Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:12]3=[O:26])=[CH:4][CH:3]=1.I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[Cu].ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:12]3=[O:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: O=C1c2ccc(Nc3ccc(Cl)cc3)cc2C(=O)N1Cc1cccnc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccc(N(c3ccccc3)c3ccc(Cl)cc3)cc2C(=O)N1Cc1cccnc1
Yield: 93.4 %

Procedure:
A mixture of 85 mg of 5-[N-(4-chlorophenyl)amino]-2-(3-pyridylmethyl)-1H-isoindole-1,3 (2H)-dione, 71 mg of iodobenzene, 30 mg of copper dust, 12 mg of 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane), 128 mg of potassium carbonate and 2 ml of 1,2-dichlorobenzene was refluxed under heating for 7 hours. After finishing the reaction, the insoluble material was filtered off, and the filtrate was concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with chloroform and methanol (100:1) to give 96 mg of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][N:14]([CH3:29])[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>O.ClCCCl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][CH2:21][CH:18]2[CH2:17][CH2:16][C:15]([N:14]([CH3:13])[CH3:29])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)=[CH:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(CNCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tryptamine (2-(1H-indol-3-yl)ethylamine, 321 mg, 2 mmol.) was dissolved in abs. 1,2-dichloroethane. After the addition of 4-dimethylamino-4-phenylcyclohexanecarbaldehyde (463 mg, 2 mmol.), the mixture was stirred for 1 h at RT. Sodium triacetoxyborohydride (660 mg, 3 mmol.) was then added, and stirring was carried out for 3 d at RT. For working up, 1,2-dichloroethane (10 ml), water (15 ml) and 2M HCl (3 ml) were added to the reaction mixture. After stirring vigorously for 15 min., the phases were separated and the aqueous phase (pH 3) was extracted again with 1,2-dichloroethane (10 ml). 5M NaOH was then added to the aqueous phase (pH 11), followed by extraction with EE (5×20 ml). The combined EE phases were dried, filtered and concentrated. The residue was the still impure diastereoisomeric mixture of the bases of the target product (690 mg, m.p. 56–64° C.), which was purified by flash chromatography on silica gel (70 g) and separated (eluant: 1200 ml of methanol/conc. ammonia solution 99.5:0.5). 220 mg (0.59 mmol.) of the non-polar diastereoisomer of (4-{[2-(1H-Indol-3-yl)ethylamino]methyl}-1-phenylcyclohexyl)dimethylamine (m.p. 78–83° C.) were obtained and were dissolved in 2-butanone; chlorotrimethylsilane (222 μl, 1.8 mmol.) was added at RT, and stirring was carried out for 2 h. The suspension was cooled for 1 h in an ice bath, and the solid was filtered off. The hygroscopic dihydrochloride was washed with cold ether and dried in vacuo. The dihydrochloride of the non-polar diastereoisomer of (4-{[2-(1H-Indol-3-yl)ethylamino]methyl}-1-phenylcyclohexyl)dimethylamine was thus obtained in a yield of 205 mg (white solid, m.p. 170–180° C. with decomposition, rearrangements at only 105° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[CH2:18]C(O)=O.C(OCC)(=O)C>C(#N)C.[Cu-]=O>[C:9]1([O:8][C:7]2[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=[C:3]([CH3:18])[C:2]=2[F:1])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Agent: O=[Cu-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Temperature: 90 °C
Yield: 67 %

Procedure:
Copper(I) oxide (0.077 g, 0.536 mmol) was added to a solution of [2-fluoro-4-nitro-3-(phenyloxy)phenyl]acetic acid (1.560 g, 5.36 mmol) in acetonitrile (20 mL). The mixture was heated in a 90° C. oil bath for 1 h. The reaction mixture was cooled to RT and the solvent was evaporated. The residue was taken up in dichloromethane and filtered through Celite. Flash chromatography (ethyl acetate:hexanes) gave 2-fluoro-3-methyl-6-nitrophenyl phenyl ether (0.888 g, 63.7% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74 (dd, 1H), 7.27-7.36 (m, 2H), 7.18 (t, 1H), 7.09 (t, 1H), 6.92 (d, 2H), 2.38 (s, 3H). ES MS: m/z 246 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]([C:12]1[C:17](I)=[C:16]([NH:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[N:15]=[C:14]([CH3:25])[N:13]=1)[CH2:6][CH2:5]2.[C:26]([Cu])#[N:27].[C-]#N.[Na+].[NH4+].[Cl-].[NH4+].[OH-]>CN(C=O)C>[C:26]([C:17]1[C:12]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[Cl:11])[CH2:5][CH2:6]2)=[N:13][C:14]([CH3:25])=[N:15][C:16]=1[NH:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])#[N:27]
Reactant: N#C[Cu]
Reactant: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1I
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1C#N
Reaction time: 0.33 h
Yield: 22.3 %

