Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)CCC.C(NC(C)C)(C)C.[C:14]1([S:20]([N:23]2[C:31]3[C:26](=[C:27]([N:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I:45]I>C1COCC1>[I:45][C:24]1[N:23]([S:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:22])=[O:21])[C:31]2[C:26]([CH:25]=1)=[C:27]([N:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)[CH:28]=[CH:29][CH:30]=2
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(I)n3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of butylmagnesium chloride (1 mL, 1 mmol, 2.0 M in ether) and di-isopropyl amine (0.279 mL, 2 mmol) in dry THF (5 mL) was stirred for 4 h under inert atmosphere at room temperature. A solution of tert-butyl 4-[1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate (220 mg, 0.5 mmol) in THF (2 mL) was added slowly and the resulting mixture stirred for 2 h at room temperature. A solution of iodine (380 mg, 2.2 mmol) in THF (2 mL) was added dropwise and the mixture was stirred overnight. After evaporation of the solvent in vacuo, the residue was treated with an aqueous solution of NH4Cl (10 mL). The mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2) using CH2Cl2 as eluent to give, 100 mg (35%). 1H NMR (500 MHz, CDCl3) δ 8.05-7.80 (m, 3H), 7.60-7.35 (m, 3H), 7.19 (t, J=8 Hz, 1H), 6.98 (s, 1H), 6.72 (d, J=8 Hz, 1H), 3.62 (m, 4H), 3.05 (m, 4H), 1.47 (m, 9H); MS (ESI+) for m/z 568 (M+H)+.
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[Br-]>O1CCCC1>[CH2:8]([C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)[CH2:9][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC1=CC(=O)CCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCCC1=CC(=O)CCC1
Temperature: 0 °C
Yield: 111.3 %

Procedure:
To a solution of 3-ethoxy-2-cyclohexenone (8.62 g, 61.50 mmol) in dry THF (tetrahydrofuran), hexylmagnesuim bromide (15.38 mL, 2.0 M, 30.75 mmol) was added dropwise with stirring. The mixture was kept at 0° C. (in an ice-water bath) during the whole process and then was allowed to warm (the ice-water bath was removed) to ambient temperature (approximately 22° C.). Hydrochloric acid (10 mL, 3.0 M) was added to the above mixture. The mixture was extracted with diethylether 3 times. The combined organic layerswere washed with water and then dried over magnesium sulfate. The product was further purified by flash chromatography on silica gel using 10:100 (dicholomethane:hexane (volume:volume)) to yield 6.17 g (xx %) of 3-hexyl-2-cyclohexenone. 1H NMR (300 MHz, CDCl3): δ 5.78 (s, 1 H), 2.40-2.20 (m,4 H), 2.20-2.10 (t, J=7.37 Hz, 2H), 1.90 (p, J=6.50 Hz, 2 H), 1.42 (t, J=7.30 Hz, 2 H), 1.22 (br, 6 H), 0.81 (t, J=6.70 Hz, 3 H). 13C NMR (75 MHz, CDCl3): 200.06, 167.00, 126.04, 38.49, 37.80, 32.02, 30.11, 29.35, 27.35, 23.21, 22.95, 14.42, GC/MS calculated for C12H20O 180.15, found 180.15. The foregoing gas chromatography/mass spectrometry measurements confirmed the structure. Preparing the Compound of Formula II
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(C=CC(=O)Cl)cc1

Procedure:
100 ml of benzene was added to 16.2 grams of p-methylcinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:13][C:12]([NH2:14])=[N:11][C:9](=O)[CH:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[N:13]=[C:12]([NH2:14])[N:11]=1
Reactant: Nc1nc(=O)cc(-c2ccccc2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)cc(-c2ccccc2)n1

Procedure:
To 10.0 g (53 mM) of 6-phenylisocytosine is added 80 ml of phosphorus oxychloride. The mixture is heated to reflux, and refluxed until solution is complete (about 30 minutes). The solution is then cooled and evaporated to dryness under vacuum at 45° C. The resulting oil is poured into 300 ml of ice water, with vigorous stirring, and the remaining oil washed into the aqueous mixture with additional 100 ml of water. The entire aqueous mixture is neutralized to pH 8 with concentrated ammonium hydroxide, filtered, and solids washed well with water until water wash is neutral. Dry at 60° in a vacuum oven to yield 9.2 g of 4-chloro-6-phenyl-2-pyrimidinamine.
Reaction SMILES: C12([OH:11])CC3CC(CC(C3)C1)C2.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[C:26]12([OH:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[OH:36])[CH2:33]2>ClC1C=CC=CC=1.C(O)(=O)C>[C:26]12([OH:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[C:27]1([OH:11])[OH:36])[CH2:33]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: OC1C2CC3CC(C2)CC1(O)C3
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: OC12CC3CC(CC(C3)C1(O)O)C2
Temperature: 85 °C
Reaction time: 20 h
Yield: 50.5 %

