Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:3]=1.O.[NH2:24][NH2:25].Cl.O>C(O)C>[NH2:9][C:8]1[C:7]2[C:6]([Cl:10])=[N:5][C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:3][C:2]=2[NH:25][N:24]=1
Reactant: NN
Reactant: C[C@@H](NC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound (R)-1-(4,6-dichloro-5-cyanopyridin-2-yl)-3-(1-phenylethyl)urea (0.10 g, 0.29 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (0.59 mL, 0.59 mmol, 1M solution in THF) and stirred at 80° C. for 2 h. After the precipitation of white solid, the reaction mixture was cooled to room temperature and a 2M solution of HCl in water (0.29 mL, 0.59 mmol) was added stirred at same temperature for 2 h. After confirming the completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure to give crude product which was purified by preparative HPLC to afford (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.88 (s, 1H), 9.05 (s, 1H), 7.44 (s, 1H), 7.36-7.32 (m, 4H), 7.23 (d, J=8.00 Hz, 2H), 5.42 (s, 2H), 4.84-4.82 (m, 1H), 1.38 (d, J=8.00 Hz, 3H), MS ES calc'd. for C15H15ClN6O [M+H]+ 331. Found 331.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11](Cl)[C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].[C:28](=O)([O-])[O-:29].[K+].[K+].CN1CCCC1=O>O>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[O:27][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([O:29][CH3:28])[C:4]=2[N:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(C)c12
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)cc(Cl)c1O
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(OC)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 120 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
A mixture of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (200 mg, 0.750 mmol), 2,4-dichloro-6-methylphenol (398 mg, 2.25 mmol), potassium carbonate (311 mg, 2.25 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was stirred at 120° C. for 12 h under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 2-30% ethyl acetate/n-hexane gradient mixture and crystallized from methanol to afford the title compound as colorless crystals (109 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1.Br[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]3=[N:21][CH:20]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1
Reactant: OB(O)c1ccc(F)c(-c2ccc(F)cn2)c1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)nc1

