Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][NH:11][CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]([O:15]CC)=O.[O-:34][C:35]#[N:36].[K+].Cl>C(O)C.O>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:12]1[N:11]([CH2:10][CH2:9][CH:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:35](=[O:34])[NH:36][C:13]1=[O:15])=[O:25])[CH3:28]
Reactant: CCCCCC(CCNC(CCCCCCC(=O)OCC)C(=O)OCC)OC1CCCCO1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCC(CCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC)OC1CCCCO1
Yield: 94.2 %

Procedure:
To a solution of diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate (7.8 g) in ethanol (32 ml) was added a solution of potassium cyanate (3.0 g) in water (6 ml). The resulting suspension was stirred and cooled during the gradual addition of 2 N-hydrochloric acid (16.7 ml). The solution was allowed to stand at room temperature for 22 hours, most of the ethanol was evaporated, water was added, and the insoluble oil was extracted with ether. The ether solution was washed with water, dried over magnesium sulphate, and evaporated. The yellow oil so obtained (8.0 g) was dissolved in light petroleum (b.p. 60°-80° C.) and the solution was refluxed for 4 hours, evaporated to dryness, and the residual oil was heated on the steambath for 2 hours to give 5-(6-ethoxycarbonylhexyl)-1-(3-(tetrahydropyran-2-yloxy)octyl)hydantoin as a yellow oil (7.3 g), which was used without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[Mg].II.[C:16](=[O:18])=[O:17].Cl>C1COCC1.O>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]([OH:18])=[O:17])=[CH:3][CH:4]=1
Reactant: O=C=O
Reactant: Brc1ccc(Br)c2ccccc12
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Br)c2ccccc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,4-dibromonaphthalene (100 g) in THF (500 ml) is added to magnesium (8.49 g) and iodine (trace) in THF (200 ml) over about 2 h and heated at 65-75° C. for up to 7 h (typically 3-4 h) to prepare a solution of the Grignard reagent. The solution is cooled to 0-10° C. and carbon dioxide gas is passed through the solution for 10-16 h. Water (100 ml) is added slowly, and after stirring for about 30 min at 0-10° C., is acidified (typically to pH 2-3) with hydrochloric acid. The THF layer is separated off, and concentrated. The residue is added to aqueous sodium carbonate (20%, 500 ml) and washed with toluene (2×200 ml). The aqueous solution is treated with hydrochloric acid (typically to pH 2-3). The product is filtered off, washed with water, and dried under vacuum at about 90-100° C. for about 12 h (dry weight 60 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[CH2:7][CH2:6]2)[O:4]CC1.Cl.O>O1CCOCC1>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:9][CH2:10]1
Reactant: N#Cc1ccccc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1C1CCC(=O)CC1
Temperature: 80 °C

