Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2C[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.CS(O[CH2:27][CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][CH2:27][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) was added 3,3-diphenylpropyl methanesulfonate (3.96 g, 13.6 mmol) followed by addition of potassium carbonate (1.90 g, 13.6 mmol), and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 3.81 g of ethyl [[2-(3,3-diphenypropyl)thio-8H-indeno[1,2-d]thiazol-7-yl]oxy]acetate. To a solution of this compound (1.10 g, 2.19 mmol) in ethanol (30 mL)-water (3 mL) was added sodium periodate (4.68 g, 21.9 mmol) and the mixture was refluxed for 14 hours. This reaction mixture was diluted with ethyl acetate and water and, after, phase separation, the aqueous layer was extracted with ethyl acetate. The organic layers were pooled, washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in acetic acid (10 mL). To this solution was added concentrated sulfuric acid (5 mL) and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate, and the combined extract was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from hexane-ethyl acetate to provide 350 mg of the title compound. Yield 17%.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=2[O:30][CH3:31])=[CH:6][CH:5]=1.[C:34](OC1C=CC=CC=1)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:1]=[N:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=2[O:30][CH3:31])=[CH:6][CH:5]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Oc1ccccc1
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C=NN)cc1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(CN=NC(C)=O)cc1
Reaction time: 3 h

Procedure:
A stirred solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (40.0 g, 87.7 mmol) in 500 mL anhydrous methylene chloride is treated with phenyl acetate (11.1 mL, 87.7 mmol). The solution is stirred 3 hours, concentrated in vacuo and the resulting liquid is purified by chromatography on silica gel (850 g) with 30% ethyl acetate/hexane as the eluent to afford 4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide as a colorless foam:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14](=[O:27])[CH2:15][CH:16]([C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=1)[CH2:17][CH2:18][OH:19])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:13][C:14](=[O:27])[CH2:15][CH:16]([C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=1)[CH2:17][CH:18]=[O:19])[CH3:12]
Reactant: CCOC(=O)CC(CCO)c1cnc(C)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)CC(CC=O)c1cnc(C)nc1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (73 μL, 0.84 mmol) in CH2Cl2 at −78° C. was added DMSO (80 μL, 1.0 mmol) dropwise. After gas evolution ceased, 2-5 (100 mg, 0.42 mmol) in CH2Cl2 was added. After 30 minutes, the cooling bath was removed and NEt3 (290 μL, 2.1 mmol) was added. After 20 minutes, the reaction mixture was diluted with CH2Cl2 and washed sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 2-6 as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH2:1]([O:3][CH2:4][C:5]([NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)=[O:7])[CH3:2]
Reactant: CCOCC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCOCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use ethoxyacetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a yellow solid (67% yield). 1H NMR (300 MHz, CDCl3) δ 9.18, 8.35, 7.75, 7.63, 7.56, 7.37, 7.04, 4.08, 4.04-3.88, 3.70-3.64, 3.60-3.58, 3.35-3.33, 1.31. MS (ES+) m/z 438.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH2:11][C:12]([NH2:22])=[O:14]
Reactant: [NH4+]
Reactant: Cc1ccccc1CCOCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1CCOCC(N)=O

Procedure:
The subtitle compound (5.02 g) was prepared according to the procedure in example 5 part b using 2-[2-(2-methylphenyl)ethoxy]acetic acid (6.726 g), oxalyl chloride (6.22 ml), concentrated ammonium hydroxide (60 ml), and toluene (60 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[N:13][OH:14].O.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C1C=CC=CC=1.CCOCC>[CH2:16]([NH:18][C:19]([O:14][N:13]=[C:6]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[O:9][CH2:8][CH2:7]1)=[O:20])[CH3:17]
Reactant: COc1ccc2c(c1)C(=NO)CCO2
Reactant: CCN=C=O
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCNC(=O)ON=C1CCOc2ccc(OC)cc21
Reaction time: 8 h

Procedure:
A 42 g (0.22 mole) portion of 6-methoxy-4-chromanone oxime in 600 ml of benzene was refluxed until all water was removed via a Dean-Stark trap. The solution was treated with 1 ml of triethylamine, followed by the dropwise addition of 14 g (0.20 mole) of ethyl isocyanate at reflux. The reaction mixture was refluxed for 4 hrs., stored overnight at room temperature, and stripped of benzene under reduced pressure. The viscous residue was taken up in 250 ml of ether, refrigerated 6 hrs., and filtered. The cream colored solid was washed with 150 ml of ether and dried, m.p. 97°-98°. Yield: 44 g (83%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:22])=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[NH:38][NH2:39]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:22])=[C:10]([C:19]([NH:39][NH:38][C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)c(C)nc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)OC(C)(C)C)c(C)nc21
Reaction time: 18 h
Yield: 54.7 %

