Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([NH:22][NH:23][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)NNc2ccccc2)cc1
Temperature: 31 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture consisting of 21.88 g. (0.130 mole) p-(methylthio)benzoic acid and 25 ml. thionyl chloride was heated at the reflux temperature until evolution of gas ceased and a clear solution was obtained. After removing the excess thionyl chloride on a rotary evaporator and then under substantially complete vacuum, the solid residue that remained was dissolved in 35 ml. dioxane. The dioxane solution was mixed with a solution consisting of 14.06 g. (0.130 mole) phenylhydrazine in 100 ml. pyridine initially at 5° to 10° C. Inadvertently, about one third of the acid chloride was added rapidly and the mixture was heated to 31° C. by the exothermic reaction. The reaction mixture was set aside at 25° C. with continuous stirring for 3 days. It was then poured into 1.5 l. water in order to precipitate the desired p-(methylthio)benzoic acid 2-phenylhydrazide. The precipitate was collected on a filter, washed with water, washed with 1N hydrochloride acid, and finally washed with water. The washed filter cake was then recrystallized from 3A alcohol to give 23.2 g. (69% yield) of p-(methylthio)benzoic acid 2-phenylhydrazide having a melting point at 165.5° to 167.5° C. Recrystallization from 250 ml. ethyl acetate gave the compound melting at 167° to 168° C. (shrinks at 162° C.). Two further recrystallizations from ethyl acetate gave the compound melting at 167° to 168.5° C. with shrinkage at 161.5° C.
Reaction SMILES: [O-]CC.[Na+].[N+:5]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].C1(C)C=CC(S(O[CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=O)=O)=CC=1>CN(C)C=O.O>[CH:28]1([O:27][CH2:26][CH2:25][O:14][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:13]=[CH:12][CH:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCCC2)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCOC2CCCCC2)c1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
To a solution of 6.8 g of sodium ethoxide and 15 g of m-nitrophenol in 250 ml of dimethylformamide, 28 g of cyclohexyloxyethyl p-toluenesulfonate were added. After heating at 100° C. for 2 hours, the resulting mixture was diluted with water and extracted with benzene. The solvent was removed under reduced pressure, and the residue was purified by vacuum distillation to give 23.8 g of 3-[2-(cyclohexyloxy)ethoxy]nitrobenzene. B.P., 118°-124° C./0.1 mmHg. nD27 1.5380.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[N:11][N:10]=[N:9]1.Cl[CH:14]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>O>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:14]([N:9]2[N:10]=[N:11][CH:12]=[N:8]2)[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:29][CH:28]=1)#[N:31]
Reactant: c1nnn[nH]1
Reactant: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(CCc2ccc(F)cc2)n2ncnn2)cc1
Temperature: 25 °C