Procedure:
4-Fluoro-3-(5-fluoropyridin-2-yl)phenylboronic acid was coupled with 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 3.5% methanol, then crystallisation from hot toluene/isohexane and further crystallisation from hot methanol, gave 3-[4-fluoro-3-(5-fluoropyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 9.28 (1H, d, J 7), 8.76 (1H, d, J 3), 8.30 (1H, s), 8.20 (1H, dd, J 7 and 2), 7.88 (3H, m), 7.62 (1H, dd, J 11 and 9), 7.53 (1H, d, J 7).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[CH3:14]I>O1CCCC1>[CH3:14][O:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1
Reactant: OCCSCc1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCSCc1ccncc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (170 mg., 7.1 mmoles, from 340 mg. of 50% dispersion in oil washed, under nitrogen, with hexane) was slurried in 5 ml. of dry tetrahydrofuran. A solution of 4-(2-hydroxyethylthiomethyl)pyridine (1.0 g., 5.9 mmoles) in 10 ml. was added dropwise over 5 minutes and the mixture stirred for 5 minutes. Finally, methyl iodide (260 mg., 0.1 ml., 5.9 mmoles) in 2 ml. of tetrahydrofuran was added and the mixture stirred overnight. The reaction mixture was clarified by filtration and evaporated to an oil (approximately 1.3 g.) which was chromatographed on silica gel with chloroform as eluent. Pure fractions of product were combined and concentrated to yield 4-(2-methoxyethylthiomethyl)pyridine [210 mg. of oil; m/e 183; pnmr/CDCl3 /TMS/delta: 7.4 (t, 2H), 6.7 (s, 3H), 6.5 (t, 2H), 6.3 (s, 2H), 2.7 (d, 2H), 1.4 (d, 2H)].
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])=[O:6].[I:17]N1C(=O)CCC1=O.CO>C(Cl)(Cl)Cl>[I:17][C:4]1[C:5](=[O:6])[C:7]2[C:8](=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[O:15][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(C(=O)C=CN(C)C)c(O)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(=O)c(I)coc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (20.0 g, 90.37 mmol) in anhydrous chloroform (100 ml) at 0° C. was added N-iodosuccinimide (23.5 g, 99.22 mmol) and silica gel (40 g). The reaction mixture was stirred at 0° C. for 60 minutes, then the insoluble material filtered off. The filtrate was washed with aqueous sodium thiosulfate (0.5M, 2×50 ml), followed by brine (100 ml), then dried over sodium sulfate. The solvent was removed under reduced pressure, providing an orange solid. To this solid was added methanol (30 ml), and the mixture was sonicated, filtered, the solid washed with methanol (2×5 ml), and the solid dried under reduced pressure, to give 3-iodo-7-methoxychromen-4-one as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:36]
Reactant: COCC(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)COC)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[S:6].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.C(OCC)(=O)C>O1CCCC1>[CH2:17]([N:4]1[CH2:3][CH2:2][N:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:5]1=[S:6])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCN(CCc1ccccc1)C(=S)NCCCc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: S=C1N(CCCc2ccncc2)CCN1CCc1ccccc1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Anhydrous tetrahydrofuran (2.5 ml) was added to a mixture of 1-(2-hydroxyethyl)-1-phenethyl-3-[3-(4-pyridyl)propyl]thiourea (Compound No. 7-2) (601 mg, 1.75 mmol) and triphenylphosphine (913 mg, 3.49 mmol), and the whole was stirred under ice/methanol-cooling. A solution of diisopropyl azodicarboxylate (710 mg, 3.49 mmol) in anhydrous tetrahydrofuran was added dropwise thereto, and after 10 minutes, ethyl acetate (100 ml) was added to the reaction mixture. The whole was washed with a saturated aqueous sodium bydrogencarbonate solution (40 ml) and saturated brine (40 ml) successively, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was filtered off with hexane to give 107 mg (19%) of the titled compound as crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:4].[OH:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:3]([NH:2][C:22](=[O:21])[C:23]([CH3:28])([CH3:27])[CH2:24][OH:25])[CH3:4])=[CH:19][CH:18]=1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(NC(=O)C(C)(C)CO)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Reference Example 1, Diastereomer a) (3.7 g, 11 mmol), 3-hydroxy-2,2-dimethylpropionic acid (2.0 g, 17 mmol) in CH2Cl2 (100 mL) was added 1-hydroxybenzotriazole (2.3 g, 17 mmol), diisopropylethylamine (7.7 mL, 44 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.2 g, 17 mmol). After stirring at room temperature overnight. The reaction mixture was diluted with EtOAc (200 mL), washed with water and saturated aqueous sodium bicarbonate, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 50% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ7.24 (d, 2H), 7.12 (d, 2H), 7.10 (d, 2H), 6.92 (d, 2H), 4.25 (m, 1H), 3.68 (ABq, 2H), 3.18 (dd, 1H), 2.93 (ddd, 1H), 2.76 (dd, 1H), 1.20 (s, 3H), 1.19 (s, 3H), 0.96 (d, 3H). LC-MS: m/e 394 (M+H)+ (3.5 min).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:1].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][S:4]([CH2:7][C:8]2[C:17]3[O:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=3[CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:5])[CH2:36][CH2:35]1
Reactant: Cc1c(-c2ccccc2)oc2c(CS(=O)(=O)CCCl)cccc2c1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCS(=O)(=O)Cc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.7 %

Procedure:
A mixture of 4.5 g of Intermediate XXV, 2.36 g of 1-(2-methoxyphenyl)-piperazine and 0.84 g of potassium carbonate in 45 ml of anhydrous dimethylformamide was stirred at ambient temperature for 2.5 hours. The reaction mixture was poured into 300 ml of water and filtered under suction, washing with water. The solid base was crystallized from ethanol and had a melting point of 143°-146° C. The crystals were dissolved in 1,2-dichloroethane and acidified with ethanolic hydrogen chloride. 4.4 g of the title compound, m.p. 229°-233° C., was obtained by recrystallization from methanol:water (1:3.5).
Reaction SMILES: SC[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C(OC(C)(C)C)(=O)C=C.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:3][CH:4]=1
Reactant: O=C(O)c1cccc(CS)c1
Agent: C=CC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 3-(mercaptomethyl)benzoic acid (12 g, 71.43 mmol, 1.00 equiv) in acetonitrile (200 mL), and tert-butyl acrylate (60 mL), DBU (21.7 g, 142.76 mmol, 2.00 equiv). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of water and adjusted to pH 2˜3 with 10% hydrochloric acid. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (50:1). This resulted in 10.5 g (47%) of 34(3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid as red oil. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.08 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.46 (t, 1H), 3.81 (s, 2H), 2.68 (t, 2H), 2.50 (t, 2H), 1.48 (s, 9H). MS (ES, m/z): 295 [M−H]−.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1Cl)=[CH:14][CH:13]=[CH:12][CH:11]=2)=O.Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)C>[CH2:19]([O:26][N:27]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:4]1[CH2:3][CH2:2][Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NOCc1ccccc1
Reactant: O=C(CCCl)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CC(C)O
Product: ClCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Temperature: 40 °C
Yield: 29.9 %