Procedure:
4-(5,7-Dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-iodo-2-methylpyrimidine (450 mg, 0.92 mmol) was heated at 140° C. in 5 mL DMF with CuCN (111 mg, 1.23 mmol) and NaCN (84 mg, 1.70 mmol) for 6 h. The reaction was poured into 20 mL 9:1 NH4Cl/NH4OH and stirred for 20 min. The product was extracted with EtOAc (100 mL) and the EtOAc was washed with water (20 mL), brine, dried over (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes as eluent to give the title compound 80 mg, mp 163-165° C.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:57])[CH:48]([O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:57])[CH:48]([O:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CC(Oc1ccccc1)C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(Oc1ccccc1)C(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-2-phenoxypropanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparative HPLC. (0.062 g, 59% yield over 2 steps): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.17 (t, 1H), 8.1 (d, 1H), 7.8-7.67 (m, 3H), 7.51 (t, 1H), 7.34-7.27 (m, 2H), 7.06-6.95 (m, 3H), 4.87 (q, 1H), 1.68 (d, 3H); ES-MS (m/z) 425 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]([C:5](Cl)=[O:6])[C:3]1([CH3:9])[CH3:8].Cl.[O:12]([NH2:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH3:13][O:12][NH:14][C:5]([CH:4]1[C:2]([CH3:10])([CH3:1])[C:3]1([CH3:9])[CH3:8])=[O:6]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)C1C(C)(C)C1(C)C
Yield: 75 %

Procedure:
Tetramethylcyclopropanecarbonyl chloride (TMC-Cl) (4 g; 25 mmol) dissolved in 20 ml of dry dichloromethane was slowly added to a stirred and dry dichloromethane solution of methoxylamine hydrochloride (2.5 g; 30 mmol) and triethylamine (6.3 g; 50 mmol). After the addition, the reaction mixture was stirred for 2 hr at room temperature. Dichloromethane was evaporated under vacuum, 10 ml of water was added and the products were extracted using 30 ml of ethyl acetate. The organic fraction was dried over MgSO4, filtered and evaporated under vacuum. The product was crystallized using 20 ml ethyl acetate and 30 ml petroleum ether to afford 3 g (75% yield) and its chemical structure was identified by elemental analysis and spectroscopic methods.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[K+].C(O)(=O)C.[OH-].[Na+]>O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][C:13](=[O:12])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
To a mixture of 2-amino-4-fluorobenzoic acid (4.0 g, 26 mmol) and potassium cyanate (3.5 g, 43 mmol) in water (200 mL) was added acetic acid (3 mL, 45 mmol) and the mixture was stirred at room temperature for about 5 h. To the mixture was added NaOH (15 g, 375 mmol) and it was stirred for another 1 h. The mixture was filtered and the solid was mixed in hot water, and it was adjusted to pH=5˜6 by addition of acetic acid. The mixture was filtered and washed with water, dried to give the title compound (3.0 g, 65% yield) as gray solid. MS: m/z 181.1 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:12]1([C@@H:10]([OH:11])[CH2:9][NH:8][C:4]2[CH:3]=[C:2]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=3)[N:7]=[CH:6][N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: OC(CNc1cc(Cl)ncn1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: O[C@@H](CNc1cc(-c2cccc(C(F)(F)F)c2)ncn1)c1ccccc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a round bottomed flask were added 2-[(6-chloropyrimidin-4-yl)amino]-1-phenylethanol (62.4 mg, 0.25 mmol), 3-trifluoromethylphenyl boronic acid (71.2 mg, 0.38 mmol), K3PO4 (106.1 mg, 0.5 mmol), Pd(OAc)2 (8.4 mg, 0.013 mmol) and 1,1′-bis(di-tert-butylphosphino)-ferrocene (5.9 mg, 0.013 mmol). The flask was then evacuated, backfilled with N2, and charged with 1,4-dioxane (2.5 mL). The reaction mixture was heated at reflux for 2.5 h, before cooling to rt, diluting with EtOAc (15 mL), washing with water (2×10 mL), drying, and concentrating to dryness. The crude residue was purified (FCC) to yield the title compound (35.7 mg, 40%). MS (ESI): mass calcd. for C19H16F3N3O, 359.1; m/z found, 360.2 [M+H]+. 1H NMR (CD3OD): 8.50 (s, 1H), 8.23 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.3 Hz, 2H), 7.37-7.33 (m, 2H), 7.28-7.24 (m, 1H), 6.96 (s, 1H), 4.93-4.90 (m, 1H), 3.79-3.69 (m, 1H), 3.61 (dd, J=13.6, 7.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>Cl[Pd]Cl.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1
Reactant: C=CC(=O)O
Reactant: COc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)O)cc1
Temperature: 130 °C
Yield: 81.2 %

