 10.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-pyridylsulfanyl)-1-propanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (13 mg, yield 10%).
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)=O)([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>CCO.O>[OH:36][N:35]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)[CH2:18][CH2:17][C:5]1[S:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: NO
Reactant: COC(=O)CCc1ccc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CCc1ccc(C(CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)=NO)cc1C
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of methyl 3-[4-[3-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-2-methylphenyl]propionate [Example 12 (7)] (70 mg, 0.15 mmol) in EtOH (1.5 ml) was added a solution of hydroxylamine hydrochloride (11 mg, 0.15 mmol) and sodium acetate (14.5 mg, 0.176 mmol) in water (1 mL). The mixture was heated under reflux for 1 hour, cooled at room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a pale yellow crystal (55 mg, 57%).
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)(=[O:4])[CH3:3].Br[CH:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[C:27]([CH:29]2[CH2:30][CH2:31]2)=[O:28])[CH2:8]/[C:7]/1=[CH:12]\[C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)(=[O:4])[CH3:3]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: CC(=O)SC1CCNC/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}piperidine hydrochloride (1.15 g) and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (0.88 g) in N,N-dimethylformamide (20 ml) was added potassium carbonate (0.24 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:1) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (0.48 g, yield: 27%) as a colourless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[C:18]([O:20][CH3:21])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C@@H:48](O)[CH3:49])=[CH:44][CH:43]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C@H:48]([N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[C:3]([C:18]([O:20][CH3:21])=[O:19])[C:4]([C:11]4[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=4)=[C:5]3[CH:10]=[CH:9]2)[CH3:49])=[CH:44][CH:43]=1
Reactant: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: C[C@H](O)c1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc2c(ccn2[C@H](C)c2ccc(F)cc2)c1-c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
A suspension of methyl 6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (117 mg, 0.417 mmol) (Example 1, Step F) and triphenylphosphine (175 mg, 0.668 mmol) in tetrahydrofuran (THF) (3960 μl) under N2 was treated with (S)-1-(4-fluorophenyl)ethanol (84 μl, 0.668 mmol), heated to 65° C., and treated with DIAD (130 μl, 0.668 mmol). After stirring for 30 min, the reaction was cooled to rt, then concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) afforded (R)-methyl 1-(1-(4-fluorophenyl)ethyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (18.6 mg, 0.046 mmol, 11.07% yield) as pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.37 (d, J=8.1 Hz, 2 H), 7.32-7.18 (m, 4 H), 7.14 (d, J=3.7 Hz, 1 H), 7.03-6.94 (m, 2 H), 6.40-6.28 (m, 2 H), 3.62 (s, 3 H), 2.68 (s, 3 H), 2.41 (s, 3 H), 1.88 (d, J=7.2 Hz, 3 H); LCMS (m/z) ES+=403 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH2:20]([O:18][C:15]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Yield: 69 %

Procedure:
To a refluxed suspension of K2CO3 (32.8 g, 238 mmol) in methanol (180 mL) and CHCl3 (350 mL) was then added a mixture of methyl 2,5-dihydroxybenzoate (10.0 g, 59.5 mmol) and bromomethylbenzene (7.10 mL, 59.5 mmol) in methanol/CHCl3 (50 mL/25 mL) drop wise over 30 minutes. The resulting mixture was stirred at reflux for another 4 hours. After cooling down and filtration, the filter cake was washed with CHCl3 (20 mL). The combined filtrate was concentrated under reduced pressure. The residue was redissolved in CHCl3 (200 mL), washed with HCl (1N) (100 mL×2). The organic was then washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (8:1) to give methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 69.0%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)CCCl)cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3,4-Dimethoxyaniline (0.3 mole), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 5 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3,4-dimethoxyphenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24]>ClCCl>[OH:1][C:2]1[C:3]([C:8]([NH:24][CH2:23][C:22]([O:21][CH3:20])=[O:25])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)CN
Reactant: COC(=O)c1nccnc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1nccnc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
In 6 mL of dichloromethane is suspended 0.30 g of methyl 3-hydroxy-2-pyrazinecaroxylate obtained according to the method described in literature [J. Heterocycl. Chem., 34, 27 (1997)]. To the suspension are successively added 0.54 ml. of triethylamine and 0.29 g of glycine methyl ester hydrochloride. The resulting mixture is stirred at ambient temperature for 5 hours. After cooling, the solvent is distilled off under reduced pressure. The residue is purified by reverse phase column chromatography (eluent: water) to obtain 0.16 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)-carbonyl] amino}acetate.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:5]=1[CH3:21].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl.CO>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][S:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)=[O:31])[C:5]=1[CH3:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OC(F)F)ccnc1CSc1nc2ccccc2[nH]1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(OC(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 71 %

