Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:8]([CH3:11])=[N:9][CH:10]=1.N1C=CN=C1.[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[Si:38]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:8]([CH3:11])=[N:9][CH:10]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ncc(CCCO)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1ncc(CCCO[Si](C)(C)C(C)(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 2-{[5-(3-hydroxypropyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.25 g, 0.564 mmol) in THF (10 ml) were added imidazole (0.077 g, 1.13 mmol) and tert-butyldimethylsilyl chloride (0.10 g, 0.676 mmol). The reaction mixture was allowed to stir overnight at rt and was then concentrated. Water (10 ml) and saturated NaHCO3 (10 ml) were added. The resulting mixture was allowed to stir for 1 h at rt. The mixture was extracted with EtOAc (2×30 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-{[5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.16g, 0.29 mmol, 51%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C@H:3]2[C@H:2]([NH:1][C:33]([C:25]3[O:24][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH:26]=3)=[O:34])[CH:7]3[CH2:6][CH2:5][N:4]2[CH2:9][CH2:8]3)[CH:12]=1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane was transferred to a 50 L glass reaction flask equipped with a mechanical stirrer under an inert atmosphere. Dichloromethane (16.5 L), triethylamine (847 mL, 6.08 mol), benzofuran-2-carboxylic acid (948 g, 5.85 mol) and O-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate (HBTU) (2.17 kg, 5.85 mol) were added to the reaction mixture. The mixture was stirred for a minimum of 4 h at ambient temperature, and the reaction was monitored by HPLC. Upon completion of the reaction, 10% aqueous potassium carbonate (12.7 L, 17.1 mol) was added to the reaction mixture and the mixture was stirred for a minimum of 5 min. The layers were separated and the organic phase was washed with 10% brine (12.7 L). The layers were separated and the organic phase was cooled to 15° C.±10° C. 3 M Hydrochloric acid (8.0 L) was slowly added to the reaction mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 5 min, and the layers were allowed to partition for a minimum of 5 min. The solids were filtered using a table top filter. The layers of the filtrate were separated, and the aqueous phase and the solids from the funnel were transferred to the reaction flask. 3 M Sodium hydroxide (9.0 L) was slowly added to the flask in portions to adjust the pH of the mixture to pH 14. The aqueous phase was extracted with dichloromethane (2×16.5 L). The combined organic phases were dried over anhydrous sodium sulfate (1.71 kg). The mixture was filtered, and the filtrate was concentrated to give (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide (1.63 kg, 77.0% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([F:7])[C:3]([F:6])([F:5])[F:4].[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[N+:14]([C:10]1[CH:9]=[C:8]([C:2]([F:7])([F:1])[C:3]([F:5])([F:4])[F:6])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: FC(F)(F)C(F)(F)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(C(F)(F)C(F)(F)F)c1
Temperature: 45 °C

Procedure:
74 G. (0.4 moles) of pentafluoroethylbenzene is cooled to 5° C. and treated dropwise with a mixture of 22 g. (0.33 moles) of concentrated nitric acid and 33 g. (0.32 moles) of concentrated sulfuric acid. The temperature is maintained at 5°-15° C. during the 1 hour addition period and then raised to 45° C. for 1 hour. The reaction mixture is cooled and poured onto ice. The aqueous mixture is extracted with ether, the ether extracts washed with water, dried over sodium sulfate, and the residue is distilled at 0.35 mm. of Hg at 74°-75° C. The yield is 84 g. (87%) of m-nitro-pentafluoroethylbenzene.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10](CN3CCCC3)[CH:9]=[N:8][C:7]=2[N:6]([CH2:20][CH2:21][CH3:22])[C:5]1=[O:23])[CH2:2][CH3:3].[Li]CCCC.[C:29]1(=[O:38])[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32][CH2:31][CH2:30]1>C1COCC1>[OH:37][C:33]12[O:38][C:29]([C:9]3[NH:10][C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:23])[N:6]([CH2:20][CH2:21][CH3:22])[C:7]=4[N:8]=3)([CH2:36][CH2:35][CH2:34]1)[CH2:30][CH2:31][CH2:32]2
Reactant: CCCn1c(=O)c2c(ncn2CN2CCCC2)n(CCC)c1=O
Reactant: O=C1CCCC(=O)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(O)(CCC3)O4)nc2n(CCC)c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1,3-Dipropyl-7-pyrrolidin-1-ylmethyl-3,7-dihydro-purine-2,6-dione (638 mg) was taken in dry THF (10 ml) at −78° C. nBuLi (0.88 ml, 2.5M in hexane) was added slowly. The reaction mixture turned orange and stirred for 30 min at −78° C. Cyclooctane-1,5-dione (280 mg) was dissolved in 3 ml of dry THF, added to the reaction mixture. Stirred at −78° C. for 30 min, slowly warmed to rt and stirred overnight. The reaction mixture was quenched with sat NH4Cl and extracted with ethyl acetate (3×50 ml). Combined organic layer was washed with 1N HCl, water, and brine. Dried over anhydrous Na2SO4 and concentrated. The crude product was purified on silica column, eluted with ethyl acetate:hexane (1:1). Mass (ES+ 377)
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:44][CH3:45])([O:36][Si](CC)(CC)CC)[CH2:34][CH3:35])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:34][CH3:35])([OH:36])[CH2:44][CH3:45])[CH2:12][C@@H:11]([OH:46])[CH2:10]1
Reactant: CCC(CC)(CCCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 98.2 %