Procedure:
A mixture of 25 g (164 mmol) of adamantanol, 5.36 g (32.8 mmol) of N-hydroxyphthalimide, 0.11 g (0.328 mmol) of vanadiumacetylacetonato [V(acac)3], 150 mL of acetic acid and 150 mL of chlorobenzene was stirred for 20 hours at 85° C. and 1 atm (0.101 MPa) in an atmosphere of oxygen. After completion of reaction, the reaction mixture was analyzed by gas chromatography and high performance liquid chromatography, and, as a result, the conversion of adamantanol was 95.6%, adamantanediol and adamantanetriol were formed in yield 50.5% (selectivity 52.8%) and yield 40.7% (selectivity 42.6%), respectively. Moreover, in the reaction mixture, 1.85 g of N-hydroxyphthalimide used as a catalyst, 1.51 g of phthalimide, and 0.40 g of phthalic anhydride were contained.
Reaction SMILES: C([O:4][C:5](=[O:20])[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)(C)C.S(=O)(=O)(O)O>>[C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]([OH:20])=[O:4])[O:11][N:10]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)OC(=O)Cc1nc(C(=O)c2ccccc2)no1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1nc(C(=O)c2ccccc2)no1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 48.1 %

Procedure:
To a flask containing 8.6 g of isopropyl(3-benzoyl-1,2,4-oxadiazol-5-yl)acetate, which had been cooled in an ice bath, was added 50 ml of cold 97% sulfuric acid. This mixture was swirled continuously for three minutes. The resultant solution was poured gradually into one liter of ice water with mechanical stirring to precipitate the product. The solid was collected by filtration, washed with excess water and dried in vacuo. Recrystallization from acetone/hexane gave 3.5 g (48%) of crystals, m.p. 143°-144.5°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (2.0 g, 1.0 eq, 9.6 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (2.1 g, 1.1 eq, 10.5 mmol) was taken in annhydrous DMF (100 mL) and stirred at room temperature. Cs2CO3 (7.2 g, 2.3 eq, 22.1 mmol) was added to the above solution and the heterogeneous mixture was heated at 100° C. overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and partioned with H2O (50 mL). The layers were separated and the aqueous layer was washed with CH2Cl2 (2×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to leave a crude solid. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using EtOAc/hexane (gradient system from 0:10 to 2:8) as eluent gave the product in 60% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(COc2cccc(N3CCOCC3)c2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 79.8 %

Procedure:
526 mg (2.0 mmol) of 1-(benzyloxy)-3-bromobenzene, 209 μl (2.4 mmol) of morpholine, 283 mg (2.8 mmol) of sodium t-butoxide, 9 mg (0.005 mmol) of tris(dibenzylidine acetone)dipalladium(0) and 19 mg (0.015 mmol) of (±)-BINAP were placed in a flask, 5 ml of toluene was added thereto, and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and filtered through Cellite. The resulting filtrate was concentrated under a reduced pressure, and the residue was subjected to column chromatography using 30% ethyl acetate/hexane as an eluent to obtain 430 mg (yield 80%) of 4-(3-(benzyloxy)phenyl)morpholine.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:37]=[CH:36][C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[CH:21][CH:20]=1.BrCC1C=CC(F)=C(C(F)(F)F)C=1.OCC1C=CC(O)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:37][CH:36]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Fc1ccc(COc2ccc(CCl)cc2)cc1C(F)(F)F
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: Fc1ccc(CBr)cc1C(F)(F)F
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(F)c(C(F)(F)F)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-(4-Chloromethyl-phenoxymethyl)-1-fluoro-2-trifluoromethyl-benzene prepared from 1-bromomethyl-4-fluoro-3-trifluoromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 283 (M−237).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:19][O:20][CH2:21][CH2:22]Br>C1COCC1>[CH3:19][O:20][CH2:21][CH2:22][C:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[S:9][CH2:10][CH2:11][CH2:12][S:13]1
Reactant: CC(C)(C)OC(=O)C1SCCCS1
Reactant: COCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Reaction time: 1 h
Yield: 69.2 %

