Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([NH:15]C(=O)C)[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.[C:24]([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:24])=[O:9])=[O:5]
Reactant: CC(=O)[O-]
Reactant: CC(=O)Nc1ccc(C(=O)CCC(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(N)cc1F
Temperature: 35 °C

Procedure:
A mixture of 35 g. of 3-(2-fluoro-4-acetamidobenzoyl)propionic acid, 700 ml. of methanol and 1.4 ml. of concentrated sulfuric acid is refluxed for 76 hours. The solution is cooled to 35° C. and poured onto 7 g. of anhydrous sodium acetate while stirring. The reaction mixture is stirred in an ice-bath. The solid is collected and washed with cold methanol to yield methyl 3-(2-fluoro-4-aminobenzoyl)propionate as a white solid. A mixture of this solid, 9.2 g. of hexadecyl bromide and 4.2 g. of potassium carbonate is stirred for 20 hours at 125° C. under nitrogen. The mixture is then cooled to 25° C. and 30 ml. of water is added. After stirring, the product is filtered and washed with water. Recrystallization from methanol affords methyl 3-[2-fluoro-4-(hexadecylamino)benzoyl]propionate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
To MeOH (125 mL) was added 5-hydroxy-2-nitrobenzoic acid (1.02 g, 5.6 mmol) followed by dropwise addition of thionyl chloride (˜4 mL) and the mixture heated at reflux overnight. The solution was cooled to room temperature, concentrated in vacuo, reconcentrated twice from MeOH, dissolved in EtOAc, washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo to give methyl 5-hydroxy-2-nitrobenzoate (1.09 g, 5.5 mmol, 98%). 1H NMR (300 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.05 (d, 1H), 7.03 (d, 1H), 7.01 (s, 1H), 3.82 (s, 3H); LC-MS (ESI) m/z 196 (M−H)+.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].[CH3:6][C:7]12[CH2:12][CH:11]1[CH2:10][CH:9]([CH2:13][CH:14]=O)[C:8]2([CH3:17])[CH3:16].[OH-].[K+].CO>O>[CH3:4][C:3](=[CH:14][CH2:13][CH:9]1[CH2:10][CH:11]2[C:7]([CH3:6])([CH2:12]2)[C:8]1([CH3:16])[CH3:17])[C:2](=[O:5])[CH3:1]
Reactant: CCC(C)=O
Reactant: CC1(C)C(CC=O)CC2CC21C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)=CCC1CC2CC2(C)C1(C)C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
560 g (8.5 mol) of butan-2-one and 234 g (1.4 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal were added to 48 g (0.75 mol) of potassium hydroxide dissolved in 500 ml of water and 1.41 of methanol. The reaction mixture was stirred overnight with ice-bath cooling, poured into 3 1, of water and extracted with diethyl ether. The extract was washed with water, dried (MgSO4) and evaporated in vacuo. The residue was distilled at 108° C./0.1 Torr to give 140 g (45% yield) of 3-methyl-5-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)pent-3-en-2-one.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1C=CC=[CH:4][CH:3]=1.C(=O)(O[CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)OC.N1CCCC1>C1COCC1>[C:16]1([CH:15]([N:8]2[CH2:1][CH2:2][CH2:3][CH2:4]2)[CH:14]=[CH2:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)OCC=Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)N1CCCC1
Reaction time: 16 h
Yield: 61 %

