Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH2:18])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].Br[CH2:26][C:27]1[N:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[C:29](=[O:38])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:37]>CN(C=O)C>[NH2:18][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:11]([CH2:26][C:27]3[N:28]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[CH3:45])[C:29](=[O:38])[C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:37])[N:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)[C:17]=12.[NH2:18][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:11]([CH2:26][C:27]3[N:28]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[CH3:45])[C:29](=[O:38])[C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:37])[N:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:17]=12
Reactant: Cc1ccccc1-n1c(CBr)cc2cccc(C)c2c1=O
Reactant: COc1cccc(-c2n[nH]c3ncnc(N)c23)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nn(Cc3cc4cccc(C)c4c(=O)n3-c3ccccc3C)c3ncnc(N)c23)c1
Product: Cc1ccccc1-n1c(Cn2nc(-c3cccc(O)c3)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 139.3 %

Procedure:
3-(3-Methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1701) (964 mg, 4 mmol) and potassium tert-butoxide (0.44 g, 4 mmol) were dissolved in anhydrous DMF (150 mL) and stirred at RT for 30 min. 3-(Bromomethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1610) (1.37 g, 4.0 mmol) was added. The resulting mixture was stirred at RT for 30 min, poured into ice water (30 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the desired product, 3-((4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1702) (1.4 g, 70% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([O:23]CC)=[O:22].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Yield: 83 %

Procedure:
3.8 g of ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate, 13 ml of ethanol and 1.0 g of sodium hydroxide are heated in 13 ml of water for 1 hour for boiling. The pH is reduced to 10 and the alcohol is distilled off in vacuo. The aqueous solution is shaken up with ether and purified with active charcoal. Acidification is carried out with dilute hydrochloric acid and with a yield of 83 % 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; F 179.5°-181°.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH2:5]1[O:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]([OH:16])[CH3:15])[CH:11]=2)[O:6]1.CCOCC.CCCCCC>C1COCC1>[Cl:3][C:1]([O:16][CH:14]([C:10]1[CH:11]=[C:12]2[O:13][CH2:5][O:6][C:7]2=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])[CH3:15])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(OC(=O)Cl)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Phosgene (500 mL of 20% w/v in toluene from Fluka: 965 mmole; 4 eq.) was added slowly to a cold, stirring solution of 50 g (237 mmole; 1 eq.) of 1-(4,5-methylenedioxy-2-nitrophenyl)ethanol in 400 mL dry THF. The solution was stirred overnight at ambient temperature at which point TLC.(20% Et2O/hexane) indicated >95% conversion. The mixture was evaporated (an oil-less pump with downstream aqueous NaOH trap is recommended to remove the excess phosgene) to afford a viscous brown oil. Purification was effected by flash chromatography on a short (9×13 cm) column of silica gel eluted with 20% Et2O/hexane. Typically 55 g (85%) of the solid yellow MeNPOC-Cl is obtained by this procedure. The crude material has also been recrystallized in 2-3 crops from 1:1′ether/hexane. On this scale, ˜100 ml is used for the first crop, with a few percent THF added to aid dissolution, and then cooling overnight at −20° C. (this procedure has not been optimized). The product should be stored desiccated at −20° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[N:9]([C:31]([C:30]3[CH:34]=[C:35]([O:39][CH3:40])[C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=3)=[O:32])[CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)N(C(=O)c1cc(OC)c(OC)c(OC)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a solution of 225 (300 mg, 0.83 mmol) in DCM (5 ml) was added TEA (0.23 ml, 1.65 mmol) and 3,4,5-trimethoxybenzoyl chloride (228 ml, 0.99 mmol). The reaction mixture was stirred at rt for 12 h. Water (10 ml) was added and the aqueous layer was extracted with DCM (3×30 ml). The combined organic phases were washed with sat. aq. NaHCO3 (10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, gradient elution 100% hex to 100% EtOAc over 25 min) afforded the title compound (240 mg, 52%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.04 (18H, d, J=6.7 Hz, 6×CH3CH), 1.14-1.24 (3H, m, 3×CH), 1.55 (6H, s, 2×CH3), 2.74 (2H, s, CH2), 3.80 (3H, s, OCH3), 3.85 (6H, s, 2×OCH3), 3.86 (3H, s, OCH3), 4.19 (2H, s, CH2), 6.53 (1H, s, CH), 6.56 (2H, s, 2×CH), 6.71 (1H, s, CH). LC/MS (ES+) tr=0.2.23 min, m/z 580.24 (M++Na). HRMS (ES+) calcd for C31H47NO6Si (M++H) 558.3245, found 558.3237.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[O:5]2.S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][C:3]1[S:2][CH:1]=[C:10]2[C:9](=[O:11])[NH:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[O:5][C:4]=12
Reactant: O=C1Nc2ccccc2Oc2cscc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ccccc2Oc2c1csc2Cl
Reaction time: 8 h

