Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:3])=[O:2].[Ca:4].[S:5]([O-:8])([O-:7])=[O:6].[Na+:9].[Na+].[S:11]([O-:15])([O-:14])(=[O:13])=[O:12]>>[S:5]([O-:8])([O-:7])=[O:6].[Ca+2:4].[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[C:1](=[O:6])([OH:3])[O-:2].[Na+:9]
Reactant: O=C=O
Reactant: [Ca]
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C([O-])O
Product: [Ca+2]

Procedure:
Another embodiment is depicted in FIG. 3 wherein the present invention is adapted to the so-called "double alkali" stack gas scrubbing system. In this alternative embodiment, a slurry 8 of finely-ground limestone is prepared in tank 10 and fed to a reactor 12 wherein it is reacted with carbon dioxide at a pressure of about 500 psig to form a pressurized slurry 9. The pressurized slurry is then introduced into a solution regenerator 14 wherein the relatively soluble unstable calcium compound readily reacts with a sodium sulfite or sulfate solution 2 exiting a stack gas scrubber 16 to form a slurry 3 containing calcium sulfite or sulfate solids and sodium bicarbonate in solution. The slurry 3 is then depressurized into let-down tank 18 and then introduced into filter 20 for removal of the calcium sulfite or sulfate solids. Alternatively, the calcium sulfite or sulfate solids may be separated from the sodium bicarbonate solution in regenerator 14. Then the solution may be depressurized into let-down tank 18. The filtered solution 5 is then heated by solution heater 22 and further depressurized in tank 24 to convert the sodium bicarbonate to sodium carbonate in solution 6 which is used to scrub the stack gas in tower 16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])=[C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[F:27])=[C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=2)[CH:7]=1
Reactant: COc1ccc(F)c(-c2ccc(CCl)cc2C(C)(C)C)c1
Reactant: Oc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(-c2ccc(COc3cncc(Br)c3)cc2C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
A dry round bottom flask containing 3-bromo-5-hydroxypyridine (0.1304 g, 0.749 mmol) (commercially available from Aldrich) in dry DMF (2 mL) was cooled in an ice bath. After 10 minutes, sodium hydride (0.0361 g, 0.903 mmol) (60% wt in oil) was added carefully, and the mixture was stirred at 0° C. After 10 minutes, 8.10 (0.2301 g, 0.750 mmol) was added. The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and then extracted five times with EtOAc. The combined organic layers wee then washed one time with brine and dried over anhydrous magnesium sulfate. The solid was filtered off, and the solvent was concentrated. The residue was purified by silica gel flash chromatography (0-25% EtOAc/hexane) to afford 96.A (203.4 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.36 (2H, dd, J=13.1, 2.2 Hz), 7.62 (1H, d, J=1.6 Hz), 7.57 (1H, m), 7.29 (1H, dd, J=7.6, 1.8 Hz), 7.10 (1H, d, J=7.4 Hz), 7.02 (1H, t, J=8.8 Hz), 6.95 (2H, m), 5.14 (2H, s), 3.80 (3H, s), 1.27 (9H, s).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[C:16]1([S:22]([N:25]2[C:29]3[CH:30]=[N:31][C:32]([C:35]#[N:36])=[C:33](O)[C:28]=3[C:27]3[CH:37]=[CH:38][CH:39]=[N:40][C:26]2=3)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[C:16]1([S:22]([N:25]2[C:29]3[CH:30]=[N:31][C:32]([C:35]#[N:36])=[C:33]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:28]=3[C:27]3[CH:37]=[CH:38][CH:39]=[N:40][C:26]2=3)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1ncc2c(c1O)c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ncc2c(c1OS(=O)(=O)C(F)(F)F)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.91 g, 0.54 mL, 3.22 mmol) was added dropwise to a suspension of 9-benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.03 g, 2.93 mmol) in pyridine (1.2 mL, 14.7 mmol) and dry DCM (20 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was treated with 1N hydrochloric acid (10 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×10 mL), the combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by chromatography (silica, 5 g column, Si-SPE, DCM) to afford the title compound as a white solid (855 mg, 60%). LCMS (Method B): RT=4.22 min, M+H+=483.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[Cl:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(-c2cc3ocnc3cc2Cl)cn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3ocnc3cc2Cl)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 5-(5-chlorobenzoxazol-6-yl)-2-pyridylamine (31) (23 mg, 0.09 mmol) and 2 mg DMAP in 2 ml DCM was added 2-chlorobenzoyl chloride (23 μl, 0.18 mmol) followed by addition of DIEA (94 μl). The resulting brown solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (135 μl) at r.t. for 30 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 17 mg 32 as pale yellow solid. (yield: 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>>[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccccc2C)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccccc2C)c1