Procedure:
A stock solution containing [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) and L1 (10.8 mg, 0.0200 mmol) in 1.0 mL of THF was prepared. By the procedure for reaction of benzylamine with methyl cinnamyl carbonate, the reaction of pyrrolidine (85.0 mg, 1.19 mmol) and methyl cinnamyl carbonate (201.5 mg, 1.049 mmol) was conducted at room temperature for 16 h. 1H NMR analysis of the crude mixture showed the ratio of branched to linear product to be 99/1. After purification, 121 mg of the title compound (61%) was isolated and HPLC analysis as described above indicated that the enantiomeric excess of the major product was 97%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N+:72]([O-:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N+:72]([O-:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:31]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 14.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 2-methoxy-4-nitroaniline (Aldrich) (0.18 g, 1.1 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide as a white solid (Yield 0.06 g, 14%).
Reaction SMILES: ClCCN1CCOCC1.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([OH:67])[C:36]2[N:45]=[C:44]([NH:46][C:47]3[CH:51]=[C:50]([CH3:52])[NH:49][N:48]=3)[C:43]3[C:38](=[CH:39][C:40]([O:53][CH:54]4[CH2:59][CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56][CH2:55]4)=[CH:41][CH:42]=3)[N:37]=2)=[CH:31][CH:30]=1.Cl.O1CCOCC1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]([C:36]2[N:45]=[C:44]([NH:46][C:47]3[CH:51]=[C:50]([CH3:52])[NH:49][N:48]=3)[C:43]3[C:38](=[CH:39][C:40]([O:53][CH:54]4[CH2:55][CH2:56][NH:57][CH2:58][CH2:59]4)=[CH:41][CH:42]=3)[N:37]=2)[OH:67])=[CH:33][CH:34]=1
Reactant: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc23)n[nH]1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: Cl
Agent: ClCCN1CCOCC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCNCC4)ccc23)n[nH]1
Reaction time: 20 h
Yield: 0.4 %

Procedure:
Intermediate compound (R,S)-tert-butyl 4424(4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate was obtained (105 mg) following the procedure described in Example 38 for the synthesis of (R,S)-(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholinoethoxy)quinazolin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 with tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate. To the crude tert-butyl 4-(2-((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate (100 mg, 18.2 mmol) in a flask at 0° C. was added 4N HCl/dioxane (5 mL). After stirring for 20 h, the solvent was removed and the residue was shaken with DCM and aq sodium bicarbonate. The solvents were removed, and the remaining residue was extracted with MeOH/DCM. The extracts were concentrated and the residue was chromatographed on reverse phase HPLC to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(piperidin-4-yloxy)quinazolin-2-yl)methanol as a white solid (32 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 2 H) 1.89 (s, 13 H) 1.89 (s., 3 H) 1.98 (m, 2 H) 2.68 (m, 2 H) 2.99 (m, 2 H) 4.66 (m, 4 H) 5.62 (s, 1 H) 5.76 (s, 1 H) 6.36 (b., 1 H) 7.08-7.18 (m, 4 H) 7.52 (m, 2 H) 8.45 (m., 1H), 10.29 (bs, 1H). LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[C:21]1([CH2:20][N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: COc1cccc(C2CCCN2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (3.0 g) in dry acetonitrile (70 ml) was added milled potassium carbonate (3.7 g) followed by benzyl chloride (2.2 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 5 hrs, warmed under reflux for 2 hrs, and cooled to ambient temperature. The reaction mixture was filtered through a pad of celite, and the solids washed with ethyl acetate. The combined filtrates were concentrated to give 4.3 g (96%) of 1-phenylmethyl-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [CH:1](=[C:8]1/[CH2:9][CH2:10][C@H:11]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[C@@H:12]([C:14]([O:16]C)=[O:15])[CH2:13]/1)/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+].O.OO>>[CH:1](=[C:8]1/[CH2:9][CH2:10][C@H:11]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[O:19])[C@@H:12]([C:14]([OH:16])=[O:15])[CH2:13]/1)/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1C/C(=C/c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1C/C(=C/c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl (1S,2S,5E)-5-benzylidene-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate (116 mg, 0.000277 mol) in tetrahydrofuran (6.0 mL, 0.074 mol) at rt was added a solution of lithium hydroxide (102 mg, 0.00416 mol) in water (2.0 mL, 0.11 mol). The resulting cloudy solution was stirred at rt for 17 h. LCMS showed that there was only 40% conversion. The reaction mixture was cooled to 0° C., hydrogen peroxide (0.113 mL, 0.00111 mol) was then added. The reaction mixture was stirred at 0° C. for 2 h. LCMS showed that there was little change. The reaction mixture was then stirred at rt over the weekend. LCMS showed the reaction was done. The reaction was quenched with 10% Na2S2O3 (10 mL), acidified with 1 N HCl (5 mL) to pH=4, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a colorless solid. (112 mg, 100% in yield). MS (ESI): (M+H)+=405.1.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](O)(=O)[CH:30]([CH3:32])[CH3:31].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH:30]([C:32]1[O:24][C:23]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C@H:15]3[CH2:16][CH2:17][C@H:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])[CH2:13][CH2:14]3)=[CH:28][CH:27]=2)=[N:25][N:26]=1)([CH3:31])[CH3:29]
Reactant: CC(C)C(=O)O
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)o1

