Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=O)C.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH3:17].[Cl-].[Na+].Cl>CN(C)C=O>[CH3:17][O:16][CH2:15][CH2:14][O:10][CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: COCCBr
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCOC1CCNCC1
Yield: 24.5 %

Procedure:
A solution of N-acetyl-4-hydroxypiperidine (30.5 g.) in dimethylformamide (200 ml.) was added dropwise to a stirred suspension of sodium hydride (11.26 g., 50% dispersion in mineral oil) in dimethylformamide (300 ml.) under an atmosphere of nitrogen. The reaction temperature was kept below 30° C. by external cooling and, after the addition was complete, stirring was continued for a further 11/4 hours. A solution of 1-bromo-2-methoxyethane (32.6 g.) in dimethylformamide (100 ml.) was then added dropwise with external cooling, and the resulting clear solution was stirred at room temperature overnight. The reaction mixture was then evaporated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried (Na2SO4) and evaporated to leave a crude residue (16.1 g.). The above aqueous phase was saturated with sodium chloride, further extracted with chloroform, and the organic phase was dried (Na2SO4), and evaporated to leave a further residue (9.2 g.). This residue was combined with the original residue and heated on a steam bath overnight with hydrochloric acid (243 ml., 2N). The reaction mixture was extracted with chloroform to remove residual mineral oil, the aqueous phase concentrated, basified with sodium hydroxide (pH 12), then reextracted with chloroform. The organic extracts were washed with brine, dried (Na2SO4) and evaporated to leave 4-(2-methoxyethoxy)piperidine (8.3 g.). A sample of this product in ethyl acetate was converted to the oxalate salt by the addition of ethereal oxalic acid followed by recrystallization from ethanol, the oxalate having an m.p. of 86°-88° C.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[CH:6]([S:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][C:42](O)=[O:43].C1(C2OC(C(F)(F)F)=C(COC(=O)C3C=CC(CC(SCCC4C=CC(F)=CC=4)C(OCC(Cl)(Cl)Cl)=O)=CC=3)N=2)C=CC=CC=1>>[Cl:28][C:2]([Cl:27])([Cl:1])[CH2:3][O:4][C:5](=[O:26])[CH:6]([S:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:42](=[O:43])[CH2:41][C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH3:29])=[CH:12][CH:13]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Agent: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1oc(-c2ccccc2)nc1CC(=O)OCc1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloroethyl ester (512 mg, 1.1 mmol) and 2-(5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (261 mg, 1.2 mmol) in the same manner as described for 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethyl ester. The product was obtained without further purification as an oil (751 mg, 94.1%). 1H NMR (500 MHz, CDCl3): δ 8.06 (d, 2H), 7.44 (m, 3H), 7.29 (m, 2H), 7.20 (d, 2H), 7.10-7.13 (m, 2H), 6.98 (t, 2H), 5.16 (s, 2H), 4.73 (q, 2H), 3.58 (dd, 1H), 3.22 (dd, 1H), 2.84-3.00 (m, 5H). Mass Spectrum: M+H+666.00.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (7 g, 41 mmol) in toluene (400 mL), trimethylaluminum (2M solution in toluene, 30.5 mL, 61 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-chlorobenzonitrile (11.3 g, 82 mmol) in toluene (200 mL) was added over 10 minutes and the reaction mixture was heated to 80–85° C. After 16 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol. The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-chloro-N-[4-(methylsulfonyl)phenyl] benzenecarboximidamide (10.93 g, 86%) was used in the next reaction without further purification: mp (DSC) 191° C. Anal. Calc'd. for C14H13N2SO2Cl: C, 54.46; H, 4.24; N, 9.07; Found: C, 54.42; H. 4.30; N, 9.07.
Reaction SMILES: O1CCCC1.[Br-].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:12]2)#[N:8].[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][C@H:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57](=O)[C:58]([O:60][CH3:61])=[O:59])=[CH:53][CH:52]=2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C1CCN2C(=NCCC2)CC1>CO>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][C@H:47]([O:50][C:51]2[CH:52]=[CH:53][C:54]([CH:57]([CH2:18][C:13]3[NH:14][C:15]4[C:11]([CH:12]=3)=[CH:10][C:9]([C:7]#[N:8])=[CH:17][CH:16]=4)[C:58]([O:60][CH3:61])=[O:59])=[CH:55][CH:56]=2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: N#Cc1ccc2[nH]c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC(=O)C(Cc1cc2cc(C#N)ccc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 7010 %