Procedure:
An 8.0 g. portion of thieno[3,4-b][1,5]benzoxazepin-10(9H)-one is suspended in 364 ml. of methylene chloride. A 3.27 ml. portion of sulfuryl chloride is added dropwise and the mixture is stirred overnight. The solid is collected and washed with methylene chloride, giving 3-chloro-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[CH2:4][CH3:5]>CC(C)=O>[I-:2].[CH2:3]([S:6][C:7]1[C:8]([C:12]2[CH:13]=[N+:14]([CH3:1])[CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[CH2:4][CH3:5]
Reactant: CCCSc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CCCSc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 8 mmol) and 3-(4-propylthio-1,2,5-thiadiazol-3-yl)pyridine (0.63 g, 2.6 mmol) in acetone (5 ml) was stirred at room temperature for 18 h and evaporated.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[S:10](=[O:12])(=[O:11])[CH2:9][C:8]3[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:7]=3[C:5]=2[N:6]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].O>C(Cl)Cl>[C:34]([NH:1][C:2]1[S:3][C:4]2[S:10](=[O:12])(=[O:11])[CH2:9][C:8]3[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:14][N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:7]=3[C:5]=2[N:6]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(N)nc1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(NC(C)=O)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To suspension of ethyl 7-amino-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyrazolo[3′,4′:4,5]thiopyrano[3,2-d][1,3]thiazole-3-carboxylate 5,5-dioxide (71 mg; 0.18 mmol; 1 eq.) and triethylamine (98.8 μL; 0.71 mmol; 4 eq.) in DCM (710 μL) at 0° C. is added acetylchloride (30 μL; 0.46 mmol; 2.5 eq.). The suspension is stirred at rt overnight then heated up to 100° C. for 1 day. Water is added to reacture mixture and the product is extracted with DCM (×2). The combined organic layers are washed with brine, dried over Na2SO4 then concentrated under vacuum affording a beige solid residue. The residue is triturated then sonicated in Et2O and the solid is filtered-off to afford the title compound. HPLC (max plot) 98.8%; Rt 3.28 min. MS (ESI+): 441.1.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH2:12][CH2:13][C:14]#[N:15])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl>O1CCCC1.C(OCC)C>[C:1]1([S:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCC(C#N)CSc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCC(CN)CSc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-(phenylthiomethyl)glutaronitrile (3.0 g.) in tetrahydrofuran (30 ml.) was stirred under an argon atmosphere while adding 10M borane-dimethyl sulphide complex (3 ml.), and the mixture was stirred at room temperature for 48 hours. The resulting gelatinous mass was treated with methanol (50 ml.) added over 1 hour and the mixture was stirred until a clear solution was obtained. The solution was acidified with a solution of hydrogen chloride in diethyl ether and then evaporated to dryness. The residue was partitioned between water and diethyl ether, and the aqueous phase was basified with 10N aqueous sodium hydroxide and then extracted three times with ether. The combined ether extracts were dried and then evaporated to dryness. The residue was purified by column chromatography on silica gel (150 g.) eluting with a mixture of ethyl acetate/methanol/concentrated ammonia, 6:1:0.5 (v/v) to give 2-(phenylthiomethyl)pentane-1,5-diamine characterised as the dihydrochloride, m.p. 166°-169°, after crystallisation from ethanol.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:31])C1C=CC=CC=1.C(Cl)Cl>CO>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([NH2:10])=[C:12]([F:31])[CH:13]=2)[CH2:18][CH2:19]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.9 %

Procedure:
{4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohex-1-enyl]-2-fluoro-phenyl}-carbamic acid benzyl ester (1.08 g, 2.37 mmol) was dissolved in MeOH (120 mL) and DCM (5 mL) to form a clear solution. The flask was flushed with nitrogen and Pd—C (10%) (108 mg) was added. The solution was stirred under hydrogen atmosphere at rt for 4 h. TLC (30% and 50% EtOAc in Heptane) indicated that the reaction was complete. The solution was filtered through a Celite pad, rinsed with MeOH. The filtrate was concentrated in vacuo to obtain 0.85 g (100% yield) of the title compound as an oil. This material was used immediately in the following reaction.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6](C(F)(F)F)=[C:7]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:8]=1.CC(O)=O>CCOC(C)=O.CO.O=[Pt]=O>[ClH:1].[Cl:1][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][C:7]=1[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: Fc1ccc(C(F)(F)F)c(C2=CCNCC2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(Cl)c(C2CCNCC2)c1
Temperature: 25 °C
Yield: 131.2 %