Procedure:
A mixture of 100 mg (0.25 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide, 0.06 ml (0.57 mmol) of isobutyric acid and 2 ml of phosphorus oxychloride was refluxed for 3 hr. To the mixture, 1N NaOH solution was added. The mixture was extracted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 40 mg (35%) of the title compound. MS (m/e): 441.1 (MH+).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1.O>[CH3:2][O:3][CH:4]=[C:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC=C1CCC(C(=O)OC)CC1
Temperature: -7.5 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
263.4 g of methoxymethyltriphenylphosphonium chloride was dispersed in 750 mL of tetrahydrofuran (THF) and 86.2 g of potassium-t-butoxide were added at −9 to −4° C. over 5 minutes. After stirring at −4 to −11° C. for 30 minutes, 100.0 g of methyl 4-oxocyclohexanecarboxylate was dissolved in 300 mL of THF and the resulting solution added dropwise at −10 to 4° C. over 80 minutes. After stirring at 0 to 4° C. for 60 minutes, 7.0 g of ammonium chloride and 20 mL of water were added. The solvent of the reaction mixture was distilled off under reduced pressure and 600 mL of hexane was added, followed by stirring at room temperature for 30 minutes. The precipitate was filtrated and the precipitate was suspended and washed again with 600 mL of hexane. After combining with the hexane filtrate, the mixture was washed in turn with a mixed solution of methanol-water (1:1), water, and saturated solution. After dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 103 g of methyl 4-methoxymethylidenecyclohexanecarboxylate as an oily substance.
Reaction SMILES: [F:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:3]1[CH3:13].P([O-])([O-])([O-])=[O:15].[K+].[K+].[K+]>C(O)C>[OH:15][C:2]1([F:1])[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:3]1[CH3:13]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCCCC1=C(C)C(F)CC1=O
Agent: [K+]
Solvent: CCO
Product: CCCCCC1=C(C)C(O)(F)CC1=O
Reaction time: 0.03 h

Procedure:
Experimental description: 4-fluoro-3-methyl-2-pentylcyclopent-2-enone was obtained according to the experimental described in Example 5. 180 mg 4-fluoro-3-methyl-2-pentylcyclopent-2-enone were dissolved in 900 μL ethanol and added to 120 mL potassium phosphate buffer pH 8.0. Var2 was added to the mixture at a final concentration of 2 μM. The mixture was split in 4.8 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 600 μL 10 mM NADPH in KPi buffer were added to each vial and stirred for 2 minutes. 600 μL cofactor regeneration solution containing 500 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 36 hours, the reaction mixtures were joined together and extracted with chloroform (3×50 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the activated product (4-hydroxy-4-fluoro-3-methyl-2-pentylcyclopent-2-enone, 135 mg). 100 mg (0.54 mmol) of activated product were dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and added with 100 μL DAST (0.7 mmol). The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the fluorinated product, 4,4-difluoro-3-methyl-2-pentylcyclopent-2-enone (85 mg, 85% yield, yellow oil). MS (EI+): m/z 202. Mw for C11H16F2O: 202.24.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3].Cl.O.[OH-].[Na+]>CO>[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 7-[2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (11.2 g) and conc. hydrochloric acid (2.3 g) in methanol (80 ml) was stirred for 3 hours at ambient temperature. The reaction mixture was poured into water (120 ml) and adjusted to pH 3.5 with 10% aqueous solution of sodium hydroxide and washed with ethyl acetate. The aqueous layer was adjusted to pH 5.0 with 10% aqueous solution of sodium hydroxide. After removing the solvent under reduced pressure, the aqueous solution was adjusted to pH 4.0 with 10% aqueous hydrochloric acid under ice-cooling. The solution was subjected to column chlomatography on macroporous non-ionic adsorption resin "Diaion HP-20:" (Trademark: prepared by Mitsubishi Chemical Industries) and eluted with 10% aqueous solution of isopropyl alcohol. The fractions containing the objected compound were concentrated and lyphylized to give 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)- 3-cephem-4-carboxylate (syn isomer) (5.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CC(C)Oc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: Cl.[CH2:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=1)[CH2:3][CH3:4].[H][H].C([O-])(=O)C>C(O)(=O)C.[Pt](=O)=O>[CH2:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH:7]([C:11]([OH:13])=[O:12])[CH2:6]1)[CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCc1ccnc(C(=O)O)c1
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: CCCC1CCNC(C(=O)O)C1
Yield: 1107.6 %

