Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[N:13][N:14]2[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:9]=1.[Br:32]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:32][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([F:17])[C:8]=1[F:7])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[N:13]=[C:12]2[NH:26][C:27](=[O:31])[CH2:28][CH2:29][CH3:30]
Reactant: BrBr
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)ccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(Br)cc12
Reaction time: 0.17 h

Procedure:
0.87 cm3 of pyridine is added to 1 g of N-[6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide described above in 30 cm3 of chloroform, followed by addition of 0.56 cm3 of bromine, and the mixture is refluxed overnight. 50 cm3 of dichloromethane and 50 cm3 of aqueous 10% sodium thiosulfate solution are added to the reaction medium. After stirring for 10 minutes, the insoluble material is removed by filtration on a sinter funnel and the organic phase is washed with 50 cm3 of water and with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out by settling of the phases, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The crude product, 1.1 g, is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 230 mg of N-[5-bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[C:10]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N+:11]([O-:26])[C:12]([OH:25])=[C:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:33])=[N-].B(Br)(Br)Br>ClCCl.CO.C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][C:9]1[C:10]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N+:11]([O-:26])[C:12]([O:25][CH3:33])=[C:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cc1c(OC(=O)OC(C)(C)C)nc(Cc2c[nH]c3ccccc23)c(O)[n+]1[O-]
Reactant: C=[N+]=[N-]
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: COc1c(Cc2c[nH]c3ccccc23)nc(OC(=O)OC(C)(C)C)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In 0.5 ml of dichloromethane-methanol (3:1) was dissolved 10 mg of 3-tert-butoxycarbonyloxy-6-hydroxy-5-(indol-3-yl)methyl-2-isobutylpyrazine 1-oxide. Thereto were added, under ice cooling, a solution of diazomethane dissolved in diethyl ether and 4-5 drops of a solution of 0.1 M of boron tribromide dissolved in methylene chloride. The container was cook-stoppered and the contents were stirred for 12 hours at room temperature. The contents were then diluted with 5 ml of dichloromethane, and the mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by a silica gel thin layer chromatography (dichloromethane:methanol=40:1) to obtain 3.6 mg of the title compound as a pale brown solid substance.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11](=[CH2:24])[CH:12]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[F:23])[OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][CH2:10][C:11](=[CH2:24])[C:12]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[F:23])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(CCO[Si](C)(C)C(C)(C)C)C(O)c1cc([N+](=O)[O-])ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C=C(CCO[Si](C)(C)C(C)(C)C)C(=O)c1cc([N+](=O)[O-])ccc1F
Yield: 82.5 %

Procedure:
To a solution of 4-(tert-butyldimethylsilyloxy)-1-(2-fluoro-5-nitrophenyl)-2-methylenebutan-1-ol (0.94 g, 2.64 mmol) from step B in chloroform (88 mL) was added manganese dioxide (3.45 g, 39.7 mmol), and the reaction mixture was heated under reflux for 24 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated in vacuo. The residue was purified by chromatography eluting with 5-10% ethyl acetate/hexanes to give the title compound as a colorless oil (0.77 g, 82% yield). Some unreacted starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ 8.26 (1H, m), 7.35 (1H, m), 6.18 (1H, s), 5.76 (1H, s), 3.83 (2H, t, J=6.0 Hz), 2.72 (2H, t, J=6.0 Hz), 0.90 (9H, s), and 0.08 (6H, s).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[CH:17]=1>CCOCC>[C:18]([C:9]1[C:10]2[O:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=2[CH:17]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:8]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Solvent: CCOCC
Product: CCNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