Procedure:
A mixture of 4-(5-fluoro-2-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (16, 0.310 g, 1.31 mmol) PtO2 (0.085 g, 0.37 mmol), and HOAc (71 μL, 1.31 mmol) in EtOAc (12 mL) stirred at ambient temperature for 18 under an atmosphere of H2 (1 atm). The reaction mixture was diluted with EtOAc (50 mL) and CH3OH (5 mL) and filtered over Celite and the filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (5 mL). To this solution was added HCl (2.0 N solution in Et2O, 2.0 mL) and the mixture stirred at ambient temperature for 5 min. The resulting suspension was diluted with Et2O (20 mL) and the solids collected by filtration to give 4-(2-chloro-5 fluorophenyl)piperidine hydrochloride (17) as an off-white solid (215 mg, 48%): 1H NMR (300 MHz, DMSO-d6) δ 8.93-8.20 (m, 2H), 7.58-7.48 (m, 1H), 7.22-7.12 (m, 1H), 7.11-7.01 (m, 1H), 3.43-3.30 (m, 2H), 3.29-3.16 (m, 1H), 3.14-2.89 (m, 2H), 2.01-1.68 (m, 4H); ESI MS m/z 214 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:42]=[CH:41][C:13]([C:14]([NH:16][S:17]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC(Cl)(Cl)Cl)=[O:32])=[C:22]([CH3:39])[C:21]=2[CH3:40])(=[O:19])=[O:18])=[NH:15])=[CH:12][CH:11]=1)=[O:5])[CH3:2].O>[Zn].CC(O)=O>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:42]=[CH:41][C:13]([C:14]([NH:16][S:17]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:22]([CH3:39])[C:21]=2[CH3:40])(=[O:19])=[O:18])=[NH:15])=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C(=N)NS(=O)(=O)c2c(C)cc(OCCCC(=O)OCC(Cl)(Cl)Cl)c(C)c2C)cc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCOc1ccc(C(=N)NS(=O)(=O)c2c(C)cc(OCCCC(=O)O)c(C)c2C)cc1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 32.6 %