Procedure:
In a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol were dissolved 5.0 g of (5-cyano-2-indolyl)methyltriphenylphosphonium bromide and 3.6 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate. With stirring at room temperature, 1.07 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the thus prepared solution, and the mixture was stirred at the same temperature for 2 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a dichloromethane/acetone mixture as an eluant, thereby obtaining methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-indolyl)acrylate as a mixture of E and Z forms. The thus obtained compound was dissolved in a solvent mixture of 50 ml of tetrahydtofuran and 50 ml of methanol, and the resulting solution was mixed with 5.0 g of palladium oxide.1H2O.barium sulfate, and then subjected to catalytic hydrogenation under normal pressure. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a dichloromethane/acetone mixture as an eluant. In this way, 345 g of the title compound was obtained in a viscous and oily form.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C1C(=O)N([Br:37])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:37][CH2:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cccnc1CBr
Temperature: 25 °C
Yield: 14.2 %

Procedure:
To a solution of 2-methyl-3-trifluoromethyl-pyridine (0.850 g, 5.28 mmol) (Ashimori, A. et al. Chem. Pharm. Bull. 1990, 33, 2446-2458) in CCl4 (30 mL) was added 1,1′-azobis(cyclohexanecarbonitrile) (0.193 g, 0.79 mmol) and NBS (1.96 g, 11.0 mmol). The mixture was stirred and heated at reflux for 24 h, and then cooled to room temperature. A solution of Na2S2O3 (5 g) in H2O (100 mL) was added, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3×40 mL), and the extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording 2-bromomethyl-3-trifluoromethyl-pyridine as a pale yellow liquid (0.180 g, 14%). 1H NMR (CDCl3) δ 4.69 (s, 2H), 7.37 (dd, 1H, J=4.5, 7.8 Hz), 7.96 (d, 1H, J=7.8 Hz), 8.78 (d, 1H, J=4.5 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.Cl>C(O)C.C(N)(C)C>[CH:6]([NH:7][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1)([CH3:8])[CH3:5]
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CC(C)N
Product: CC(C)Nc1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 2.26 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 30 ml of ethanol, 4.26 ml of isopropylamine was added, and the mixture was heated for 44 hours at 80°-90 ° C. in a sealed tube. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.36 g of the desired compound as pale yellow needles, m.p. 272°-274 ° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH2:10]
Reactant: COc1cccc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C)c1N
Yield: 100.6 %

Procedure:
Palladium charcoal (1.0 g of 10%) was added to a solution of 3-methyl-2-nitroanisole (16.8 g, 0.1 mol) in ethanol (150 mL) and the solution was hydrogenated (50 lb initial hydrogen pressure) until hydrogen uptake ceased (2 hours). The solution was filtered and evaporated to give 13.8 g of 2-methoxy-6-methylbenzenamine (compound XLIV) as an oil. The product was dissolved in acetic anhydride (100 mL) and the resulting solution was refluxed for 1 hour. Part of the solvent (50 mL) was slowly removed over a 1-hour period, after which time the solution was cooled and the remainder of the solvent was removed under reduced pressure. The residual oil was crystallized from ethyl acetate:hexane (200 mL of 1:2) to give 20.5 g of N-acetyl-N-(2-methoxy-6-methylphenyl)-acetamide, mp 116°-119° C. Anal Calcd for C12H15NO3 : C, 65.14; H, 6.83; N, 6.33. Found: C, 65.44; H, 7.04; N, 6.39.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH2:17][N:18]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[C:19]2=O)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH2:17][N:18]2[CH2:19][C:20]3[C:25](=[CH:24][C:23]([CH3:27])=[C:22]([CH3:28])[CH:21]=3)[CH2:26]2)=[CH:5][CH:6]=1
Reactant: Cc1cc2c(cc1C)C(=O)N(CCC1CCCCN1CCCc1ccncc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)CN(CCC1CCCCN1CCCc1ccncc1)C2

