Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]>C1(C)C=CC=CC=1.C(O)C>[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40].[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([NH:49][C:50]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([O:28][C:19]3[C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[N:22]=[CH:21][CH:20]=3)=[C:30]([F:36])[CH:31]=2)=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCCCc1ccc(C(=O)Cl)cc1
Agent: CCCCc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4-Butyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-butyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-butyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH:20][CH3:21].O.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:20]([O:19][CH3:18])[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylanine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 1.0 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH:19][OH:20])=[C:13]2[CH:12]=[N:11]1.O(N)[CH3:23]>>[CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH:19][O:20][CH3:23])=[C:13]2[CH:12]=[N:11]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ncc2c(NO)ncnc21
Reactant: CON
Product: CONc1ncnc2c1cnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O

Procedure:
Nucleoside 119 was prepared from the nucleoside 143 (Example 6, step 3) substituting hydroxylamine for methoxylamine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[I:15])=[CH:5][CH:4]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[I:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:5]=1
Reactant: CCCCN
Reactant: BrCc1ccc(-c2ccccc2I)cc1
Solvent: C1CCOC1
Product: CCCCNCc1ccc(-c2ccccc2I)cc1

Procedure:
A solution of 4-bromomethyl-2'-iodobiphenyl (4.0 g; preparable as in Example 2(b)) and butylamine (40 ml) in dry tetrahydrofuran (55 ml) was stirred for 18 hours an ambient temperature then boiled under reflux for 45 minutes. The solvent was evaporated under reduced pressure and the resulting residue was then dissolved in dichloromethane (100 ml) to give a solution which was washed with aqueous potassium hydroxide solution (1M; 2×50 ml), water (50 ml), then hydrochloric acid (5M; 2×50 ml), then organic layer was dried over magnesium sulphate and the organic solvent was evaporated. The residue obtained was purified by flash chromatography on silica gel (eluting with dichloromethane/methanol (9:1) to give the intermediate compound N-(2'-iodobiphenyl-4ylmethyl)butylamine (1.9 g; m.p. 134°-136° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:25]CC1>ClCCl>[NH2:1][C:2]1[C:7]([CH:8]=[O:25])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: C1CCOC1
Reactant: CSc1ncc(C#N)c(N)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CSc1ncc(C=O)c(N)n1
Yield: 39 %

Procedure:
To a stirred solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carbonitrile (4.50 g, 27.1 mmol) in 120 mL of THF is slowly added 27 mL of a 1 M solution of diisobutyl-aluminum hydride in dichloromethane for 5 minutes at 0° C. The ice bath is removed, and an additional 27 mL of 1M solution of diisobutylaluminum hydride in dichloromethane is added. After 30 minutes an additional 13 mL of 1 M solution of diisobutylaluminum hydride in dichloromethane is added. After 30 minutes the reaction is carefully quenched by the addition of 45 mL of methanol. This mixture is partitioned between 250 mL of EtOAc and 160 mL of 1 N HCl. The aqueous layer is treated with 80 mL of 2 N NaOH and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash column chromatography (SiO2, EtOAc/hexane=1/3) to give pure 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1.80 g, 39%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[S:17][C:18]3[C:19]([N:28]=2)=[C:20]2[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.Cl>N1CCCCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:21]1\[C:22](=[O:27])[NH:23][C:24]2[CH:25]=[CH:26][C:18]3[S:17][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:28][C:19]=3[C:20]\1=2
Reactant: COc1cc[nH]c1C=O
Reactant: O=C1Cc2c(ccc3sc(-c4ccccc4)nc23)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3sc(-c4ccccc4)nc3c21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (11 mg, 0.088 mmol)(Bellamy, supra), piperidine (3 drops)(Aldrich), and 2-phenyl-6,8-dihydro-thiazolo[4,5-e]indol-7-one (21.4 mg, 0.08 mmol) (Example 3) were dissolved in DMF (3 mL). The mixture was heated to 90° C. and stirred at that temperature for 1 h. The mixture was cooled, poured into water, and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the crude product was purified by reverse phase HPLC using acetonitrile—water as solvent, then crystallization from ethanol. (Yield 4.5 mg, 15%)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3]2)=[O:21]
Reactant: O=C(Cl)CCCCCl
Reactant: CS(=O)(=O)NC1Cc2ccccc2C1
Product: CS(=O)(=O)NC1Cc2ccc(C(=O)CCCCCl)cc2C1