Procedure:
NaH (0.45 g of 55% suspension in mineral oil) is added to anhydrous DMF under nitrogen atmosphere. Tetrazole (1.1 g) is added and the mixture is gently heated for 20 minutes. The mixture is cooled to room temperature and 1-chloro-1-(4-cyanophenyl)3-(4-fluorophenyl)propane (1.53 g) is added. The reaction mixture is then heated for 6 hours. Water is added and the products are extracted into ethyl acetate. After drying and solvent evaporation the products are purified by flash chromatography. Elution, staring with pure methylene chloride with increasing methanol content, affords first 2-[1-(4-cyanophenyl)-3-(4-fluorophenyl)propyl]tetrazole which 1H NMR spectra is as follows:
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH3:24])[N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CI
Reactant: CS(=O)(=O)N1CCOc2ccc(C3=NNC(=O)CC3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1N=C(c2ccc3c(c2)N(S(C)(=O)=O)CCO3)CCC1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one (3 g) was suspended in 50 ml of dimethylformamide and one equivalent of 60% sodium hydride in oil was added. When gas evolution ceased, one equivalent of methyl iodide was added and the mixture allowed to stand for 1.5 hours followed by one hour at 40° C. The mixture was cooled and then poured into 200 ml of ice water, giving a precipitate that was collected by filtration, washed with water and recrystallized from ethanol. The material was further purified by chromatography on silica gel eluted with 1:1 EtOAc:Et2O yielding 0.97 g of the title product, mp 162°-165° C.
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH3:15]S(C)=O>C(Cl)Cl.O>[CH3:15][O:12][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][CH:4]([OH:3])[CH2:5][C:6]1([CH3:14])[CH3:13]
Reactant: CS(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
A solution of 9.0 g (79 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over a 10-minute period to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 31.4 g (64.1 mmol) of ferric sulfate pentahydrate, and 200 ml of dimethyl sulfoxide at a temperature of 20° C. No temperature change is observed as the hydrogen peroxide solution is added. After the addition is complete, the reaction mixture is stirred for 10 minutes. Water (50 ml) is added, and the temperature increases to 45° C. The mixture is diluted with methylene chloride (200 ml) and water (50 ml), and the aqueous layer is extracted with methylene chloride (2×100 ml). The organic layers are concentrated at reduced pressure, and the crude product is purified by flash chromatography on silica gel (4:1 heptane/ethyl acetate) to afford 1.25 g (11% yield) of the title compound, mp 93°-94° C.
Reaction SMILES: CC1C=CC(S(O[CH:12]([CH2:22][CH2:23][S:24](=[O:27])(=[O:26])[NH2:25])[CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O.Cl>CN(C=O)C>[CH2:15]([O:14][CH2:13][CH:12]1[CH2:22][CH2:23][S:24](=[O:27])(=[O:26])[NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC(CCS(N)(=O)=O)COCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)CCC(COCc2ccccc2)N1
Temperature: 25 °C
Yield: 105.2 %

Procedure:
Sulfonamide 6 (109 g, 0.26 mol) was dissolved in DMF (800 mL) and stirred at ambient temperature. To this was added K2CO3 (63 g, 0.46 mol) in one portion and the resultant mixture heated at reflux (oil bath 160° C.) for 3 hours. After this time the heating was ceased and the reaction allowed to cool with stirring overnight. The completed reaction was poured into water (1 L) and acidified with aqueous HCl (1 M, ˜500 mL) to pH 2. The resultant brown suspension was extracted with DCM (5×500 mL) and the combined organics washed with brine (1 L). A thick emulsion formed which was separated by the addition of iPrOAc until two distinct layers were visible. The organics were separated, dried (MgSO4) and evaporated to give an orange oil (66 g). This oil was purified by flash column chromatography (silica gel, 5% MeOH/DCM) to yield dioxide 7 as a yellow-orange oil (40 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH2:21][CH:20]2[C:43]([O:45]CC)=[O:44])=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH2:21][CH:20]2[C:43]([OH:45])=[O:44])=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C1CN(C(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)/C=C/C=C/c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(C(=O)O)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Added to a solution of 339 mg (0.52 mmol) of ethyl 1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine-2-carboxylate synthesized by the process of Example 33 in methanol-tetrahydrofuran (1 ml-1.5 ml) was 0.50 ml (1.5 mmol) of a 3N aqueous solution of potassium hydroxide, and the mixture was stirred for 1 hour at room temperature. A saturated saline solution (3 ml) and 1N hydrochloric acid (2 ml) were added to the reaction mixture to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant crude oil (356 mg) was purified by column chromatography on silica gel to obtain 325 mg (quantitative) of the title compound as a pale yellow amorphous powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CCCCCCCCBr
Product: CCCCCCCCN1C(C)(C)CCCC1(C)C

Procedure:
A mixture of 56.4 parts of 2,2,6,6-tetramethylpiperidine and 38.6 parts of 1-bromooctane was heated at 125°-30°C for 120 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidine hydrobromide formed during the reaction. Fractional distillation of the residue gave 1-n-octyl-2,2,6,6-tetramethylpiperidine having a boiling point of 168°C/17 mm of Hg.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=CC(=O)O)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H](c2ccc(CCC(=O)O)cc2)CC1