Procedure:
Prepared from 2-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid-2-yl)-ethyl]-5,6-dimethyl-1-oxo-1,3-dihydro-isoindole and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:41][C:42](=[O:44])[CH3:43]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:41][C:42](=[O:44])[CH3:43])[CH2:26][CH2:27]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(C)=O)CC2)c(OC(C)C)c1

Procedure:
The compound was prepared by the treatment of [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]piperazin-1-yl-methanone (example 10 g) with chloroacetone and triethylamine at 40° C. overnight. HR-MS (ES, m/z) calculated for C33H36N4O4Cl2[(M+H)+]623.2187, observed 623.2194.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]1[CH2:13][N:14]([CH3:19])[C:15](=O)[C:16](=O)[N:8]1[C@@H:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6]2.[ClH:26].Cl.COC1C=C2C(=CC=1)[C@H]1CN(C)CCN1[C@@H](C1C=CC=CC=1)C2>>[ClH:26].[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]1[CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][N:8]1[C@@H:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6]2
Reactant: COc1ccc2c(c1)C[C@H](c1ccccc1)N1C(=O)C(=O)N(C)C[C@@H]21
Agent: COc1ccc2c(c1)C[C@H](c1ccccc1)N1CCN(C)C[C@H]21
Agent: Cl
Product: COc1ccc2c(c1)C[C@H](c1ccccc1)N1CCN(C)C[C@@H]21

Procedure:
Cis-1,3,4,6,7,11b-hexahydro-9-methoxy-2-methyl-6-methyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione (16.0 g, 0.04 mol) was added with stirring to a solution of 1M borane in tetrahydrofuran (350 ml) under nitrogen and the resulting mixture was refluxed for 4 hrs, then cooled to 0° C., and then treated with 10% HCl (150 ml). The mixture was refluxed for 1 hr and cooled, and then the solvent was evaporated. The aqueous residue was basified to pH 11 with 50% NaOH and extracted with chloroform (3×250 ml). The combined chloroform extracts were dried over MgSO4 and evaporated to an oily residue. The residue was dissolved in methanol/isopropanol (150 ml) and acidified with HCl gas. A solid salt crystallized (10.3 g) which was recrystallized from methanol (300 ml) and water (10 ml) to give 9.8 g of cis-1,3,4,6,7,11b-hexahydro-9-methoxy-2-methyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride as an off-white solid. An analytical sample had mp. 274°-275° C. Following the same procedure and substituting trans-1,3,4,6,7,11b-hexahydro-9-methoxy-2-methyl-6-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione for cis-1,3,4,6,7,11b-hexahydro-9-methoxy-2-methyl-6-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione, trans-1,3,4,6,7,11b-hexahydro-9-methoxy-2-methyl-6-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride may be obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 158 mg (1 mmole) of n-nonanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 231 mg (Yield: 54%) of the title compound having the following structure as a red oil.
Reaction SMILES: [OH-].[NH3+]N.[CH2:4]([O:6][C:7]1[C:8]2[S:21][C:20]3[N:22]=[C:23]([CH3:37])[C:24]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=4)=[C:25]([CH3:26])[C:19]=3[C:9]=2[N:10]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:12]=1)[CH3:5]>C(O)C.[Pd]>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:24]2[C:23]([CH3:37])=[N:22][C:20]3[S:21][C:8]4[C:7]([O:6][CH2:4][CH3:5])=[N:12][C:11]([N:13]5[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]5)=[N:10][C:9]=4[C:19]=3[C:25]=2[CH3:26])=[CH:29][CH:30]=1
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(C)c(Cc3ccc([N+](=O)[O-])cc3)c(C)c12
Agent: [Pd]
Agent: N[NH3+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(C)c(Cc3ccc(N)cc3)c(C)c12
Reaction time: 10 h