Procedure:
A mixture of 3-chloro-N-(4-chloroquinolin-3-yl)propanamide (1.682 g, 6.243 mmol) and O-benzylhydroxylamine hydrochloride (1.10 g, 6.87 mmol) in 60 mL of isopropanol was heated to 40° C. under an atmosphere of N2. After 25 hours the mixture was cooled, solids were filtered off and rinsed with hexane. Chromatography (SiO2, 8-100% EtOAc/dichloromethane) gave 0.6308 g of 1-(benzyloxy)-2-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:24]([O:25][CH3:26])[CH3:23])=[O:10])[CH:5]=[N:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cncc(Cl)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 100 ml round bottom flask, 6-chloropyrazine-2-carboxylic acid (1 g, 6.31 mmol) was suspended in dry CH2Cl2 (30 ml). Oxalyl chloride (3.78 ml, 7.57 mmol) was added along with a few drop of DMF, the mixture was stirred at room temperature for 12 hrs, N,O-Dimethylhydroxylamine hydrochloride (0.800 g, 8.20 mmol) was added, the resulting mixture was cooled down to 5° C., TEA (2.64 ml, 18.92 mmol) was added via a dropping funal, the reaction mixture was stirred at room temperature for 30 minutes, filtered and the filter cake was washed with EtOAc, the combined filtrate was washed with saturated sodium bicarbonate and brine, concentrated to an oil, purified on silica gel with Hexanes/EtOAc solventsto give product (1.06 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.[OH-].[Na+].CN(C)[CH:35]=[O:36]>C(O)(=O)C>[CH:35]([C:25]1[C:24]2[C:19](=[CH:20][C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:36]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)OC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCc1[nH]c2cc(C(=O)OC)ccc2c1C=O
Reaction time: 2 h

Procedure:
A solution of phosphorus oxychloride (20 ml) in dimethylformamide (80 ml) was added to a solution of methyl 2-(n-undecyl)indole-6-carboxylate (58.3 g) in dimethylformamide (250 ml) and the mixture was stirred at a temperature of 55°-90° C. for 2 hours. After cooling, the mixture was poured into rapidly stirred water. Aqueous sodium hydroxide (50% w/v) was added until pH 12, the mixture was stirred for 10 minutes, and then glacial acetic acid was added to pH 5. The mixture was stirred until the gummy product solidified. The solid was then collected and recrystallised from ethanol to give methyl 3-formyl-2-(n-undecyl)indole-6-carboxylate (52.5 g), in the form of a buff powder, m.p. 147°-149° C.
Reaction SMILES: C([Sn:9]([Cl:19])([Cl:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])CCCCCCC.C([Cl:28])CCCCCCC.[Cl-].C[S+](C)C>>[CH2:10]([Sn:9]([Cl:18])([Cl:19])[Cl:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC[Sn](Cl)(Cl)CCCCCCCC
Reactant: CCCCCCCCCl
Agent: C[S+](C)C
Agent: [Cl-]
Product: CCCCCCCC[Sn](Cl)(Cl)Cl

Procedure:
Following the procedure outlined in Example 1, except that di-n-octyltin dichloride is used in place of dimethyltin dichloride, n-octyl chloride in place of methyl chloride, and trimethylsulfonium chloride in place of trimethylsulfonium iodide, there is obtained n-octyltin trichloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])=[N:9][C:5]=2[CH:4]=1.CC(C)([O-])C.[Na+].Cl[CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1.N1(CN2C3C=CC(OC)=CC=3N=C2S(CC2C(C)=C(OC)C(C)=CN=2)=O)C2C=CC=CC=2N=N1>ClCCl.C(Cl)(Cl)Cl.CO>[N:33]1([CH2:32][N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:24]=[CH:23][C:6]=3[N:7]=[C:8]2[S:10]([CH2:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=2)=[O:11])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1
Reactant: ClCn1nnc2ccccc21
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CC(C)(C)[O-]
Agent: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2Cn1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(Cn3nnc4ccccc43)c2c1
Temperature: 30 °C
Reaction time: 72 h