Procedure:
Using N-(2,3-dihydro-1H-inden-2-yl)methanesulfonamide and 5-chlorovaleryl chloride according to the same method as that of Example 1, the title compound was obtained as colorless crystals.
Reaction SMILES: C1OC1.C1C2C=CC=CC=2CCON1.[OH:15][CH2:16][CH2:17][N:18]1[O:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[CH2:19]1.[O-:29][C:30]#[N:31].[Na+]>C(Cl)(Cl)Cl.CO>[C:30]([O:15][CH2:16][CH2:17][N:18]1[O:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[CH2:19]1)(=[O:29])[NH2:31]
Reactant: OCCN1Cc2ccccc2CCO1
Reactant: N#C[O-]
Agent: [Na+]
Agent: c1ccc2c(c1)CCONC2
Solvent: CO
Solvent: C1CO1
Solvent: ClC(Cl)Cl
Product: NC(=O)OCCN1Cc2ccccc2CCO1
Reaction time: 8 h

Procedure:
8 Grams of ethylene oxide was dissolved at room temperature in 80 ml. of methanol. To this solution, 8 mg. of 1,2,4,5-tetrahydro-3,2-benzoxazepine were added. After standing overnight, the reaction mixture was refluxed for one hour and then evaporated in vacuo. The residue was distilled at 120° C./0.1 mm Hg. giving 9.3 g. of 2-(2-hydroxyethyl)-1,2,4,5-tetrahydro-3,2-benzoxazepine. To 2.9 g. of the latter compound in 160 ml. of chloroform, 2.47 g. of sodium cyanate was added, then hydrogen chloride was bubbled therethrough for about 30 minutes under stirring. The reaction mixture was then transferred to a separatory funnel and treated with 90 ml. aqueous of 5 percent sodium hydroxide. The organic layer was separated, washed with a saturated solution of sodium chloride and dried over sodium sulfate. After evaporation of the chloroform solution, the residue was crystallized from diisopropyl ether giving 1.82 g. of 2-(2-carbamyloxyethyl)-1,2,4,5-tetrahydro-3,2-benzoxazepine, m.p. 110°-111° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[N:14][O:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:17].O1CCOCC1>CO>[ClH:17].[CH3:16][O:15][N:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CON=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CON=C1CCNCC1
Temperature: 25 °C