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-{4-ethyl-4-(triethylsilyloxy)hexyloxymethyl}androsta-5,7-diene (180 mg), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (6 ml), followed by reflux under heating for 5 hours. After adding ethyl acetate, the mixture was washed with saturated brine, a saturated aqueous sodium bicarbonate solution and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the resulting residue was purified by column chromatography (ethyl acetate) to give the titled compound (0.10 g).
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[OH-].[Na+]>CO.O>[N:7]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCNCC1
Temperature: 25 °C

Procedure:
250 ml of water and 500 ml of methanol are added to 194 g (1 M) of piperazine hexahydrate, while stirring, and the pH is adjusted to 3 with about 163 ml of concentrated hydrochloric acid. The mixture is then cooled to 25° C. and 100 g (0.59 M) of benzyl chloroformate are added dropwise, while stirring, during which the pH is kept between 3 and 4.5 with sodium hydroxide solution (4 M; about 230 ml). About 700 ml are then stripped off on a rotary evaporator and the residue is washed with water, rendered acid with about 1.5 ml of concentrated HCl and extracted twice with 200 ml of toluene each time. The aqueous phase is cooled and brought to pH 12 with about 115 ml of 12.5 N NaOH. The oil which separates out is extracted several times with toluene, and the extract is dried over K2CO3 and concentrated under reduced pressure. Yield: 74 g
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][CH:7]([O:9][C:10]1[CH:21]=[CH:20][C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[NH:18][C:12]=2[CH:11]=1)[CH3:8].C(=O)([O-])O.[Na+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[N+:1]([C:21]1[C:10]([O:9][CH:7]([CH3:8])[CH3:6])=[CH:11][C:12]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)Oc1ccc2c(c1)NC(=O)CCC2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])CCCC(=O)N2
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
460 mg of potassium nitrate are added to a solution of 797 mg of 8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8 ml of trifluoroacetic anhydride, cooled to −5° C. The reaction medium is stirred for 5 minutes at −5° C., brought back to pH 7 by adding a saturated aqueous sodium hydrogen carbonate solution, and then extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with a heptane/ethyl acetate (1/1) mixture, so as to obtain 489 mg of 7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow solid. 100 mg of sodium hydride at 60% are added to a solution of 485 mg of 7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8 ml of DMF, cooled to 0° C. The reaction medium is stirred for 5 minutes and then 263 mg of iodomethane are added. The reaction medium is brought back to ambient temperature and stirred for 1 hour at this temperature. The reaction medium is poured into 100 ml of ice-cold water and the mixture is extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with a heptane/ethyl acetate (1/1) mixture, so as to obtain 318 mg of 1-methyl-7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].C(OCC)C.[CH3:17][NH:18][CH3:19]>C(#N)C>[CH3:17][N:18]([CH3:19])[S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])=[O:9]
Reactant: CNC
Reactant: O=S(=O)(Cl)CCCCCCCl
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)S(=O)(=O)CCCCCCCl
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
6-Chlorohexanesulfonyl chloride (6.57g, 30 mmol) was added dropwise to a solution of diethyl ether (60 ml) and a 12% acetonitrile solution of dimethylamine (24.8 g, 66 mmol) with stirring under ice-cooling. Thereafter, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was concentrated in vacuo. Thereafter, the concentrate was diluted with diethyl ether (60 ml). The resulting solution was washed twice with water (10 ml) and then with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The crude product was purified by column chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give N,N-dimethyl-6-chlorohexanesulfonamide (6.59 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([Cl:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([Cl:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccccc1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: Cc1c(O)cc(C=O)c(O)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(OC2CCCCO2)cc(C=O)c(O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
2,5-Dihydroxy-3,4-dimethyl-benzaldehyde (2.0 g) was dissolved in dichloromethane (50 mL) and 3,4-dihydro-2H-pyran (1.5 g) was added followed by addition of p-toluenesulfonic acid monohydrate (200 mg). The solution was stirred at room temperature for 1 hour and quenched by adding sodium bicarbonate solution (1 mL). Then the dichloromethane solution was dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with hexane and ethyl acetate (8:2) to give 1.5 g of 2-hydroxy-3,4-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzaldehyde product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)(=[O:12])=[O:11].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])=[C:2]([NH:1][S:27]([C:19]2[O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=2)(=[O:28])=[O:29])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NS(=O)(=O)c1cccs1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1NS(=O)(=O)c1cccs1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To a solution of N-(2-amino-4-chlorophenyl)thiophene-2-sulfonamide (CAS RN: 926205-90-5) (140 mg, ˜0.47 mmol) in pyridine (2.5 ml) was added benzofuran-2-sulfonyl chloride (102 mg, 0.47 mmol) and the mixture was stirred at room temperature for 16 h. More benzofuran-2-sulfonyl chloride (51 mg, 0.24 mmol) was added and the reaction was stirred for another 24 h, concentrated in vacuo to remove most of solvent. The residual thick syrup was quenched with 6M HCl and diluted with H2O. The resulting suspension was filtered and washed with H2O (×3). The crude product was purified by flash column chromatography on silica gel (25-50% EtOAc-hexane) to yield 43 mg of product slightly contaminated with impurities. This material was triturated with CH2Cl2 to form a sandy colored solid, which was filtered and rinsed with minimal amount of CH2Cl2 to yield 23 mg (10%) of Compound 24.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 89.7 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 1022 mmol), and dimethylformamide (90 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and concentrated to afford 7.4 g of a yellow solid. The solid was chromatographed on a Waters Prep LC 500 utilizing dichloromethane/methanol (4%) as eluent, and subsequent concentration of the appropriate fraction afforded 4.0 g of a yellow solid. The solid was recrystallized from ethyl alcohol to yield 3.1 g (38%) of 1-[4-[2-14-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxyl-3-methoxyphenyl]ethanone, as slightly yellow flakes, m.p.=132-134° C.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[CH2:9][C:10]#N.Cl.CC[O:15]CC>[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>[CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[CH2:9][CH:10]=[O:15]
Reactant: CCOCC
Reactant: C[C@@]12CCC(C[C@H]1CC#N)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: C[C@@]12CCC(C[C@H]1CC=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
19.5 g (0.13M) of the nitrile (XI) obtained in 1-9) above was dissolved in 200 ml of absolute ether under a nitrogen gas stream and 160 ml of a 1M solution of diisobutylaluminum hydride in hexane was added dropwise thereto at room temperature. Then the resulting mixture was stirred for one hour, poured into ice/water and acidified with 1N hydrochloric acid. The organic phase was collected and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was distilled under reduced pressure to give 19.0 g (theoretical yield: 96%) of the aimed compound (XII) as a colorless oily material. b.p.: 45° to 47° C./0.5 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C:8](=[O:16])[C:7]2[C:17]([CH3:26])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:6]1=2.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[Br:32][CH2:26][C:17]1[C:7]2[C:8](=[O:16])[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:10][N:5]([CH2:4][C:3]3[C:2]([F:1])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])[C:6]=2[S:19][C:18]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Yield: 79.1 %