Procedure:
5-Methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (172 mg) was dissolved in 20 ml of dichloromethane. Sodium tert-butoxide (55 mg) and 1-(chloromethyl)-1H-benzotriazole (85 mg) was added. The reaction mixture was stirred at 30° C. for 3 days. TLC analysis (developing solvent; chloroform-methanol 15:1) showed major one spot of 1-[(benzotriazol-1-yl)methyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole above 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole. The titled product was purified by preparative thin layer chromatography. 195 mg of product, a mixture of 1-[(benzotriazol-1-yl)methyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole and 1-[(benzotriazol-1-yl)methyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole was obtained (3:2 ratio).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:15][C:16](O)=[O:17])#[N:14].CCN=C=NCCCN(C)C.Cl>C(#N)C.Cl>[C:13]([CH2:15][C:16]([NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)=[O:17])#[N:14]
Reactant: N#CCC(=O)O
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: N#CCC(=O)Nc1nnc(-c2ccccc2)s1

Procedure:
5-phenyl-1,3,4-thiadiazol-2-amine (600 mg, 3.3 mmol), cyano acetic acid (300 mg, 3.6 mmol), and EDC-HCl (861 mg, 4.5 mmol) were stirred in acetonitrile (15 mL) at room temperature for 2 hours. The mixture was diluted with aqueous 1N HCl and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate/hexanes (1/9) to afford 2-cyano-N-(5-phenyl-1,3,4-thiadiazol-2-yl)acetamide as a white solid which was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[O:14].C1COCC1>CO.Cl[Ni]Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)=[O:14]
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Agent: Cl[Ni]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Ref. J. of Org. Chem., 2000, 65, 8001. To a stirred solution of amide 42 (0.086 g, 0.249 mmol) and NiCl2 6H2O (0.118 g, 0.498 mmol, 2 eq) in methanol (8 ml) and THF (4 ml) NaBH4 (0.028 g, 0.749 mmol, 4 eq) was added portionwise over 20 min at 0° C. After stirring for 1 h at room temperature, the solvent was distilled off under reduced pressure. Water (10 ml) and ethyl acetate (10 ml) was added. The resulting mixture was filtered through a celite bed which was washed with ethyl acetate (20 ml). After collecting the filtrate, the organic phase was separated, dried over Na2SO4 and the solvent was distilled off under reduced pressure to give the pure product 69 as a white solid (0.066 g, 0.190 mmol, 79%), mp 119-121° C. 1H NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J 7.2 Hz, CH2CH3) 2.75 (2H, t, J 7.2 Hz, CH2CO), 3.23 (2H, t, J 7.2 Hz, CH2—Ar), 4.35 (2H, q, J 7.2 Hz, CH2CH3), 7.12 (1H, bs, N—H), 7.37 (1H, dd, J 1.6, 8.4 Hz, CH, Ar), 7.42-7.50 (4H, m, 4×CH, Ar), 7.69 (1H, bs, CH, Ar), 7.76-7.82 (3H, m, 3×CH, Ar), 7.97 (2H, d, J 9.2 Hz, 2×CH, Ar). MS (API-ES): m/z 348 [M+H]+ (100%), HRMS (API-ES) m/z found 348.1602 [M+H]+.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.ClS(O)(=O)=O.O.CCCCCCC>C(Cl)Cl>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCCCCCC
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.03 h

Procedure:
9α-Hydroxyandrostenedione (5.00 g.) is dissolved in methylene chloride (50 ml.) and cooled to 0°-5°. A solution of chlorosulfonic acid (2.5 ml.) in methylene chloride (10 ml.) is added slowly over a period of 4 minutes. At the end of the addition TLC shows the reaction is completed. Water (60 ml.) is added to the reaction mixture keeping the temperature at 3°-15°. The mixture is stirred for 2 minutes and heptane (135 ml.) is added. The organic phase is separated and washed twice with water (30 ml. each time). The organic phase is concentrated with heat to about 30 ml. with crystals forming as the solution cools. The mixture is cooled to 0°-5°, filtered, washed with a minimum amount of heptane, and dried at 70° to give androsta-4,9(11)-diene-3,17-dione; 4.45 g. (89.0% weight yield, 94.7% chemical yield), m.p., 195.5°-202°; [α]D +220° (chloroform); UV (methanol) λmax =240 nm (ε=16,300).