Procedure:
p-bromo anisole (8.4 g), acrylic acid (3.9 g), water (13.5 g), PdCl2 (0.3 mg) and triethyamine (14.3 g, 89.3% pure by titration, the balance being water, recovered by phase separation from a previous run) were charged into an autoclave and heated for 2 hours at 130° C. The work up detailed in Example 1 gave 6.5 g (81%) of >98% pure p-methoxy cinnamic acid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][C:18]1[CH:22]=[C:21]([CH2:23]Cl)[O:20][N:19]=1>CS(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:23][C:21]2[O:20][N:19]=[C:18]([CH3:17])[CH:22]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CCl)on1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(COc2ccc(Oc3ccccc3)cc2)on1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
At 10° to 20° C., 18.6 g of p-phenoxyphenol in 50 ml of dimethyl sulfoxide is dripped into 3.1 g of sodium hydride (85% strength in paraffin) in 100 ml of dimethyl sulfoxide. The mixture is stirred for 30 minutes at 50° C. and then 3-methyl-5-chloromethylisoxazole is dripped in at 15°-20° C. The mixture is worked up in the usual manner after 8 hours at 70° C. There is obtained 26.7 g of compound no. 31.25 of m.p. 48°-51° C.
Reaction SMILES: [C:1](#[N:3])C.[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][N+:6]=1[O-].C[Si](C#N)(C)C>C(N(CC)CC)C>[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:1]#[N:3])[N:6]=1
Reactant: CC#N
Reactant: [O-][n+]1ccc(C(F)(F)F)cc1Cl
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)cc(Cl)n1
Temperature: 25 °C

Procedure:
To 16 ml of acetonitrile were added 1.5 g of 2-chloro-4-trifluoromethylpyridine N-oxide, 2.12 ml of triethylamine, and 2.26 g of trimethylsilyl cyanide, and the mixture was heated to reflux for 23 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.9 g of 2-chloro-6-cyano-4-trifluoromethylpyridine.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][O:21][C:22]1[C:29]([OH:30])=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.Cl>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:28][C:29]=1[OH:30]
Reactant: C1CCNC1
Reactant: COc1ccc(C=O)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN2CCCC2)cc1O
Yield: 84.9 %

Procedure:
NaB(OAc)3H (32 g, 0.15 mol) was added in portions for 15 min to a mixture of pyrrolidine (9.1 mL, 0.11 mol) and 4-methoxy-5-hydroxybenzaldehyde (15.2 g, 0.1 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (21 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with K2CO3 to pH 9 (60 mL) and extracted with chloroform (3×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compounds (17.6 g, 85%) as white crystals. LCMS-data: 208.1 and 209.1 (M+H)+, (calculated for C12H17NO2 207.1). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 8.81 (br s, 1H, OH); 6.80 (d, 1H, ArH, J=8.3 Hz); 6.73 (d, 1H, ArH, J=2 Hz); 6.65 (dd, 1H, ArH, J1=2 Hz, J2=8 Hz); 3.72 (s, 3H, OCH3); 3.40 (s, 2H, CH2Ar); 2.41-2.33 (m, 4H, CH2CH2CH2CH2); 1.70-1.62 (m, 4H, CH2CH2CH2CH2,).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[OH:27])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:29][CH:30]([F:32])[F:31].[F-].[Cs+]>CN(C=O)C>[C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[O:27][CH2:29][CH:30]([F:32])[F:31])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: FC(F)CBr
Reactant: CC(=O)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)cccc2s1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)cccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the crude 2-acetyl-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene, 142.0 mg (1 mmol) of 2-bromo-1,1-difluoroethane and 410 mg (2.7 mmol) of CsF in 10 mL of dry DMF was stirred at room temperature overnight. After work-up the crude oil was filtrated over a short pad of silica gel (eluent: 10/90 ethyl acetate/hexane) to give 2-acetyl-4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thiophene as an oil, directly used without further purification. The crude ketone was treated with the anion of triethylphosphonoacetate (previously prepared from 336 mg of triethylphosphonoacetate and 86 mg of NaH in 3 mL of dry DMF) at 60° C. After completion of the reaction (TLC monitored) and work-up, the crude ester was purified over silica gel column (eluent: 5/95 ethyl acetate/hexane) to afford 315 mg (0.65 mmol, yield: 75%, 2 steps) of pure 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-but-2-enoic acid ethyl ester as an oil. 1H-NMR (CDCl3), δ: 7.80 (dd, J=7.2, 1.6 Hz, 1H), 7.43 (m, 4H), 7.23 (d, J=2.5 Hz, 1H), 6.29 (s, 1H), 5.17 (dt, J=55.4, 4.1 Hz, 1H), 4.21 (dd, J=14.4, 7.2 Hz, 2H), 3.50 (m, 2H), 2.57 (s, 3H), 1.47 (s, 9H), 1.34 (s, 9H), 1.31 (t, J=7.0 Hz).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([CH2:12][C:13]#[N:14])=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:20]I>O1CCCC1>[C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([CH:12]([CH3:20])[C:13]#[N:14])=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=1)#[N:2]
Reactant: CI
Reactant: CC(C)c1cc(CC#N)c(C(C)C)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C#N)c(C(C)C)cc1C#N