Procedure:
A solution of tert-butyl[1,3]dithiane-2-carboxylate (2 g, 9.08 mmol) in THF (16 mL) was cooled to −78° C., and a solution of n-butyllithium (1.58 M in Hexane, 8.62 mL, 13.6 mmol) was added. After stirring for 1 hour, 2-bromoethyl methyl ether (1.70 mL, 18.1 mmol) was added. After stirring at −78° C. for 15 minutes, the cooling bath was removed, and, while allowing the temperature to gradually return to room temperature, the solution was stirred at room temperature for 16 hours. After confirming the consumption of the starting materials by LCMS, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated brine, and subsequently dried over anhydrous sodium sulfate. The organic layer was filtered, and the solvent was distilled off. The resulting residue was purified with SP1 (SiO2 cartridge) to obtain tert-butyl 2-(2-methoxy-ethyl)-[1,3]dithiane-2-carboxylate (1.75 g, 69% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)[C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)[C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCCCN(C(=O)c2ccc3c(c2)OCO3)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(N(CCCOc2ccc(C(=O)O)cc2)C(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 60 °C
Reaction time: 23 h
Yield: 80.8 %

Procedure:
Methyl 4-[3-[N-(4-tert-butylphenyl) -N-(3,4methylenedioxybenzoyl)amino]propoxy]benzoate (2.0 g) was dissolved in methanol (40 ml) and thereto was added a solution of sodium hydroxide (0.33 g) in water (10 ml), the mixture was heated with stirring at 60° C. for 23 hours. The reaction solution was cooled, and the solution was adjusted to pH 4-5 with conc. hydrochloric acid. The mixture was diluted with water and the precipitate was collected by filtration and washed with water. The precipitate was recrystallized from ethyl acetate/hexane to give the desired product (1.57 g). mp. 199°-203° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[NH:15][C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OCc2ccccc2)c2cc(OCCCl)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a suspension of NaH (0.959 mmol, 0.038 g, 60% in mineral oil, rinsed twice with hexanes) in 5 mL of DMF at 0° C. under N2 was added a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 3.73 mL of DMF. The ice bath was removed and the solution was stirred for 2 hours at room temperature. Benzyl bromide (0.959 mmol, 0.114 mL, Aldrich) was added dropwise via syringe and the solution was stirred for 19 hours. Water (10 mL) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off, the filtrate was extracted with ethyl acetate (3×10 mL), and the extracts were washed with brine (1×10 mL), dried over MgSO4, and concentrated. The residue was combined with the solid and purified by silica gel flash column chromatography (10-20% ethyl acetate/hexanes) to give an off-white solid (0.236 g, 62%): 1HNMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H, ArCH3),3.86-3.89 (m, 2H, CH2Cl), 4.09-4.12 (m, 2H, CH2OAr), 5.30 (s, 2H, CO2CH2Ph), 5.46 (s, 2H, NCH2Ph), 6.78 (dm, J=8.79 Hz, 1H, ArH), 6.96 (d, J=7.33 Hz, 2H, ArH), 7.18-7.30 (m, 3H, ArH), 7.32-7.40 (m, 4H, ArH), 7.44-7.49 (m, 3H, ArH); MS(APCI+): m/z 434.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]([Cl:16])([Cl:15])[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:10][C:11]([Cl:16])([Cl:15])[C:12]([OH:14])=[O:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[C:4]([O:13][C:12](=[O:14])[C:11]([Cl:16])([Cl:15])[Cl:10])[C:3]=1[O:14][C:12](=[O:13])[C:11]([Cl:16])([Cl:15])[Cl:10]
Reactant: O=Ic1ccc(Cl)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Oc1c(Cl)ccc(I)c1OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A quantity of 135 g. (0.53 mole) p-chloroiodosobenzene is suspended in 800 ml. of methylene chloride contained in a 2-liter Erlenmeyer flask. To the suspension is added 190 g. (1.16 mole) trichloroacetic acid dissolved in 500 ml. of methylene chloride with agitation over a 5-minute period, the reaction temperature being maintained at room temperature. After 30 minutes, the solution is filtered and solvent is removed under reduced pressure. The solid residue is triturated with ether and filtered. The solid is collected on the filter, washed with ether and dried. The slightly off-white crystalline solid thereby obtained melts with decomposition at 155°-157°C. The yield is 80-85%. The carbon, hydrogen and iodine analyses and infrared spectra are consistent with the named structure. The substitution of dichloroacetic acid for trichloroacetic acid gives the corresponding 4-chloro-bis(dichloroacetoxy)iodobenzene which melts at 111°-112°C. with decomposition.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][C:17](=[O:25])[C:18](=[C:21]([S:23][CH3:24])[CH:22]=1)[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][C:17](=[O:25])[C:18](=[C:21]([S:23]([CH3:24])=[O:34])[CH:22]=1)[C:19]#[N:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a cold (0° C.) solution of 6-[2-(benzyloxy)phenyl]-4-(methylthio)-2-oxo-1,2-dihydro-nicotinonitrile (4.00 g, 11.5 mmol) in CH2Cl2 was added m-chloroperbenzoic acid (mCPBA) (69%, 3.45 g, 13.8 mmol) in one portion. The reaction mixture was stirred at 0° C. to room temperature for 1 hr, quenched with saturated NaHCO3 solution (80 mL) including Na2S2O3.5H2O (5 g), and diluted with CH2Cl2. The separated organic phase was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual solid was triturated with diisopropyl ether to give 6-[2-(benzyloxy)phenyl]-4-(methylsulfinyl)-2-oxo-1,2-dihydro-nicotinonitrile as a yellow solid (4.00 g, yield; 96%).
Reaction SMILES: [ClH:1].[Na].Cl.[S:4]1[CH:8]=[CH:7][C:6]2[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([CH3:29])=[CH:27][C:26]([NH:30][CH:31]=O)=[CH:25][C:24]=4[O:33][CH3:34])[CH2:15][CH2:14]3)=[CH:10][CH:11]=[CH:12][C:5]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[ClH:1].[CH3:31][NH:30][C:26]1[CH:27]=[C:28]([CH3:29])[C:23]([O:22][CH2:21][CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:9]3[C:6]4[CH:7]=[CH:8][S:4][C:5]=4[CH:12]=[CH:11][CH:10]=3)[CH2:14][CH2:15]2)=[C:24]([O:33][CH3:34])[CH:25]=1
Reactant: COc1cc(NC=O)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1cc(C)c(OCCCN2CCN(c3cccc4sccc34)CC2)c(OC)c1