Procedure:
Platinum(IV) oxide (79.8 mg, 0.35 mmol) was added to a solution of 1.05 g (5.22 mmol) of 4-propylpyridine-2-carboxylic acid hydrochloride synthetized according to a literature (J. Med. Chem. 1984, 27, 216.) in acetic acid (8 ml), and the mixture was stirred in a hydrogen atmosphere under the atmospheric pressure overnight. The reaction solution was filtered through Celite, and the solvent was then removed by distillation to give 9.90 g (yield 90%) of the title compound as acetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:26])[C:7]=2[CH:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 G. 3-cyanodibenzo[b,f]thiepin (0.021 mole) are dissolved in 300 cc. methylene chloride and 3.45 g. m-chloroperbenzoic acid (0.020 mole) are added in portions. The solution is stirred for two hours at room temperature, then excess calcium hydroxide is added. The mixture is stirred for a few minutes and filtered through celite, the filtrate is evaporated down and the residue chromatographed on silica gel, eluting with a 50:50 mixture of chloroform and benzene. A small amount of starting material is recovered, and the yield of sulfoxide is 4.92 g. (92%), light yellow solid, m.p. 220° C.-222° C.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>O1CCCC1.CO>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:4](=[S:3])[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:6]=2[CH:12]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)n(C(=O)OC(C)(C)C)c(=S)n2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in oil) (5.55 g; 138 mmol) is added in small portions at 10° C., with stirring, to a solution of 2-mercapto-5-methoxybenzimidazole (10 g; 55.5 mmol) in solution in 400 ml of tetrahydrofuran under argon. The reaction mixture is then stirred for 30 minutes at 0° C., and then BOC2O (26.64 g; 122 mmol) is added in one go. Stirring of the reaction mixture is then carried out for 18 hours at ambient temperature. The reaction mixture is diluted with methanol, filtered over Celite and then concentrated to dryness. The residue obtained is subsequently taken up in a 1/1 mixture of petroleum ether/isopropyl ether. The solid which precipitates is then suction-filtered off to yield the title product in the form of a white powder.
Reaction SMILES: [SH:1][CH2:2][CH:3]([N:6]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7](=[O:20])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])[CH2:4][SH:5].N>CO>[S:1]1[CH2:2][CH:3]([N:6]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7](=[O:20])[NH:8][C@@H:9]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]([OH:12])=[O:11])[CH2:4][S:5]1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(CCc1ccccc1)C(CS)CS
Agent: N
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(CCc1ccccc1)C1CSSC1
Yield: 66.2 %

Procedure:
(2S)-2-[3-[2-Mercapto-1-(mercaptomethyl)ethyl]-3-phenethylureido]-3-phenylpropionic acid (Compound No. 9-1, 780 mg) is dissolved in methanol (2 ml). To the solution are added 1 N aqueous ammonia (10 ml) and a 1% aqueous ferric chloride solution (0.5 ml), and the mixture is stirred at room temperature for two hours while bubbling air through it. The reaction mixture is concentrated under reduced pressure, 2 N hydrochloric acid is added to the concentrate under ice cooling to acidify it, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 514 mg (66%) of the titled compound (Compound No. 10-1) as oily matter.