Procedure:
A mixture of 4-cyano-2,5-diisopropylbenzeneacetonitrile (22.6 parts), 4.8 parts of a 50% sodium hydride suspension in mineral oil, and 14.2 parts of methyl iodide in 300 parts tetrahydrofuran is stirred and heated at 50° for two hours. The reaction mixture is cooled and the tetrahydrofuran stripped under reduced pressure. The solid is washed with pentane and water and dried to give 4-cyano-2,5-diisopropyl-α-methylbenzeneacetonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][NH:12][C:13](=[O:38])[NH:14][C:15]2[CH:37]=[CH:36][C:18]([C:19]([N:21]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH2:11][NH:12][C:13](=[O:38])[NH:14][C:15]2[CH:37]=[CH:36][C:18]([C:19]([N:21]([CH3:22])[CH:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
2,2,2-Trifluoroacetic acid (1.88 mL, 24.39 mmol) was added to a solution of tert-butyl 4-(4-(3-(cyclopropylmethyl)ureido)-N-methylbenzamido)piperidine-1-carboxylate (420 mg, 0.975 mmol) in dichloromethane (10 mL). The mixture was stirred at ambient temperature for 4 hours and then treated with strong cation exchange column chromatography to afford the title compound (300 mg). MS (ESI) m/z 331.1 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C=O)C>[CH3:14][C:12]1[O:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[C:18](=[O:28])[C:19]4[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:21]3=[O:23])=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=2)[N:13]=1
Reactant: Cc1nc(-c2ccc(CBr)c([N+](=O)[O-])c2)no1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CN3C(=O)c4ccccc4C3=O)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of compound 1c (5.64 g, 19 mmol) and potassium pthalimide (3.9 g, 20.9 mmol) in DMF (42 mL) was heated to 40° C. for 4 h. The reaction mixture was cooled to rt and poured into water (200 mL). The solid was filtered, washed with water (3×), and dried in vacuo to give compound 1d as a white solid (6.2 g, 90%). ESI-MS m/e 365.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].C([O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([OH:27])=[O:19]
Reactant: CCOC(=O)CCCCCBr
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCOc1cc(Cl)c(Cl)cc1Cl
Yield: 85 %

Procedure:
First, 987 mg (5 mmol) of 2,4,5-trichlorophenol (III) and 1.04 g (7.5 mmol) of anhydrous potassium carbonate were added to 8 ml of anhydrous dimethyl formamide and the mixture was stirred. Then, 1.67 g (7.5 mmol) of 6-bromohexanoic acid ethyl ester was added thereto, and the mixture was stirred at 60° C. for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was extracted with dichloromethane, washed with water, and was then concentrated under reduced pressure to dryness. The residue was dissolved in a mixed solution of 10 ml of dioxane and 12.5 ml of methanol, and 2.5 ml of 10 N sodium hydroxide was added thereto with stirring. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, 5 ml of water was added to the mixture and neutralized with 6 N hydrochloric acid. The solvent was evaporated under reduced pressure to dryness, 1 N hydrochloric acid was added to the residue and the residue was extracted with chloroform. After washing with water, the residue was concentrated under reduced pressure to dryness and was powdered using a mixed solution of hexane and ether to obtain 6-(2,4,5-trichlorophenoxy) hexanoic acid (Ia) (hereinafter, referred to as “compound (Ia)”) in an amount of 1.32 g (yield: 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2([OH:38])[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC.N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2([OH:38])[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)[CH2:9][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(O)(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCC(O)(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 13.6 %

Procedure:
0.25 g of 4-{1-(4-Fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-1-methylpiperidin-4-ol was dissolved in 3 ml of tetrahydrofuran, and 18 mg of lithium aluminum hydride was added, followed by stirring at 50° C. for 15 minutes. The reaction solution was cooled to room temperature and diluted with ether, and 25% aqueous ammonia solution was added dropwise. The precipitate was removed by Celite filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 33 mg of 4-{1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]ethyl}-1-methylpiperidin-4-ol as an oil.