Procedure:
The compound obtained in Example 15 (1.8 g) was admixed with N-bromosuccinimide (0.88 g), azobisisobutyronitrile (70 mg) and ethyl acetate (18 ml) and the mixture was heated under reflux for 2 hours. At the time when about 1 hour and 30 minutes had elapsed during this procedure, the suspension turned into a solution. The suspension obtained after allowing to cool was cooled on ice, and the precipitated crystal was recovered by a filtration, washed with cool ethyl acetate and water to obtain the title compound (1.68 g, 79.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:33].[Na+]>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:16])=[O:33])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)NCCO)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A slurry of 4-[3-(2-benzyloxy-5-methylthiophenyl)-propyl]-N-(2-hydroxyethyl)benzenecarboxamide (0.22 g) in methanol (10 ml) was added to a stirred solution of sodium metaperiodate (0.113 g) in water (1 ml) maintained at 0° C. by external cooling. The reaction mixture was stirred at 0° C. for 2 hours, then concentrated to a volume of approximately 2 ml. This residue was dissolved in ethyl acetate (10 ml), the ethyl acetate solution was dried (anhydrous magnesium sulphate) and the solution evaporated to dryness. The residue was subjected to chromatography on silica (Merck) eluted with a mixture of methanol/ethyl acetate (1:9 v/v). The only porduct obtained was triturated with ethyl acetate (2 ml) to give 4-[3-(2-benzyloxy-5-methylsulphinylphenyl)propyl]-N-(2-hydroxyethyl)-benzenecarboxamide (mp. 105°-108° C.; 43% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O>ClC(Cl)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COc1ccc(C=CC(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
p-Methoxycinnamic acid (52.7 g=0.45 mole) was slurried under N2 in 500 mL of sieve-dried dichloroethane. Oxalyl chloride (146.0 gm=1.15 moles) was added in one portion followed by three drops of DMF. Complete solution was achieved in 30 minutes. The solution was stirred an additional 2 hours, and then the dichloroethane containing excess oxalyl chloride was removed on a 50° C. rotary evaporator. Fresh dichloroethane was twice added to the residue and removed on the rotary evaporator. The amber oil was used without purification. Yield 90.4 gm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)c1

Procedure:
The title compound, MS: m/e=308.2 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-4-methyl-pyridine.