Ethylisocyanate (0.18 mL, 2.28 mmol) is added dropwise to a solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (500 mg, 2.28 mmol) in Et2O (5 mL). A solid forms after 10 min and the reaction is quenched with H2O (10 mL) after 40 min. The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to a tan solid (657 mg). This solid is recrystallized from EtOAc to give the title compound as white prisms (335 mg, 51%), mp=197°-198° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]([O:25]CC)=O)[C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[H][H]>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[CH2:1]([N:8]1[CH2:22][C:23](=[O:25])[NH:19][C:18]2[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[N:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN(Cc1ccccc1)c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
Methyl 6-(benzyl(2-ethoxy-2-oxoethyl)amino)-5-nitronicotinate (445 mg g, 1.19 mmol) was dissolved in dichloromethane (5 mL). To the yellow solution was added ammonium metavanadate (10.0 mg, 0.085 mmol), triphenyl phosphite (aprox 10 ul, 0.032 mmol), and Pt/C (50 mg, 5% w/w). The reaction mixture was pressurized with hydrogen gas (75 psi) and stirred at room temperature for 48 h. The reaction was then depressurized and diluted with dichloromethane (20 mL) which was then refluxed for 30 min. The hot solution was filtered through a pad of celite and washed with hot dichloromethane (3×10 mL). The filtrate was concentrated to yield the title compound (250 mg, 71%) as a white solid. [M+H] calc'd for C16H15N3O3, 298; found, 298.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[Si:7]([CH3:10])([CH3:9])[CH3:8]>C(OCC)C>[CH3:8][Si:7]([CH3:10])([CH3:9])[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)Cl
Reactant: C1CCNC1
Solvent: CCOCC
Product: C[Si](C)(C)N1CCCC1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
Step 1—To an ice-cold solution of pyrrolidine (167 ml, 2.00 mol) in diethyl ether (500 ml) was added a solution of chlorotrimethylsilane (127 ml, 1.00 mol) in diethyl ether (100 ml) over 1 hour. The solid was removed by filtration and washed with diethyl ether (100 ml). The filtrates were concentrated in vacuo then distilled at atmospheric pressure to give N-trimethylsilylpyrrolidine (104 g, 73%) as a colorless liquid: b.p. 139-140° C.; 1H NMR (CDCl3) 0.09 (s, 9H), 1.74 (m, 4H), 2.91 (m, 4H); 13C NMR (CDCl3) 3.50, 28.26, 48.33
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](O)=O)=[O:41])([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]2[O:10][C:47]([C:46]3[CH:45]=[C:44]([CH:52]=[CH:51][CH:50]=3)[CH2:43][NH:42][C:40](=[O:41])[O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[N:12][N:11]=2)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nnc(-c3nc(Br)cnc3N)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-amino-6-bromo-pyrazine-2-carbohydrazide (1.2 g, 5.172 mmol), TBTU (1.333 g, 5.689 mmol), 3-[(tert-butoxycarbonylamino)methyl]benzoic acid (1.300 g, 5.172 mmol) and DIPEA (1.338 g, 1.803 mL, 10.35 mmol) in a solution in DMF (13.98 mL) were stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (35 mL), washed with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to a solid. This solid was suspended in MeCN (83.89 mL) at room temperature followed by the addition of dibromo(triphenyl)phosphorane (2.183 g, 5.172 mmol) and DIPEA (1.338 g, 1.803 mL, 10.35 mmol). The resulting mixture was stirred at room temperature for 2 h and then concentrated in vacuo to leave a solid. This was purified by column chromatography on silica eluting with EtOAc/petroleum ether, Product fractions were combined and concentrated in vacuo to leave the product as a white solid. The mixture was conc. to a solid and purified by column chromatography using ethylacetate/pet ether as elaunt to afford the product as a white solid (924 mg, 40% yield); 1H NMR (400 MHz, DMSO) d 1.43 (s, 9H), 4.26 (m, 2H), 7.55 (m, 3H), 7.80 (br s, 2H), 7.97 (m, 1H) and 8.45 (s, 1H) ppm; MS (ES+) 449.08
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17]>O1CCCC1>[C:3]([CH:5]([C:16](=[O:17])[C:15]1[CH:19]=[C:20]([F:25])[C:21]([F:24])=[C:22]([F:23])[C:14]=1[F:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (12.8 g) was added to tetrahydrofuran (400 ml) and the mixture cooled with stirring using an ice bath. tert-Butyl cyanoacetate (22.8 g) was added dropwise over a 20 minute period with continued ice bath cooling such that the temperature remained below 10° C. 2,3,4,5-Tetrafluorobenzoyl chloride (34 g) was then added dropwise over a one hour period while maintaining the temperature between -5° C. and 0° C. using an ice-acetone bath. The cooling bath was removed and stirring continued for another 30 minutes while the mixture was warmed to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (1.5 liter) and toluene (100 ml) were added with stirring. The layers were separated and the