Procedure:
40 mg 10% Pd/C and 0.5 ml (10 mmol) hydraziniumhydroxide are added to 0.36 g (0.8 mmol) 4-ethoxy-7,9-dimethyl-8-(4-nitrobenzyl)-2-piperazin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine in 3 ml ethanol. Then, refluxing is carried for 10 h, the solvent is removed and the residue is taken up with 50 ml chloroform. Following filtration, the solvent is removed and the residue is recrystallized from chloroform/cyclohexane. 0.16 g (45%) of the title substance is obtained.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:17])=O>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([Cl:17])=[O:14])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
A solution of 5 g of para-n-pentyl-transcyclohexanoic acid is refluxed in 8 ml of thionyl chloride for 2 hours. The thionyl chloride is then eliminated by distilling under atmospheric pressure. The acid chloride is then distilled under reduced pressure and under a dry nitrogen stream. This gives a product with a boiling point of 87° C. under 0.5 mm Hg.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][Mg]Cl)=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:13][C:14]1[CH:22]=[CH:21][C:17]([CH3:18])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: Cc1ccc(C[Mg]Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1ccc(C)cc1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (32) prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═9/1) to give 1,1-diethoxy-3-(4-methylphenyl)propan-2-one (33) as a colorless oily substance (1.96 g, 8.27 mmol, 82.4%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: FC(F)(F)c1ccc(CC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
Combine (S)-1,4-dibenzyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine (3.34 g, 7.62 mmol), ammonium formate (2.40 g, 38.09 mmol), 5% Pd/C (368.7 mg), and ethanol (100 ml). Stir and heat the mixture at reflux. After 3 hrs, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and then dissolve it in dichloromethane. Wash the organic with 1N NaOH and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue to give 1.83 g (93%) of the title compound as an off-white solid: mp 135°–141°; mass spectrum (ion spray): m/z=259.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:29])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=O>CO.O1CCCC1>[NH2:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:14][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:29])[CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: O=Cc1cccc(-c2cccc(C(=O)NCCN3CCCC3)c2)c1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(CCNCc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(2-Aminoethyl)benzene sulfonamide (2.37 g) and molecular sieves 3A (4.0 g) were added to a solution of 3′-formyl-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide (3.81 g) in methanol (50 ml), and the mixture was stirred at room temperature for 1.5 hours. After the reaction mixture was diluted with tetrahydrofuran (THF), the molecular sieves were filtered off, and the filtrate was concentrated under reduced pressure. The residues were dissolved in a mixed solvent (100 ml) of methanol-THF (1:1), and sodium borohydride (0.89 g) was added thereto. The reaction mixture was stirred at room temperature for 5 hours, and then the solvent was evaporated under reduced pressure. The residues were diluted with water and extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residues were crystallized from hexane, whereby the title compound (3.71 g) was obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=[O:4].[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[Cl:20][C:2]([Cl:1])([Cl:19])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[C:15]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:9][CH2:10]1)=[O:4]
Reactant: COc1ccccc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 2-(4-trichloroacetylpiperazin-1-yl) anisole (D3) (10 g) in dichloromethane (115 ml) was added over 0.3 h to ice-cooled chlorosulfonic acid (52 ml). After 0.5 h at 0° C. then 1 h at ambient temperature, the solution was poured onto a mixture of ice-water (500 g) and dichloromethane (500 ml) with rapid stirring. The layers were separated and the organic phase was washed with water (2×800 ml), dried (MgSO4) and concentrated to give the title compound (D4) as a foam (6.0 g, 46%). MH+ 435/437.