Procedure:
Zn powder (0.32 g) was added to a mixture of 4-ethoxycarbonylpropoxy-N-{4-[3-(2,2,2-trichloroethoxycarbonyl)propoxy]-2,3,6-trimethylbenzenesulfonyl}benzamidine (0.65 g), water (2 ml), and AcOH (18 ml) under ice-water cooling. The reaction mixture was stirred at room temperature for 3.25 hours, and then evaporated. The resulting precipitate was removed by filtration, and was washed with AcOEt and isopropyl ether (IPE). The filtrate, AcOEt, and IPE were combined, and then washed with water. The organic phase was dried over MgSO4, and evaporated. The resulting residue was purified by chromatography over silica gel (CHCl3-MeOH as eluent) to give 4-ethoxycarbonylpropoxy-N-[4-(3-carboxypropoxy)-2,3,6-trimethylbenzenesulfonyl]benzamidine (0.17 g) as an oil compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][OH:34])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1>CO.[C].[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][OH:34])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Agent: [Pd]
Solvent: CO
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
10% Palladium carbon (0.35 g.) was added to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer: 0.7 g.) in methanol (70 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 1.5 hours. The resultant mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added an aqueous solution of sodium bicarbonate and the insoluble substance was filtered out. The filtrate was washed with ethyl acetate and methylene chloride in turn, bubbled with nitrogen gas and then lyophilized. The residue was dissolved in water (30 ml.) and adjusted to pH 3.8 with 10% hydrochloric acid. The solution was subjected to column chromatography on macroporous, nonionic adsorption resin "Diaion HP-20" (Trade mark; manufactured by Mitsubishi Chemical Industries, Ltd., 20 ml.), washed with water, and then eluted with 40% aqueous acetone. After acetone was removed from the eluate under reduced pressure, the residue was lyophilized to give 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 0.25 g.)
Reaction SMILES: [NH2:1][C:2]1[C:6]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([S:21]([N:24]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[C:16]([F:42])[CH:15]=2)=[CH:5][N:4]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[N:3]=1.[C:49](OC(=O)C)(=[O:51])[CH3:50].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:41][O:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[CH2:31][N:24]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][N:26]=1)[S:21]([C:17]1[C:16]([F:42])=[CH:15][C:14]([O:13][C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[C:6]2[C:2]([NH:1][C:49](=[O:51])[CH3:50])=[N:3][N:4]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:5]=2)=[C:19]([CH3:20])[CH:18]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3N)cc2F)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3NC(C)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
To a solution of the 4-({(1S*,2R*)-2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (78 mg, 0.115 mmol) prepared in Example 96a in pyridine (0.50 mL), acetic anhydride (0.021 mL, 0.229 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. To the reaction solution, water (10 mL) and ethyl acetate (10 mL) were added, and the organic layer was washed with water (10 mL) and then saturated saline (10 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (37.2 mg, 45%) as a colorless amorphous solid.
Reaction SMILES: [Cl-].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CN(C)[CH:15]=[O:16]>>[CH:15]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[NH:2][CH:3]=1)=[O:16]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Product: N#Cc1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Phophoyl chloride (4.24 ml, 45.48 mmol) was added dropwise to dimethylformamide (3.52 ml, 45.48 mmol) and stirred for 30 mins at room temperature. A solution of 1H-indole-5-carbonitrile (5.39 g, 37.9 mmol) in dimethylformamide (10 ml) was added dropwise. A solid precipitated, further dimethylformamide (10 ml) was added to aid stirring and the reaction mixture was then stirred at room temperature for 3 hr. Water was s added to quench the reaction mixture which was then stirred for 18 hr. The stirring was stopped and the reaction mixture was left to stand, after 24 hr a pink solid had precipitated in the organic layer. The layers were separated and organic layer filtered, washed with water and dried to give the desired product (5.44 g, 84%). 1H NMR (DMSO) δ 7.60-7.80 (m, 2H), 8.20-8.30 (m, 2H), 10.00 (s, 1H), 12.20-12.35 (s, br, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.C[N:22]([CH:24]=O)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:32][CH:31]=1)=O>O.CCOC(C)=O>[CH2:4]([C:24]1[N:18]([C:17]2[CH:19]=[CH:20][C:14]([O:13][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]4)=[CH:15][CH:16]=2)[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:32][CH:31]=2)[N:22]=1)[CH2:3][CH2:12][CH3:11]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc2cc(Oc3ccc(N)cc3)ccc2c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of an 4-(6-methoxy-naphthalen-2-yloxy)aniline (5 mmol) in anhydrous DMF (20 mL) DIEA (15 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation without additional purification.
Reaction SMILES: C([O-])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[CH3:19][O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:29])[CH:27]=[CH2:28].O>CO>[CH3:19][O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:29])[CH:27]1[O:2][CH2:28]1
Reactant: O=C([O-])[O-]
Reactant: C=CC(=O)CCCCC(=O)OC
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCC(=O)C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
39.1 g (250 mmol) of sodium percarbonate were added in four portions at room temperature, over a period of 2 hours, with stirring, to 13.9 g (82 mmol) of 6-oxo-7-octenoic acid methyl ester in 210 ml of methanol. After stirring for a further one hour at room temperature, the reaction mixture was added to 1000 ml of water and extracted several times with methylene chloride. The combined organic phases were washed with water. After drying over sodium sulfate, the solvent was distilled off using a rotary evaporator. 13.5 g (88%) of 7,8-epoxy-6-oxo-octanoic acid methyl ester were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1C=CC=CC=1.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
4-Benzylpiperazine(3.3 ml, 18.9 mmol) was added to a solution of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), which was then stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.38 g of the titled compound. (Yield 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[O:14]1[CH:16]([CH2:17][CH3:18])[CH2:15]1>C(O)C>[OH:14][CH:16]([CH2:17][CH3:18])[CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: CCC1CO1
Solvent: CCO
Product: CCC(O)CN1C2CCCCC2C(C)CC1(C)C

Procedure:
Following the procedures given above, 2,2,4-trimethyl decahydroquinoline of about 76% cis structure was reacted with 1,2-epoxybutane in the presence of ethanol to yield 58 grams of 1-(2'-hydroxybutyl)-2,2,4-trimethyl decahydroquinoline, which had a boiling point of 110°-112° C. at 0.50 mm Hg. Calculated contents for the formula C16H31NO were 75.83% carbon, 12.33% hydrogen, and 5.53% nitrogen and the measured values were 76.55% carbon, 13.13% hydrogen, and 5.49% nitrogen.