Procedure:
To a stirring solution of 2-(1,4-Dioxaspiro[4.5]dec-8-yl)benzonitrile (8.7 g, 35.7 mmol) in dioxane (200 mL) was added 1N HCl (200 mL) and the reaction heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into water (1 L) the mixture was extracted with ethyl acetate (3×250 mL). The combined organics were washed with brine (200 mL) and then dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give the product.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.CN(C=O)C>O.C(OCC)(=O)C>[CH3:19][N:18]([CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1
Reactant: N#Cc1cncc(Cl)n1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CC(=O)OC(C)(C)C)c1cncc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
2-Chloro-6-cyanopyrazine (2.09 g, 15.0 mmol), sarcosine tert-butyl ester hydrochloride salt (2.72 g, 15.0 mmol) and triethylamine (2.38 ml, 17.0 mmol) were added to DMF (30 ml), and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.00 g, 27%) as pale yellow crystals.
Reaction SMILES: [F:1]/[C:2](=[C:6](/[CH3:29])\[CH:7]=[CH:8]\[C:9](\[F:28])=[C:10](/[C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=2[CH:14]=1)\[CH2:11][CH3:12])/[C:3]([OH:5])=[O:4].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:23][C:22]1[C:13](/[C:10](/[CH2:11][CH3:12])=[C:9](/[F:28])\[CH:8]=[CH:7]\[C:6](\[CH3:29])=[C:2](/[F:1])\[C:3]([OH:5])=[O:4])=[CH:14][C:15]2[C:16]([CH3:27])([CH3:26])[CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]=2[CH:21]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC/C(=C(F)/C=C/C(C)=C(\F)C(=O)O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Solvent: c1ccncc1
Product: CC/C(=C(F)/C=C/C(C)=C(\F)C(=O)O)c1cc2c(cc1OC(C)=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
To a solution of (2Z,4E,6E)-2,6-difluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-nona-2,4,6-trienoic acid (Intermediate 22, 108 mg, 0.27 mmol) in pyridine (2 mL) at 0° C. was added acetic anhydride (100 μL, 1.1 mmol). The mixture was stirred for 4 h while warmed to ambient temperature. The reaction was quenched with aqueous Na2CO3, stirred for 30 min, acidified with 1M HCl and extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10%→50% EtOAc-hexane) to give the title compound as a yellow solid (82 mg, 69%).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[SH:22][CH2:23][CH2:24][OH:25].[H-].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[S:22][CH2:23][CH2:24][OH:25]
Reactant: OCCS
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)c3c(SCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (300 mg, 0.60 mmol) and neat 2-mercaptoethanol (Sigma, 4 mL) was treated with NaH (Aldrich, 98%, 210 mg that was emulsified with 0.4 mL of mineral oil) in small portions at room temperature. After the evolution of gas stopped, the mixture was heated gradually to 120° C. and stirred at this temperature for 6 hours. The reaction mixture was then poured in a mixture of ethyl acetate and water. The aqueous layer was extracted few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by HPLC (silica gel, with 25% ethyl acetate in hexanes) and then precipitated out of THF with excess pentane to give 6-fluoro-5-(2-hydroxy-ethylsulfanyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 98 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=2)C#N)=[CH:4][CH:3]=1>Br>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[N:13]=2)=[O:22])=[CH:6][CH:7]=1
Reactant: N#CC(C(=O)c1cccc(C(F)(F)F)n1)c1ccc(F)cc1
Agent: Br
Product: O=C(Cc1ccc(F)cc1)c1cccc(C(F)(F)F)n1
Reaction time: 16 h
Yield: 65.5 %

Procedure:
A slurry of 2-(4-fluoro-phenyl)-3-oxo-3-(6-tri fluoromethyl-pyridin-2-yl)-propionitrile (1.4 g, 4.4 mmol) in 48% HBr is warmed to reflux for 8 h, allowed to stand at ambient temperature 16 h, then warmed at reflux for 8 h. The mixture is extracted with ether, treated with a small amount of sodium bicarbonate, extracted with ether, made basic with solid sodium hydroxide, and extracted again with ether. Ethereal extracts are combined, dried over magnesium sulfate, and concentrated in vacuo to a dark oil. The residual oil is purified on a silica gel cartridge prepared with hexane then eluted with methylene chloride to yield 816 mg (65%) of the title compound as a dark oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C@H:11]2[NH:14][CH2:15][C:16]2[N:17]([C:21](OC(C)(C)C)=[O:22])[CH:18]=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH2:30]1COCC1>>[CH3:30][C:18]1[N:17]2[C:21](=[O:22])[N:14]([C@H:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:13]=4)[CH2:9][CH2:10]3)[CH2:15][C:16]2=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NCc1cccn1C(=O)OC(C)(C)C)CC2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2n1C(=O)N([C@@H]1CCc3ccc(C(=O)O)cc31)C2
Temperature: 25 °C
Reaction time: 14 h
Yield: 26 %