Procedure:
4-Methoxyimino-piperidine-1-carboxylic acid tert-butyl ester in MeOH (10 mL) was treated with 4.0 M HCl/dioxane (1.0 mL) and stirred at room temperature over night. The solution was concentrated to yield 213 mg of the title compound without further purification. 1H NMR (DMSO, 300 MHz) δ ppm 2.47 (t, 2H, J=6.62 Hz), 2.68 (t, 2H, J=6.07 Hz), 3.17 (m, 4H), 3.77 (s, 3H), 9.08 (bs, 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.COC(=O)CCC1CCCC1.C(OCC(=O)C[N:40]1[C:44](=[O:45])[C:43]([CH3:47])([CH3:46])[N:42]([CH3:48])[C:41]1=[O:49])(C)(C)C.OS(O)(=O)=O>CCCCCC.C1COCC1.O>[CH3:48][N:42]1[C:43]([CH3:47])([CH3:46])[C:44](=[O:45])[NH:40][C:41]1=[O:49]
Reactant: CN1C(=O)N(CC(=O)COC(C)(C)C)C(=O)C1(C)C
Agent: CC(C)[N-]C(C)C
Agent: COC(=O)CCC1CCCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1C(=O)NC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
203 ml 1.6M Butyllithium in hexane were added to a solution of 46.0 ml diisopropylamine in 120 ml THF at 0° over 1 h. The resultant LDA-solution was stirred at 0° for 1 h and then cooled down to −75°. 50.8 g 3-cyclopentyl-propionic acid methylester dissolved in 65 ml THF were added at −75° over 1 h and stirring at that temperature was continued for 1 h. 67.6 g 3-(3-tert-butoxy-2-oxo-propyl)-1,5,5-trimethyl-imidazolidine-2,4-dione dissolved in 65 ml THF were added at −75° over 1 h and after additional stirring at −75° for 1 h, 50 ml conc. H2SO4 were added over 15 minutes. The reaction mixture was refluxed for 3 h, cooled down to r.t. and hydrolyzed with 300 ml deionized water. The organic layer was separated, washed with 10% brine and dried over Na2SO4. Filtration and evaporation of the solvent afforded 96.5 g crude 3-(4-cyclopentylmethyl-3-hydroxy-5-oxo-tetrahydro-furan-3-ylmethyl)-(1,5,5-trimethyl-imidazolidine-2,4-dione as a yellow oil, which was used without purification for the next step. 3-Cyclopentyl-propionic acid methylester was prepared from the corresponding acid (ACROS No. 11161). The methylester is also available at Chemische Fabrik K. Bucher.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1.O.[C:20](#[N:22])[CH3:21]>C1(N)CCCCC1>[CH:21]1([CH2:20][NH:22][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH2:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:4]([NH2:18])[N:3]=2)[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1
Reactant: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Reactant: CC#N
Solvent: NC1CCCCC1
Solvent: O
Product: Nc1nc(NCC2CCCCC2)nc2c1ncn2CC1CCOCC1

Procedure:
A solution of 2-chloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (150 mg) in cyclohexylamine (363 ul) was heated in the microwave at 170° C. for five minutes. The crude reaction mixture was subjected to C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford a white solid (98 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1)c1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 5 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] hydrazine carbothioamide and benzoyl isothiocyanate. The analytical values are summarized in Table I.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[NH:19]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cn[nH]c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 1H-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-isoquinolin-3-yl]-amine. LC-MS m/e 291 (MH+).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH:23]=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1COCC1.CCO>O>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH2:23][OH:24])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C=O)c2ccccc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CO
Temperature: 100 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate (6.0 mg, 14 μmol), NaBH4 (1.5 mg, 40 μmol), THF (250 μL), and EtOH (absolute, 500 μL) was stirred at 23° C. for 1 h. H2O (500 μL) and LiOH monohydrate (50 mg, 1.18 mmol) were added. The reaction was sealed and heated to 100° C. After 2 h, the reaction cooled to 23° C., filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (2.6 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.72-7.65 (m, 2H), 7.58-7.48 (m, 2H), 7.39-7.33 (m, 2H), 7.18 (d, J=8.6 Hz, 1H), 5.07 (s, 1H), 5.01 (d, broad, J=2.7 Hz, 2H), 2.62 (s, 3H), 0.94 (s, 9H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH2:5]1[CH2:10][CH2:9][CH:8]([CH:11]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][CH:13]2[NH:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:7][CH2:6]1>C(#N)C.CO>[CH2:5]1[CH2:6][CH2:7][CH:8]([CH:11]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][CH:13]2[NH:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:10]1.[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: C1CCC(C(CC2CCCCN2)C2CCCCC2)CC1
Solvent: CO
Solvent: CC#N
Product: O=[N+]([O-])[O-]
Temperature: 0 °C