Procedure:
A solution of 12.6 g of 3-[4-(trans-4-propyl-cyclohexyl)-phenyl]-propenoic acid (obtained by condensation of 4-(trans-4-propylcyclohexyl)-benzaldehyde with malonic acid in pyridine) in 120 ml of ethyl acetate is hydrogenated at room temperature and atmospheric pressure, using 4 g of Pd/C (5% Pd) as catalyst. The catalyst is filtered off, and the filtrate is evaporated. Colourless crystals are obtained.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:13])[CH:7]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])#[N:15]>C1COCC1>[CH:12]([C:8]1[CH:7]=[N:6][CH:11]=[CH:10][C:9]=1[CH:19]([OH:20])[C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[C:14]#[N:15])=[O:13]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2ccncc2C=O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N,N,N′-trimethylethane (1.55 mL, 12 mmol) was dissolved in THF (30 mL) and cooled to −78° C. 2.5 M n-butyllithium (4.4 mL) was added into the reaction mixture, which was then stirred for 15 min, before the addition of pyridine-3-carbaldehyde (0.94 mL, 10 mmol). The reaction mixture was maintained at −78° C. for 15 min, then n-butyllithium (8 mL) was added slowly so that the temperature was always below −42° C. The reaction mixture was stirred 1 hour at 42° C., then cooled to −78° C. before it was transfer through a cannula into a solution of 3-cyanobenzaldehyde (23.9 g) in THF (5 mL) at −78° C., then stirred again for 15 min. The reaction mixture was then quenched with ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-[(3-formyl-pyridin-4-yl)-hydroxy-methyl]-benzonitrile as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:10][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:24]
Reactant: NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Product: O=C(NCCCl)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (prepared in Example 12, 182 mg, 0.64 mmol) in toluene (10 mL) was treated with 2-chloroethyl isocyanate (0.08 mL, 0.95 mmol). The reaction was heated at reflux for 16 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 1-(2-chloro-ethyl)-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionyl]-urea (189 mg, 76%) as a colorless oil: EI-HRMS m/e calcd for C17H21Cl3N2O2 (M+) 390.0669, found 390.0659.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]([O:11][C:12]2[CH:17]=CC=C[CH:13]=2)=[O:10])[CH:5]([CH3:18])[CH:4]=1.[CH3:19]C(C)([O-])C.[K+]>O1CCCC1>[CH3:18][CH:5]1[CH2:4][C:3](=[O:2])[CH:8]=[CH:7][N:6]1[C:9]([O:11][C:12]([CH3:13])([CH3:17])[CH3:19])=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: COC1=CC(C)N(C(=O)Oc2ccccc2)C=C1
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CC(=O)C=CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
A 3-L four neck round-bottom flask was purged and maintained with a nitrogen atmosphere and a solution of phenyl 4-methoxy-2-methylpyridine-1(2H)-carboxylate (454.1, 70.0 g, 285 mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) was added. The solution was cooled to −78° C. then potassium tert-butoxide (128 g, 1.14 mol, 4.00 equiv) was added portion-wise. The resulting mixture was stirred at 10-15° C. for 20 h then concentrated in vacuo. The residue was dissolved in EtOAc (1.5 L), then carefully quenched with ice water (200 mL). The layers were separated and the aqueous was extracted with additional ethyl acetate (100 mL). The combined organics was washed with aqueous sodium hydroxide (1.5 M, 3×100 mL), aqueous hydrochloric acid (1 M, 2×100 mL), and brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether, 1:200-1:20) as the eluent to obtain the title compound as a light yellow oil (31.0 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:20][CH:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:24][CH2:23][CH2:22][CH:21]([CH3:25])[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)nc1
Reactant: CC(C)CCN
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 99 %

Procedure:
Using the compound of Example 223, step 1, and using 3-methylbutylamine, the title compound was prepared by reductive amination as described previously.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:26][C:34](=[O:35])[NH:28][N:27]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Yield: 17.2 %

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (710 mg) in dioxane (10 mL) was added CDI (42.6 mg, 2.63 mmol). The resulting mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (130 mg, 17% over 2 steps). ESI-MS m/z [M+H]+ 431.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[N+:9]([CH2:12][S:13][C:14]1[C:19]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:18]=2[CH:17]=[CH:16][CH:15]=1)([O-:11])=[O:10]>O.COCCOC>[N+:9]([CH2:12][S:13]([C:14]1[C:19]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:2])([O-:11])=[O:10]
Reactant: O=S(=O)([O-])O[O-]
Reactant: O=[N+]([O-])CSc1cccc2c1oc1ccccc12
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])CS(=O)c1cccc2c1oc1ccccc12
Reaction time: 18 h
Yield: 98.4 %