Procedure:
A solution of (R)-tert-butyl 2-((6-(methoxycarbonyl)-2,3-dihydro-1H-inden-1-ylamino)methyl)-1H-pyrrole-1-carboxylate (500 mg, 1.3 mmol, 1.0 eq.) in THF (5 ml) was added to a stirred suspension of NaH (104 mg, 2.6 mmol, 2.0 eq., 60% in mineral oil) in THF (15 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was quenched with water (50 ml) and washed with ethyl acetate (50 ml). The aqueous layer was acidified with 2 N HCl (5 ml) and extracted with ethyl acetate (2×100 ml). The combined organic fractions were washed with brine (50 ml), dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue obtained was used for the next step without further purification. Yield: 26% (100 mg, 0.34 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4].[C:28](O)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:4][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH2:2][O:1][C:28](=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 420 mg (1.08 mmol) of benzyl rac-α-[[(2-hydroxy-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate, 610 mg (2.15 mmol) of oleic acid, 710 mg (1.88 mmol) of HBTU and 660 mg (5.38 mmol) of 4-dimethylaminopyridine in 10 ml of methylene chloride was stirred at room temperature for 15 hours. The reaction solution was subsequently poured into 70 ml of ice-cold 2N sodium carbonate solution and extracted three times with 150 ml of ethyl acetate each time. The organic extracts were washed with 70 ml of ammonium chloride solution, then combined, dried over magnesium sulphate and evaporated under reduced pressure. For purification, the crude product (1.25 g) was chromatographed on 50 g of silica gel with a 95:5 mixture of toluene and ethyl acetate as the eluent. There were obtained 580 mg of benzyl rac-α-[[[1,1-dimethyl-2-[[(Z)-9octadecenoyl]oxy]ethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 655 (M+H)+.
Reaction SMILES: COC[N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][CH2:15][CH:16]=O)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]1.[C-]#N.[BH4-].[Na+].[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1.C(O)(=O)C>[CH2:29]([O:28][C:26]([CH:25]1[CH2:31][CH2:32][N:22]([CH2:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4[N:18]=[CH:19][CH:20]=[N:21][C:5]=4[NH:4][C:9]=3[CH:10]=2)[CH2:23][CH2:24]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COCN1c2cc(CCC=O)ccc2Sc2nccnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CCCc2ccc3c(c2)Nc2nccnc2S3)CC1
Yield: 49.6 %

Procedure:
To a solution of 0.6 g of 3-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]propionaldehyde and 0.31 g of ethyl isonipecotate in acetonitrile (50 ml) was added 0.2 g of sodium borohydride cyanide. Further, acetic acid was added so as to maintain the pH value at 4. Then the resulting mixture was reacted at room temperature for 12 hours. After adding an aqueous solution of sodium hydroxide, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the crude product thus obtained was dissolved in 30 ml of tetrahydrofuran. After adding 1 ml of 6 N hydrochloric acid, the resulting mixture was reacted for 1 hour. After adding an aqueous solution of sodium bicarbonate, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with methanol/dichloromethane) to thereby give 0.39 g of the title compound as a brown oily substance.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].C(=O)([O-])[O-].[K+].[K+]>O>[N:12]1[NH:13][C:14](=[S:15])[N:16]=[C:2]2[C:4]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[NH:1]2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: S=c1nc2[nH]c3ccccc3c2n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A mixture of 7.36 g (50.0 mmoles) of isatin, 250 ml of water, 5.01 g (55.0 mmoles) of thiosemicarbazide and 10.4 g (75.0 mmoles) of potassium carbonate was heated to reflux. After 30 minutes, a red solution resulted which was cooled to room temperature and filtered through celite. The pH was adjusted to 4.5 with glacial acetic acid and the resulting yellow solid was collected and washed with hot ethanol. After drying, 8.04 g of material was obtained. (J. Medicinal Chemistry, 15:277 (1972))
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH2:22][CH2:23][N:24]2[CH2:40][CH2:39][C:27]3([N:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][NH:29][C:28]3=[O:38])[CH2:26][CH2:25]2)=O)=[CH:15][CH:14]=1.O>C1C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:20][CH2:22][CH2:23][N:24]2[CH2:40][CH2:39][C:27]3([N:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][NH:29][C:28]3=[O:38])[CH2:26][CH2:25]2)=[CH:17][CH:18]=1
Reactant: O=C(CCN1CCC2(CC1)C(=O)NCN2c1ccccc1)Nc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCN(c2ccccc2)C12CCN(CCCNc1ccc(F)cc1)CC2

Procedure:
To a mixture of 4 g of lithium aluminum hydride and 40 ml of tetrahydrofuran was added portionwise 2 g of 8-{2-[N-(p-fluorophenyl)carbamoyl]ethyl}-1-phenyl-4-oxo-1, 3, 8-triazaspiro[4, 5]decane under cooling. Then, the mixture was heated under reflux for 4 hours. To the reaction mixture were gradually added water and benzene under cooling, and the precipitate was filtered off. The organic layer was separated, dried over sodium sulfate evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 8-{3-(p-fluoroanilino)propyl}-1-phenyl-4-oxo-1, 3, 8-triazaspiro[4, 5]decane, m.p. 158°-162° C; recrystallized from benzene, m.p. 177°-178° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:3][CH:2]=1.S(Cl)(Cl)=O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1Nc1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Reaction time: 3 h
Yield: 103.5 %