Procedure:
A 6N aqueous sodium hydrochloride solution was added to N-(4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl formamide hydrochloride (0.23 g, 0.48 mmol) and the solution mixture was extracted with dichloromethane. The extraction solution with dichloromethane was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in a tetrahydrofuran (THF) solution (5 ml) and lithium aluminum hydride (30 mg, 0.71 mmol) was added thereto under ice cooling and refluxed with heating for 15 minutes. The reaction solution was cooled on ice, and water (0.03 ml), 15% aqueous sodium hydroxide solution (0.03 ml), and water (0.09 ml) were added to the reaction mixture in this order and stirred. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→3:1) and concentrated under reduced pressure. A solution of 4N-hydrochloric acid/ethyl acetate was added to an ethyl acetate solution of the residue, and the insoluble matter precipitated was obtained by filtration to obtain N-methyl-4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline hydrochloride (63 mg) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:10]O)[S:7][CH:6]=1)=[O:4].C(N(CC)CC)C.S(Cl)([Cl:21])=O.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:10][Cl:21])[S:7][CH:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1csc(CO)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1csc(CCl)c1
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A solution of 5-hydroxymethyl-thiophene-3-carboxylic acid methyl ester (8.8 g, 51.1 mmol) and triethylamine (7.8 mL, 56.2 mmol) in dichloromethane (135 mL) is cooled to 0° C. and treated with a solution of thionyl chloride (4.1 mL, 56.2 mmol) in dichloromethane (40 mL) in a dropwise maner. After stirring for 1 h, water is added and the mixture is extracted with dichloromethane. The combined organics are dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, 10% ethyl acetate in heptane) to give 5-chloromethyl-thiophene-3-carboxylic acid methyl ester (4.5 g, 46%) an amber oil. 1H NMR (CDCl3, 300 MHz) δ 8.04 (s, 1 H), 7.43 (s, 1 H), 4.78 (s, 2 H), 3.84 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[F:8].B.C1COCC1.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[CH2:10][CH2:11][NH:12][C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCC(O)c1ccc(F)c(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: O=C(NCCC(O)c1ccc(F)c(Br)c1)C(F)(F)F

Procedure:
Reduction of 3-(3-bromo-4-fluorophenyl)-3-hydroxypropanenitrile with BH3-THF following the method used in Example 17, followed by protection of the amine with ethyl trifluoroacetate following the method used in Example 9 gave N-(3-(3-bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a clear oil. Yield (4.3 g, 73%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (bs, 1H), 7.62 (dd, J=6.8, 2.0 Hz, 1H), 7.37-7.33 (m, 1H), 7.30 (t, J=8.8 Hz, 1H), 5.48 (d, J=4.4 Hz, 1H), 4.60-4.56 (m, 1H), 3.28-3.15 (m, 2H), 1.84-1.71 (m, 2H).