Procedure:
A solution of potassium peroxymonosulphate (`Oxone`, trade mark; 12.8 g, 20.8 mmol) in water (52 ml) was added in one portion to a stirred solution of the nitromethylthio derivative (C) (3.64 g, 14.1 mmol) in 1,2-dimethoxyethane (75 ml). The mixture was stirred vigorously for 18 hours. The reaction mixture was diluted with water (300 ml). The solid obtained was collected by filtration, air dried and recrystallised from toluene to give 4-(nitromethylsulphinyl)dibenzofuran as a white solid (3.82 g), m.p. 174°-176° C.; microanalysis found: C,56.8; H,3.2; N,5.0%; C13H9NO4S requires: C,56.7; H,3.3 N,5.1%.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C1(C)C=CC=CC=1>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1C(F)(F)F)C(=O)OCC
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Diethyl ethoxymethylenemalonate (compound III, 50.4 mL, 249.3 mmol) and 2-(Trifluoromethyl)aniline (compound II, 31 mL, 249.3 mmol) was taken into toluene (250 mL) and refluxed overnight twice. Toluene was evaporated and the resulting liquid was taken into hexane and allowed to sit in a freezer for 1 hour. A white solid crashed out and was filtered and dried to yield 69.73 g (84.4%) of the title compound as white crystals. MS ESI (m/z) 332 ([M+H]+); MS ESI (m/z) 330 ([M−H]−); Anal Calcd. For C15H16F3NO4: C, 54.38; H, 4.87; N, 4.23. Found: C, 54.49; H, 4.68; N, 4.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([OH:18])=O.[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:28]=1[NH2:29])([CH3:26])[CH3:25]>>[CH:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:27]([CH:24]([CH3:26])[CH3:25])[C:28]=1[NH:29][C:16](=[O:18])[CH2:15][CH:14]([C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:36])[CH3:35]
Reactant: CCCCCC(CC(=O)O)c1cc([N+](=O)[O-])cc(OC)c1OC
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CCCCCC(CC(=O)Nc1c(C(C)C)cccc1C(C)C)c1cc([N+](=O)[O-])cc(OC)c1OC

Procedure:
A mixture of 3-(2, 3-dimethoxy-5-nitropheyl) octanoic acid and 2, 6-diisopropylaniline was allowed to react in a conventional manner to give N-(2, 6-diisopropylphenyl)-3-(2, 3-dimethoxy-5-nitrophenyl) octanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([S:31][CH3:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].ClC1C=C(C=CC=1)C(OO)=[O:38].C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[C:29]([S:31]([CH3:32])=[O:38])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(SC)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(S(C)=O)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of methyl {o-{5-[2-chloro-4-(methylthio)phenoxy]-2-nitrophenoxy}phenoxy}acetate (4.30 g, 0.009 mol) in methylene chloride is cooled to 0° C. and treated with 3-chloroperoxybenzoic acid (1.73 g, 0.010 mol). The reaction mixture is warmed to room temperature, stirred overnight, quenched with triethylamine (1.4 mL) and concentrated in vacuo. The residue is dissolved into ethyl acetate and the organic solution is washed sequentially with water and 2 N hydrochloric acid, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an amber oil. Column chromatography of the oil using silica gel and ethyl acetate gives the title product as an amber oil (2.6 g) which is identified by NMR spectral analyses.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]4)=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:13]2[N:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=2)[CH2:17]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: c1cc2nnc(C3CCCNC3)n2nc1N1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(c2nnc3ccc(N4CCCCC4)nn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution mixture of 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo[4,3-b]pyridazine (670 mg), triethylamine (360 mg) and methylene chloride (15 ml), methanesulfonyl chloride (320 mg) was added and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The extract was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant crude crystals were recrystallized from ethanol to obtain 3-(1-methanesulfonylpiperidin-3-yl)-6-piperidin-1-yl-1,2,4-triazolo[4,3-b]pyridazine (230 mg) as colorless crystals.