aqueous layer extracted again with toluene (100 ml). The aqueous layer was acidified to pH 1 using 36% hydrochloric acid. The crystals were collected and washed with excess water and dried under vacuum at room temperature to give tert-butyl 2-cyano-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (47 g, 93%), mp 90°-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:36]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:36])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1cc(Br)c(N)c(Br)c1)CC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCNc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-(4-amino-3,5-dibromophenylamino)-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O>ClCCl>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: Cn1ccc2cc(C(=O)O)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCc2cc(C(=O)O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
Dichloromethane (2 ml) and triethylsilane (1 ml) were added to 1-methyl-1H-indole-5-carboxylic acid (100 mg). The mixture was cooled to 0° C., trifluoroacetic acid (1 ml) was added dropwise thereto, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and precipitate was collected by filtration. The precipitate was washed with ether and dried under reduced pressure to give the title compound (66 mg, Y.:65%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:42]([N:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[CH3:45])=[O:43])[CH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH:18]=[CH:19][C:20]2[N:21](C(OC(C)(C)C)=O)[C:22]3[C:27]([C:28]=2[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C>[Pd].C(O)C.CCOC(C)=O>[NH2:8][C@H:9]([C:42]([N:44]([C:46]1[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=1)[CH3:45])=[O:43])[CH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][C:20]2[NH:21][C:22]3[C:27]([C:28]=2[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1c(C=CCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)n(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N(C)C(=O)[C@@H](N)Cc2cccc(CCCc3[nH]c4ccccc4c3CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (5)-tert-butyl 2-(3-(3-(2-(tert-butoxycarbonylamino)-3-((4-methoxyphenyl)(methyl)amino)-3-oxopropyl)phenyl)prop-1-enyl)-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (178 mg, 0.24 mmol) and palladium on carbon (134 mg, 10%) in 2.5 ml of ethanol and 2.5 ml of EtOAc, was degassed with nitrogen. The reaction was stirred at room temperature for 3 hours under an atmosphere of H2 at 1 atm. The suspension was purged with nitrogen and filtered through celite. The filtrate was concentrated and the crude product was used without further purification. MS (m/z) 728 [M+H]+. The crude product was redissolved in 1 ml of tetrahydrofuran and 1 ml of methanol and 2 ml of 2N (aq.) lithium hydroxide was added to the solution. The solution was heated at 60° C. for 2 hours. The solution was cooled in an ice bath and acidified with 1N (aq) HCl. The resulting mixture was extracted with EtOAc (2×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated. TFA (2 ml) was added to the crude product. After 20 minutes, the solvent was removed and the residue was dried under high vacuum. The crude product was used without further purification. The crude product yield was (100 mg, 0.2 mmol). MS (m/z) 500 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1.CN1CCNCC1.C(#N)C=C.[C:23](Cl)(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCN)CC1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CN1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: C=CC#N
Product: CCCCCCCCCCCCCC(=O)NCCCN1CCN(C)CC1

Procedure:
4.7 g. (0.03 mol) of N-methyl-N'-(3-aminopropyl)-piperazine (prepared from N-methyl piperazine and acrylonitrile and subsequent reduction to the primary amine) in 200 mL chloroform was cooled down in an ice bath. To this was added 7.3 g. (0.03 mol) of myristoyl chloride dropwise for two hours. The reaction mixture was brought to room temperature and then allowed to react for another four hours. The reaction mixture was treated with 10 g. of sodium bicarbonate in 100 mL water and the separated chloroform layer was washed with water (2×200 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Crystallization from acetonitrile afforded 8 g. (72.3%) of the subject product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[N:7]([O])[C:6]([CH3:10])([CH3:9])[CH2:5][CH:4]([OH:11])[CH2:3]1.[Br-].[K+].C(=O)(O)[O-:16].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.ClCCl>[CH3:1][C:2]1([CH3:12])[N:7]([OH:16])[C:6]([CH3:10])([CH3:9])[CH2:5][CH:4]([OH:11])[CH2:3]1
