Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([I:6])=[CH:8][CH:9]=2)=[O:12])[CH2:28][CH2:29]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To tetrahydrofuran (60 mL) were added 4-iodobenzoyl chloride (5 g), 1-(2,4-dimethylphenyl)piperazine (3.6 g) and 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added and the mixture was partitioned. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (8 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27]3)[CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:25])[F:24])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][N:29]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27]3)[CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:24])[F:25])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCN1
Reactant: O=C(O)Cc1c[nH]cn1
Product: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCN1C(=O)Cc1c[nH]cn1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclopentyloxy-4-difluoromethoxy-phenyl)-3-isobutyl-piperazine (Example 36, Compound 124) as starting materials. Product as an off-white solid (20%). LC/MS (Method B) 3.04 min, [M+1]+ 477.1. Potency class B.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])/[CH:17]=[CH:18]/[CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[C:3]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1.[O:40]=[C:41]1[NH:45][CH:44]2[CH2:46][S:47][C@@H:48]([CH2:49][CH2:50][CH2:51][CH2:52][C:53](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:54])[CH:43]2[NH:42]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])/[CH:17]=[CH:18]/[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]4[CH:43]5[CH:44]([NH:45][C:41](=[O:40])[NH:42]5)[CH2:46][S:47]4)[CH2:22][CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[C:3]=1[C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:31][CH:32]=1
Reactant: Nc1ncnc(Oc2cccc(NC(=O)/C=C/CN3CCNCC3)c2)c1-c1ccc(Oc2ccccc2)cc1
Reactant: O=C1NC2CS[C@@H](CCCCC(=O)Oc3c(F)c(F)c(F)c(F)c3F)C2N1
Product: Nc1ncnc(Oc2cccc(NC(=O)/C=C/CN3CCN(C(=O)CCCC[C@@H]4SCC5NC(=O)NC54)CC3)c2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 45 %

Procedure:
((E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide was prepared from (E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(piperazin-1-yl)but-2-enamide and perfluorophenyl 5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate using Method F (45% yield). HPLC: 100%, RT=3.635 min. MS: m/z=750 [M+H]+, RT=1.84 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:38])(=[O:37])[NH:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:18][CH:17]=1)(C)(C)C>ClCCl>[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:37])=[O:38])=[CH:18][CH:17]=1
Reactant: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NS(=O)(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.9 %

Procedure:
Trifluoroacetic acid (25 ml) was at room temperature added to a solution of (4-(dodecanoylsulfamoyl)benzyl)carbamic acid tert-butyl ester (170 mg, 0.40 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 1 h at room temperature. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (40 ml) and the solvent was removed in vacuo. The latter procedure was repeated once to give 0.19 g of the trifluoroacetic salt of 4-aminomethyl-N-(dodecanoyl)benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCn1c(=O)[nH]c(Cl)c(-c2ccccc2)c1=O
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c(-c2ccccc2)c(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.9 %

Procedure:
A mixture of 6-chloro-5-phenyl-3-propyl-pyrimidine-2,4(1H,3H)-dione (0.5 g), 4-bromomethyl-2'-(N-trityltetrazol-5yl)biphenyl (1.11 g) and potassium carbonate (0.32 g) in DMF (20 ml) was stirred at room temperature for 22 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.67 g, 48%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([OH:11])=[O:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1](=[N:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(S(=O)(=O)N=Cc2ccccc2)cc1

Procedure:
In the same manner as Example 2, 4.00 g (38 mmol) of benzaldehyde, 7.58 g (38 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of toluene were heated for 36 hours to afford 7.40 g (71%) of SULF-4 as a light tan powder: IR (Nujol) 3800-2600 (br), 1685, 1600, 1283, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 9.05 (s, 1), 8.2-7.2 (m, 9).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17](=[N:21][NH:20][C:22]([C:24]3[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=3)=[O:23])[CH3:19])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)s1
Yield: 59.7 %

Procedure:
2-(4-t-Butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (80 mg, 0.29 mmol) and methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (58 mg, 0.29 mmol) were stirred in dimethylformamide (2.9 mL) at 120° C. under heating overnight. The resulting reaction solution was concentrated, and chloroform/n-hexane was added. The precipitated solid was recovered by filtration to give the desired product as a yellow solid (79 mg, yield 60%).
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:8][C:7]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[C:3]([S:4][CH3:5])[C:6]=1[C:9]#[N:10]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: NNc1ccccc1
Solvent: CCO
Product: CSc1nn(-c2ccccc2)c(N)c1C#N
Yield: 9.1 %