Procedure:
Nitric acid 65% (0.75 ml) is added to a Perhexiline solution (3.02 g, 10.9 mmole) in acetonitrile and methanol (10 ml), cooled at 0° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11][S:12][C:13]3[NH:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11][S:12]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[N:14]=3)=[O:30])[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: Brc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(Cc1nccc2c(Br)csc12)c1nc2ccccc2[nH]1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of 90 mg (0.239 mmol) of 2-[(3-bromothieno[2,3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-6) in 4 ml of CHCl3 and 1 ml of MeOH was added 52 mg (1.0 equivalent) of 80% m-CPBA at -20° C., and the mixture was stirred for 1 hr. at -20° C. When 10% aqueous sodium sulfite and saturated aqueous NaHCO3 were added to the mixture, crystals separated out and collected by filtration. The extract of the mother liquid with CHCl3 was combined with the crystals and subjected to silica gel column chromatography for purification, whereby 61 mg (Yield : 65.0%) of 2-[(3-bromothieno[2, 3-c]pyridin-7-yl)methylsulfinyl]benzimidazole (Ic-18) was obtained as an objective compound.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[Cl:27].Cl>C(Cl)(Cl)(Cl)Cl>[CH:4]1([CH2:7][CH2:8][CH2:9][C:10]([C:23]2[CH:24]=[C:19]([O:18][CH3:17])[C:20]([Cl:27])=[CH:21][C:22]=2[O:25][CH3:26])=[O:11])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: O=C(Cl)CCCC1CCCCC1
Reactant: COc1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(=O)CCCC2CCCCC2)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
3.77 g of 4-cyclohexanebutyryl chloride dissolved in 10 ml of CCl4 are added to a suspension of 2.8 g of AlCl3 in 20 ml of CCl4 at +4° C. under nitrogen. 5.2 g of 2,5-dimethoxychlorobenzene in 10 ml of CCl4 are added dropwise and the mixture is then left stirring for 3 hours at RT. The reaction medium is hydrolysed with dilute HCl solution, the phases are then separated by settling and the organic phase is extracted with DCM. After drying over MgSO4, the solution is evaporated and the residue is then purified by chromatography on silica, eluting with a heptane/DCM mixture (60/40; v/v) and then with pure DCM. 3.37 g of the expected compound are obtained: m.p.=80-81° C.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:21])=[C:14]2[C:15]([CH3:20])=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c(C)nn2CC)c1O

Procedure:
14.8 g. of [[(1-ethyl-3-methyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.05 mol.) are dissolved in 50 g. of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1 to 2 hours, while the resulting ethanol is continuously distilled off. The last part of the alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p. 0.1-0.5 125°-129°, yield 10.7 g. (86%), m.p. 91°-93°. The compound is recrystallized from ligroin (90°-100°), m.p. 93°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:29][C:26]1[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2ccc(Cl)nc2)c(Cl)c1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a mixture of 0.40 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenol, 0.21 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.25 g of 6-chloro-3-(chloromethyl)pyridine dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.44 g of 3,5-dichloro-4-(6-chloro-3-pyridylmethyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), m.p. 93.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[C:9]1=[O:13]
Reactant: Brc1nccs1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2nccs2)C1=O
Yield: 56.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 2-bromo-thiazole (138.8 mg, 0.846 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform) afforded 125 mg of the product (56.8% yield). 1H NMR (DMSO-D6, 300 MHz): δ 8.6 (s, 1H), 8.4 (s, 1H), 7.45-7.35 (m, 2H), 7.2 (d, 1H), 4.4 (t, 2H), 4.2 (t, 2H), 2.3 (s, 3H)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:5][CH:6]=1>CC(O)C.O>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Solvent: O
Solvent: CC(C)O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Yield: 128.1 %

Procedure:
A suspension of 31.73 g of L-N-[(4-methoxyphenyl)sulfonyl]-glutamic acid (0.1 mol) in 400 ml of 2-propanol and 20 ml of water was stirred and heated till all solid entered solution. Then there were added 20.43 g of tetramisole. The whole was stirred and heated till an homogeneous solution was obtained. The solution was further stirred for 4 hours while the temperature was allowed to reach room temperature. The precipitate was filtered off, washed with 100 ml of 2-propanol and 5 ml of water and dried under vacuo at 50° C., yielding 26.17 g levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield 100.3%) αD20 =-62.8° (c5. 1N HCl); mp. 127.4°-129.1° C.