Reactant: CC1(C)CC(O)CC(C)(C)N1[O]
Reactant: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(O)CC(C)(C)N1O

Procedure:
A mixture of bisnoralcohol (I, 4 g), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (4-hydroxy-TEMPO, 10 mg), potassium bromide (133 mg), sodium bicarbonate (133 mg), dichloromethane (14 ml) and water (2.2 ml) are cooled to 1°. While maintaining this temperature, aqueous sodium hypochlorite (14%, 6.3 ml) is added over a five hr period. The reaction is complete and aqueous sodium thiosulfate is added, the two phases were separated, and the bisnoraldehyde product is crystallized by replacing the dichloromethane with heptane to give the title compound, mp=153-154°; NMR (CDCl3) 9.56, 5.73, 2.2-2.5, 1.2-2.1, 1.20, 1.10, 0.79 δ; [α]D22=+83.4° (methylene chloride, c=1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14].[CH3:15][S:16]([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>N1CCCCC1.C(O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[C:20]#[N:21])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: COc1cc(C=O)ccc1OCCO
Reactant: CS(=O)(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C(C#N)S(C)(=O)=O)ccc1OCCO

Procedure:
A mixture of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde (0.98 g, 0.005 mol), (see Example 1 of U.S. Pat. No. 4,707,537, supra), methylsulfonylacetonitrile (0.60 g, 0.005 m), ethanol (10 mL) and piperidine (5 drops) is heated at reflux for 1 hour, during which time the product crystallizes. The reaction mixture is allowed to cool and the very pale yellow product is collected by filtration, washed with ethanol and dried in air. The yield of product is 1.05 g (70.9%). Mass spectrometry supports the following structure: ##STR22## In methylene chloride the product has an absorption maximum at 362 nm.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:20][CH:21]1[C:41](=[O:42])[N:23]2[C:24]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[CH:25][CH2:26][S:27][C@H:22]12.CN(C)C=O.P(Cl)(Cl)(Cl)=O>O.CC(C)=O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[C:24]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=4)=[O:29])=[CH:25][CH2:26][S:27][C@H:22]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CCCCCON=C(C(=O)O)c1csc(NC=O)n1
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 100.2 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 4.14 g.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (4.5 g.), N,N-dimethylformamide (1.41 g.), phosphoryl chloride (2.96 g.), tetrahydrofuran (72 ml.), acetone (15 ml.) and water (15 ml.) were treated in a similar manner to that of Example 15-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 8.1 g.).
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3[OH:21])C2=CC=1.[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:46]([CH2:47][CH2:48][CH3:49])[CH2:45][CH2:44][C:43]([C:50]([NH:52][C:53]4[CH:58]=[CH:57][C:56]([S:59][CH2:60][C:61]5[N:65]([CH2:66][CH2:67][CH3:68])[CH:64]=[N:63][N:62]=5)=[CH:55][CH:54]=4)=[O:51])=[CH:42][C:41]=3[CH:69]=2)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH3:26].[O-]O.[O-]O.C1(C(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:46]([CH2:47][CH2:48][CH3:49])[CH2:45][CH2:44][C:43]([C:50]([NH:52][C:53]4[CH:54]=[CH:55][C:56]([S:59]([CH2:60][C:61]5[N:65]([CH2:66][CH2:67][CH3:68])[CH:64]=[N:63][N:62]=5)=[O:21])=[CH:57][CH:58]=4)=[O:51])=[CH:42][C:41]=3[CH:69]=2)=[CH:35][CH:36]=1)[CH2:24][CH2:25][CH3:26]
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCN3CCC)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)c1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCN3CCC)cc1
Reaction time: 1 h
Yield: 420.5 %

Procedure:
To a solution of (S)-(−)-1,1′-bi-2-naphtol (87.5 mg) in toluene (10 ml) were added titanium tetraisopropoxide (45.2 μl) and water (55 μl) at room temperature and the mixture was stirred for 1 hour. To the reaction solution were added 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.0 g) and cummene hydroperoxide (80%, 0.31 ml) and the mixture was stirred for 20 hours at room temperature Cumene hydroperoxide (80%, 0.14 ml) was added to the mixture, and the mixture was further stirred for 10 hours. To the reaction solution was added an aqueous solution of sodium thiosulfate and the mixture was stirred for several minutes and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate→ethanol:ethyl acetate 1:19), to give (−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 177) (860.9 mg) as yellow amorphous.