Procedure:
In chloroform (20 ml) - methanol (10 ml) was dissolved 2-[(4-difluoromethoxy-3-methyl-2-pyridyl)methylthio]benzimidazole (2.0 g). To the solution was added dropwise, under ice-cooling, a solution of m-chloroperbenzoic acid (MCPBA) (80%, 1.5 g in chloroform (20 ml). The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, in that order, then dried (MgSO4). The solvent was distilled off. The residual solid was subjected to a silica gel column chromatography. From the portion eluted with ethyl acetate - methanol (100:3, v/v), was obtained 2-[(4-difluoromethoxy-3-methyl-2-pyridyl)methylsulfinyl]benzimidazole (1.5 g, 71%). Recrystallization from ethyl acetate--ether gave colorless needles, m.p. 157°-158° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C>C(O)C>[F:26][C:25]([F:28])([F:27])[C:24]([NH:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:23]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: CCO
Product: O=C(NCCCC[C@H](NC(=O)C(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 g (356.7 mmol) of 6-N-benzyloxycarbonyl-lysine is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[S:28])=[C:15]([C:18]4[S:19][C:20]5[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=5[N:22]=4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl>[NH2:10][CH:11]1[C:43](=[O:44])[N:13]2[C:14]([C:27]([O:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[S:28])=[C:15]([C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Temperature: -15 °C
Reaction time: 3 h

Procedure:
557 mg of diphenylmethyl 7-phenylacetamido-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate were dissolved in 6 ml of methylene chloride, and the resulting solution was then cooled to -15° C. Afterward, to the cooled solution were added 0.16 ml of pyridine and 268 mg of phosphorus pentachloride, followed by stirring the resultant mixture at -5° C. for 1 hour and 30 minutes. Next, the mixture was cooled to -20° C., and 2.1 ml of methanol were then added thereto. The resulting solution was stirred again at -5° C. for 3 hours to continue the reaction (for the removal of the 7-phenylacetyl group). Thereafter, 6 ml of water were added to the reaction solution which was then further stirred at the same temperature for 1 hour, followed by separation into the aqueous and organic layers. 6 ml of water were added to the resultant organic layer which was then adjusted to pH 7 with an aqueous saturated solution of sodium hydrogen carbonate. After separation from the aqueous layer, the collected organic layer was dried over anhydrous magnesium sulfate. The dried organic solution obtained was distilled under reduced pressure to remove the solvent therefrom, and the resultant residue was then purified by a column chromatography on 35 g of silica gel (as developed with mixed solvents of toluene and ethyl acetate at ratio of 1:1 by volume) to give diphenylmethyl 7-amino-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][CH:14]=[C:15]([CH:17]=O)[N:16]=2)=[O:11])=[C:4]([F:19])[C:3]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:16]=2)=[O:11])=[C:4]([F:19])[C:3]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc(C=O)c[nH]3)c2F)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc(CN4CCOCC4)c[nH]3)c2F)c1
Yield: 10.8 %

Procedure:
A solution of N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-formyl-1H-imidazole-2-carboxamide (0.11 mmol), morpholine (0.020 mL, 0.22 mmol), NaBH(OAc)3 (0.047 g, 0.22 mmol) in CH2Cl2 (1.5 mL) was stirred at RT overnight. Sat'd NaHCO3 was added and the solution was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) and silica gel chromatography to afford the title compound (0.006 g, 11%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (t, J=1.47 Hz, 1H), 7.36-7.42 (m, 2H), 7.28 (t, J=2.06 Hz, 1H), 7.22-7.25 (m, 1H), 7.20 (br. s., 1H), 4.63 (s, 2H), 3.65-3.75 (m, 4H), 3.54 (br. s., 2H), 2.44-2.60 (m, 4H). ES-LCMS: m/z 504.1, 506.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([OH:10])=[O:9])[N:6]=1.[CH2:12]([O:14][C:15]([CH:17]([O:19][NH2:20])[CH3:18])=[O:16])[CH3:13]>CN(C)C=O.CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:20]/[O:19][CH:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH3:18])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(C)ON
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)O/N=C(\C(=O)O)c1csc(N)n1
Reaction time: 12 h
Yield: 86.1 %

Procedure:
17.2 g of (2-amino-4-thiazolyl)glyoxylic acid are added whilst cooling with ice to a solution of 14.6 g of O-(1-ethoxycarbonylethyl)hydroxylamine in 20 ml of dimethylformamide. The solution is stirred for 12 hours without cooling, and then diluted with 180 ml of methanol. In order to complete crystallisation, stirring continues for 5 hours at -5°, and then the product is filtered off by suction and dried. 24.7 g (86%) of the title compound are obtained. M.p.: 166°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[O:11])[CH2:3]1.[Br:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>C(#N)C>[Br-:27].[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:17][CH2:16][N+:15]([CH2:28][C:29](=[O:30])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH2:20][CH2:19]3)[CH2:14]2)=[O:11])[CH2:3]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC1CC(C)CN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)C1
Solvent: CC#N
Product: CC1CC(C)CN(C(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)C1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
(R)-quinuclidin-3-yl 2-(3,5-dimethylpiperidin-1-yl)-2-phenylacetate (120 mg, 0.34 mmol) and 2-bromo-1-phenylethanone (73.7 mg, 0.37 mmol) were dissolved in acetonitrile (5 ml) and stirred at room temperature for 16 hours. Acetonitrile was evaporated, the residue was taken up with little EtOAc (2 ml) and then Et2O was added. The white solid that precipitated out was recovered by suction filtration and washed on the filter paper with Et2O. The solid was dried to obtain (3R)-3-(2-(3,5-dimethylpiperidin-1-yl)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (115.8 mg, 61.9% yield).