Procedure:
Intermediate 60 (0.253 g, 0.83 mmol), EDC (0.223 g, 1.17 mmol) and HOBT (0.135 g, 1.0 mmol) in DMF (5 ml) was stirred at 20° C. for 30 minutes. t-Butyl carbazate (0.110 g, 0.83 mmol) was added and stirring continued for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in DMF (5 ml) additional EDC (0.159 g0) and HOBT (0.112 g) added. After 30 minutes t-butyl carbazate (0.019 g) was added and stirring continued for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with aqueous sodium hydrogen carbonate then evaporated in vacuo. The material was applied to a SPE cartridge (silica, 10 g) and eluted with cyclohexane:ethyl acetate (1:1 followed by 2:1) to afford Intermediate 62 as a white solid (0.19 g). LCMS showed MH+=419; TRET=2.35 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1OB(O)O>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH3:14])[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COc1ccccc1OB(O)O
Product: COc1ccc2cc(-c3ccccc3OC)ccc2c1
Reaction time: 18 h

Procedure:
The compound is prepared by the reaction of 2-bromo-6-methoxynaphthalene (300 mg, 1.26 mmol, 1 eq) with 2-methoxyphenylboric acid (192 mg, 1.26 mmol, 1 eq) according to method A within 18 h. Purification by column chromatography was not performed, but the raw product was used for further syntheses.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO.CC(O)=O>[CH3:2][O:3][C:4]([CH:6]1[CH2:9][N:8]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[CH2:7]1)=[O:5]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2cccc([N+](=O)[O-])c2)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of amine INT 1 (6.00 g, 39.6 mmol) in CH2Cl2 (396 mL) and MeOH (50 mL) was added DIPEA (6.9 mL, 39.6 mmol). HOAc was added to adjust the pH of the solution to 4-5. 3-Nitrobenzaldehyde (6.58 g, 43.5 mmol) was added and the mixture was stirred at 40° C. for 1 hour. After cooling to room temperature, NaBH(OAc)3 (16.78 g, 79.2 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH) to afford INT 2.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[N:16]=[C:15]([Cl:17])[C:14]([N+:18]([O-:20])=[O:19])=[C:13](Cl)[N:12]=1.O>C1COCC1.CCOC(C)=O>[Cl:10][C:11]1[N:12]=[C:13]([NH:5][CH3:3])[C:14]([N+:18]([O-:20])=[O:19])=[C:15]([Cl:17])[N:16]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A 2 M solution of methylamine and triethylamine (1.8 mL) in THF (4.6 mL) were added to a solution of 2,4,6-trichloro-5-nitropyrimidine (2 g) in THF (30 mL) under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. After water was added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=99:1 to 90:10), whereby 2,6-dichloro-N-methyl-5-nitropyrimidine-4-amine (680 mg) was obtained as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:14]([C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[C:12]([CH3:13])[N:11]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)NN=Cc1nc(C(C)(C)C)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(C(C)(C)C)n2c(=O)[nH]ncc12