Procedure:
2-(4-Pyridinylamino)benzoic acid (244 g, 1.14 moles) was added with stirring at room temperature to 1.4 liters of thionyl chloride containing a catalytic amount (about 1.4 ml) of N,N-dimethylformamide. A mildly exothermic reaction ensued. The reaction was stirred at room temperature for 3 hours when the excess thionyl chloride was removed in vacuo. The residual oil was azeotroped twice with toluene. The yellowish gummy acid chloride was suspended in 1.5 liters of acetonitrile and 556 ml of piperidine was added with cooling (15°-20° C.) and stirring. Stirring was continued for 3 hours. The precipitated white solid was filtered and washed with a little cold acetonitrile. It was slurried once in about 2 liters of water while adjusting the pH to 9 by addition of potassium carbonate. The solid was dried and recrystallized from 2.7 liters of ethyl acetate to afford 166 g (51.6%) of 1-[2-(4-pyridinylamino)benzoyl]piperidine, m.p. 153°-156° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N+:10]([O-])=O)[CH:7]=2)[O:2]1>C(N)CCC>[CH2:8]([NH:10][C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14])[CH2:3][CH2:4][CH3:5]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CCCCN
Product: CCCCNc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C

Procedure:
0.05 mol (10.6 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to 40 ml n-butylamine. The reaction is exothermic. The boiling point of butylamine is reached. As soon as the exothermic effect has finished, 200 g of ice are added to the reaction medium. After neutralization of the excess butylamine with concentrated hydrochloric acid, the expected product crystallizes. After recrystallization from 96° strength ethanol or from ethyl acetate, it melts at 137° C. (literature 137° C.).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[NH:6][C:5](=[O:14])[CH:4]=1)[NH2:2].[C:15]1([CH:25]=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>CO>[CH2:9]([N:8]1[C:3]([NH:1][N:2]=[CH:25][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5](=[O:14])[NH:6][C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Reactant: O=Cc1cccc2ccccc12
Solvent: CO
Product: CC(C)Cn1c(NN=Cc2cccc3ccccc23)cc(=O)[nH]c1=O
Reaction time: 24 h
Yield: 99.2 %

Procedure:
6-hydrazino-1-isobutylpyrimidine-2,4(1H,3H)-dione (1.8 g) was dissolved in warm methanol (90 ml) and treated with 1-naphthaldehyde (1.5 g). After 24 hours, the precipitated solid was filtered and dried to give the subtitle compound (3.03 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1CCCCC1.O1CCCC1>[Cl:13][C:14]1[N:15]=[N:16][C:17]([O:20][CH3:21])=[C:18]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1
Reactant: COc1ccc(Cl)nn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1nnc(Cl)cc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a 2-necked round bottom flask under argon placed 4.0476 g of distilled diisopropylamine and 60 mL of tetrahydrofuran (Aldrich, anhydrous, no stabilizer). The mixture was cooled to −78° C., then ca 20 mL of 2.0 M butyl lithium in cyclohexane was added. The mixture was set in an ice bath for 20 minutes, then cooled to −78° C. and a solution of 2.8912 g of 3-chloro-6-methoxy-pyridazine and 3.05 mL of chlorotrimethyl silane in 12 mL of tetrahydrofuran was added over 15 minutes. The mixture was stirred for 2 hours (a deep red color formed, then faded to yellow), then quenched by the addition of 10 mL of saturated sodium dihydrogen phosphate solution. The mixture was taken up in 350 mL of ethyl acetate, washed 1×75 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[Si:36]([O:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1>[Si:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]4[N:33]=[CH:34][N:35]=[C:9]34)[CH2:4][CH2:3]2)=[CH:48][CH:49]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](O)CC2)c2ncnn12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 45 h

Procedure:
4′-{[4-(cis-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.46 g), 4-{[tert-butyl(dimethyl)silyl]oxy}phenol (0.49 g) and triphenylphosphine (0.29 g) were dissolved in tetrahydrofuran (2 mL), a solution of diisopropyl azodicarboxylate (0.58 mL, 1.9 M toluene solution) in tetrahydrofuran (1 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for 45 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as an oily compound (0.22 g, 33%).