Procedure:
A mixture comprised of 17.0 g (100 mmol) of bis (methylthio)methylenepropanedinitrile, 10.8 g (100mmol) of phenylhydrazine and 80 ml of ethanol was heated under reflux for 2 hours. The solvent was removed through distillation, and 20 ml of ethanol was added to the residue, which was thus crystallized. The resulting crystals were taken out by means of filtration under suction to give 20.9 g (9.1 mmol) of the entitled product as colorless, needle-like crystals having a melting point of from 136° to 137° C. The yield was 91%.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH3:14])[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH3:14])=[O:31])[CH3:3]
Reactant: CSc1ccccc1CC[C@H]([C@H](C)O)n1cnc(C(N)=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@H](O)[C@@H](CCc1ccccc1S(C)=O)n1cnc(C(N)=O)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-(methylthio)phenyl)-3-pentyl]imidazole-4-carboxamide (7.1 mg) and m-chloroperbenzoic acid (75%; 5.12 mg) in dichloromethane (1 ml) was stirred at 5° C. for 2 hours. The mixture was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (5:1) to give a colorless oil of 1-[(2S,3R)-2-hydroxy-5-(2-(methylsulfinyl)phenyl)-3-pentyl]imidazole-4-carboxamide (3) (5.4 mg).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:29][C:30](=[O:40])[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[CH3:32])C>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:39][C:35]3[CH:34]=[C:33]([CH:31]([CH3:32])[C:30]([OH:40])=[O:29])[CH:38]=[CH:37][CH:36]=3)=[O:25])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)C(C)c1cccc(N)c1
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: CC(C(=O)O)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with (±)-2-(3-amino-phenyl)-propionic acid ethyl ester (S. Mutti et al. Synth. Comm. 1997, 27, 425) according to the procedure of Example 20, step d. The ethyl ester was hydrolysed using the same procedure as in Example 247, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.20 (2H, br s), 9.44 (1H, s), 7.64 (2H, m), 7.23 (1H, m), 6.96 (1H, d), 3.61 (1H, m), 2.86 (2H, m), 2.60 (1H, m), 1.98-1.19 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.88; H, 8.66; N, 7.68%. C38H58N4O8.1.5 mols H2O requires: C, 62.87; H, 8.47; N, 7.72%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=3[CH3:23])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:25])=[C:19]([CH:20]=[CH:21][C:22]=3[CH3:23])[O:24][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CNc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 3-[[3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (168 mg, 0.50 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (245 mg, 0.75 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (109 mg, 0.6 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 40:1 to 30:1) to give the title compound as a colorless oil (151 mg, 69%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](O)=[O:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:38]([C:34]4[S:33][CH:37]=[CH:36][CH:35]=4)=[O:39])[CH2:25][CH2:26]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1cccs1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCNCC3)c2-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCN(C(=O)c4cccs4)CC3)c2-c2ccccc2)cc1
Temperature: 37 °C
Yield: 48.6 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-1-yl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.43 mmol, prepared according to the procedure described in preparation 2) in dimethylformamide (20 ml) was added thiophene-2-carboxylic acid (0.149 g, 0.78 mmol) under stirring at 37° C., and then after 10 minutes EDCI (0.149 g, 0.78 mmol), and HOBt (0.023 g, 0.173 mmol) were added. Further TEA (0.179 ml, 2.9 mmol) was added to the resultant clear solution and it was stirred for 18 hours. Subsequently the reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed successively with water, 10% sodium bi carbonate solution (100 ml), and brine (100 ml) respectively and dried over anhydrous sodium sulphate. Evaporation of the solvent and purification by column chromatography (0.4% MeOH:DCM) gave the title compound (0.12 g, yield 48.6%); m.p. 189-194° C. 1H-NMR (CDCl3) δ: 2.98 (s, 3H), 3.4-3.41 (t, 4H), 3.66-3.68 (t, 4H), 7.02-7.77 (m, 12H). MS m/z: 573.2 (M++1).
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[CH:9][C:10]([Cl:13])([Cl:12])[Cl:11].O>C(OCC)C>[Cl:11][C:10]([Cl:13])([Cl:12])[CH:9]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[OH:8]
Reactant: Brc1cccs1
Reactant: O=CC(Cl)(Cl)Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: OC(c1cccs1)C(Cl)(Cl)Cl
Temperature: 5 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
Under a dry argon atmosphere a Grignard reagent was prepared by combining 13.1 g (0.54 mole) of magnesium turnings with 86.4 g (0.53 mole) of 2-bromothiophene in dry diethyl ether. The Grignard reagent was stirred and cooled to 5° C., and 77.8 g (0.53 mole) of chloral was added slowly. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured into 500 ml of cold water and extracted with three 250 ml portions of ethyl acetate. The combined organic extracts were dried with magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to yield a liquid. The liquid was distilled under reduced pressure to give 67.2 g of 2,2,2-trichloro-1-(2-thienyl)ethanol; bp 113°-115° C./19.95 pa. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)([OH:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: O=C1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
Isopropylmagnesium chloride (2M tetrahydrofuran solution) (11.73 ml) was added to a tetrahydrofuran solution (20 ml) of 4-iodobenzotrifluoride (3.45 ml, 23.5 mmol) dropwise at −10° C. under an argon atmosphere. The mixture was stirred at the same temperature for 5 minutes and further stirred at room temperature for 2 hours. After cooling the mixture to −10° C., a tetrahydrofuran solution (40 ml) of 1-(4-benzyloxyphenyl)piperidin-4-one (6 g, 21.3 mmol) was added thereto dropwise. While gradually returning to room temperature, the mixture was stirred. After 10 hours, a saturated ammonium chloride aqueous solution/ice water was poured into the mixture, followed by extraction with ethyl acetate. The result was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→66:34). The resultant was washed with a mixed solvent of isopropyl ether and hexane and filtered to afford the title compound as a white powder (6.69 g, 73%).