Procedure:
A mixture of 5.11 gm. of 3-[(2-tert-butyl-5-methyl-4-imidazolyl)methylene]carbazic acid ethyl ester and 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 198°-200° C.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[CH:30]=[O:31])[CH:23]=1>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:30](=[O:31])[CH:29]([CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:32])[CH:23]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: Cc1cccc(/C=C/C=O)c1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: Cc1cccc(CC2C(=O)Oc3[nH]c(-c4cc(F)ccc4F)nc3C2c2ccccc2)c1
Yield: 61 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(m-tolyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 8 as an off-white solid (78 mg, 61%). Analytical data for 8: 1H NMR (500 MHz, CDCl3) δ 9.39 (d, J=7.3 Hz, 1H), 7.88 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.37-7.29 (m, 3H), 7.20-7.12 (m, 3H), 7.11-7.01 (m, 2H), 6.97 (ddd, J=6.2, 4.9, 1.9 Hz, 3H), 4.18 (d, J=6.9 Hz, 1H), 3.62 (ddd, J=9.7, 6.9, 4.8 Hz, 1H), 3.27 (dd, J=15.3, 4.8 Hz, 1H), 2.53 (dd, J=15.3, 9.8 Hz, 1H), 2.04 (s, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.1, 159.1 (d, JCF=243.5 Hz), 155.4 (dd, JCF=241.0, 2.4 Hz), 148.8, 137.2, 136.7, 136.4, 135.9, 130.7, 129.3, 128.7, 128.3, 127.9, 126.7, 126.0, 118.4 (dd, JCF=12.8, 8.9 Hz), 117.1 (dd, JCF=25.8, 8.6 Hz), 116.6 (dd, JCF=24.8, 9.5 Hz), 114.5 (dd, JCF=26.8, 3.8 Hz), 110.9 (d, JCF=3.8 Hz), 45.6, 38.5, 29.5, 19.4; IR (film) cm−1 11773, 1636, 1618, 1529, 1481, 1463, 1452, 1411, 1240, 1171, 1122, 1100, 1078, 766, 747, 700; LRMS (ESI): Mass calcd for [M+H]+ C26H21F2N2O2: 431.2. found 431.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 4% IPA/2% MeOH/hexanes; 0.7 mL/min, 280 nm), Rt1 (minor)=39.1, Rt2 (major)=69.4 min; er=97:3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Yield: 54.6 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.55 mmol) in anhydrous DMF (5 mL) were added chlorotrimethylsilane (1.95 mL, 15.37 mmol) and triethylamine (4.18 mL, 30.0 mmol). The resulting milky mixture was heated at 80° C. for 17 h, then cooled to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a pale yellow oil (1.86 g, 55%). To a solution of 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.86 g, 6.852 mmol) in acetonitrile (80 mL) was added Selectfluor™ (2.7 g, 7.622 mmol) and the mixture was stirred at RT for 2 h. The resulting solution was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a colourless oil (1.13 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 84 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)Cl.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][S:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:42])=[O:41])[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Yield: 114.7 %

Procedure:
85 mg of 1-diphenylmethyl-4-(3-aminopropyl)-piperazine and 102.5 mg of triethylamine were added to ml of methylene chloride, and under ice cooling and stirring, 39.4 mg of benzenesulfonyl chloride was added. The mixture was further stirred at this temperature for 1 hour. Chloroform was added to the reaction mixture, and the mixture was washed with water and dried. The solvent was then evaporated to give 115 mg of the captioned compound as a crude product. It was converted to a dihydrochloride in a customary manner, and recrystallization from ethanol/ether gave 92.7 mg of the captioned compound as a colorless powdery crystal having a melting point of 160° to 165° C. (decomp.). ##STR4##
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33](Cl)=[O:34])=[N:25]1>ClCCl.C(OCC)(=O)C>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33]([N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)=[O:34])=[N:25]1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: O=C(Cl)c1noc2ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1noc2ccccc12)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of 4-(4-chlorophenoxy)piperidine (26 mg, 0.12 mmol), and N,N-diisopropylethylamine (0.086 mL, 0.49 mmol) in dichloromethane (0.5 mL) was added dropwise a solution of benzo[d]isoxazole-3-carbonyl chloride (22 mg, 0.12 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (3 mL) and washed with water (1.5 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 16.3 mg (37% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[OH:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[C:2]([F:17])([F:18])[F:1])(=[O:22])=[O:21]
Reactant: COc1ccc2cc(C(O)C(F)(F)F)ccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc2cc(C(OS(C)(=O)=O)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethanol (500 mg, 2 mmol) and TEA (610 mg, 6 mmol, 3 eq) in DCM (10 mL) was added MsCl (680 mg, 6 mmol, 2 eq) at 0° C. dropwise. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL), washed with brine (5 mL*3), dried over Na2SO4 and concentrated to give 2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethyl methanesulfonate (420 mg, yield: 65%) as a white solid. ESI-MS (M+1)+: 335.1. 1HNMR (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.83-7.78 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 7.16 (s, 1H), 5.90 (q, J=6.4 Hz, 1H), 3.94 (s, 3H), 2.93 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=O)=[CH:5][CH:4]=1)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.C(=O)([O-])O.[Na+]>ClCCl.C(#N)C>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([Cl:17])=[C:10]([CH2:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:15]=1
Reactant: CCc1ccc(C(=O)c2cc(Br)ccc2Cl)s1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)ccc2Cl)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.2 %

Procedure:
A solution of the above 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) in dichloromethane (50 ml)-acetonitrile (50 ml) was cooled under ice-cooling, and thereto were added dropwise triethylsilane (7.69 ml) and boron trifluoride.diethyl ether complex (6.1 ml). Subsequently, the mixture was stirred at room temperature for 3.5 hours, and was cooled again under ice-cooling. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(5-ethyl-2-thienylmethyl)benzene (4.52 g) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([CH3:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([CH3:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(C)c(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(C)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-2,7-dimethyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.