Procedure:
0.38 g of compound 74 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.51 g of ethyl 4-(2-aminophenoxy)butyrate and 0.45 g of 3-[1-(2,4'-dimethylbenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C@@H:4]2[CH2:3]1.Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][C@@H:4]2[CH2:3]1
Reactant: O[C@@H]1C[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: O[C@@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Temperature: 100 °C
Yield: 9.3 %

Procedure:
A mixture of 3.81 g (26.8 mmol) of (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6, Step A), 19.8 g (134 mmol) of 2,5-dichloropyridine, 7.10 g (67.0 mmol) of sodium carbonate and 275 mL of isoamyl alcohol was heated at reflux for 72 h. The mixture was cooled to about 100° C., filtered hot, and the filtrate concentrated in vacuo. Purification of the residue by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.63 g (9%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 254.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:10][C:9]=2[F:24])[S:6][CH:7]=1.[CH3:25][NH2:26]>>[CH2:18]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([F:24])=[C:8]([C:5]3[S:6][CH:7]=[C:3]([CH2:2][NH:26][CH3:25])[N:4]=3)[CH:17]=2)[C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14]1)[CH3:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3nc(CCl)cs3)cc21
Reactant: CN
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3nc(CNC)cs3)cc21

Procedure:
A solution of 0.40 g 7-(4-chloromethyl-2-thiazolyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 100 ml 40% aqueous methyl amine was stirred at room temperature overnight and evaporated to dryness. The resulting solid was crystallized from water to afford 0.33 g of the title compound, mp 216°-218° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][NH:20][C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18]([Cl:23])=[N:19][N:20]([CH3:28])[C:21](=[O:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3c(=O)[nH]nc(Cl)c32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Cl)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 50 %

Procedure:
The procedure of Example 32 was repeated except that 1-[4-(4-chlorobenzoyl)benzyl]-7-chloroimidazo[4,5-d]pyridazin-4(5H)-one was used as the starting compound. Thus, this starting compound (424 mg) was dissolved in DMF (7 ml) followed by addition of potassium carbonate (465 mg). Then, methyl iodide (0.2 ml) was added and the mixture was stirred at room temperature for 65 hours. To this reaction mixture was added water (50 ml) and the resulting crystals were harvested by filtration. This crystal crop was purified by silica gel column chromatography (stationary phase 30 g; ethyl acetate: methanol=1:0-20:1) to provide 218 mg (50%) of the title compound. 1H-NMR (CDCl3) δ: 3.87(3H,s), 5.74(2H,s), 7.23(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].CI>C1COCC1>[CH3:9][C:10]([CH3:2])([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(C)Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of LDA (2.9 mL of 2 M) in THF (30 mL) at −78° C. add ethyl 2-methyl-3-[4-(trifluoromethyl)phenyl]propanoate (1 g, 3.85 mmol). Stir for 10 min, then add methyl iodide (1.48 g, 10.4 mmol) and stir for an additional 15 min Quench the reaction with 10 mL of 1 N HCl and allow to warm to ambient temperature. Extract with EtOAc (50 mL). Wash extract with brine, dry over sodium sulfate, filter, and concentrate. Purify the residue by flash chromatography (5% EtOAc in petroleum ether) to give the title compound (475 mg).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:31]O>>[C:1]([NH:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[C:11]([O:13][CH3:31])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(NC(C(=O)O)c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1)c1ccccc1
Agent: Cl
Product: COC(=O)C(NC(=O)c1ccccc1)c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Reaction time: 2.5 h

Procedure:
To a mixture of 12.46 g (30.31 mmol) of α-(benzoylamino)-4'-sulfo[1,1'-biphenyl]-4-acetic acid in 60 mL of methanol was added 6 g of anhydrous hydrogen chloride. When the addition was complete, the mixture was stirred for 2.5 h. The solvent was removed under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.O1CCOCC1>O>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:38]4[CH:37]=[CH:36][N:35]=[C:34]([O:33][CH3:32])[CH:39]=4)=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)[CH3:25]
Reactant: CCN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Reactant: COc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3ccc(-c4ccnc(OC)c4)n4ncnc34)cc2)CC1
Temperature: 107.5 °C
Yield: 69.8 %

Procedure:
To a reaction vial (40 mL), is added 5-chloro-N-(4-(4-ethylpiperazin-1-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (110 mg, 0.3 mmol), potassium carbonate (207 mg, 1.5 mmol, 5 eq.), 2-methoxypyridin-4-ylboronic acid (70 mg, 0.45 mmol, 1.5 eq), PddppfCl2 (44 mg, 20%), dioxane (4.0 mL) and water (1.0 mL). The reaction mixture is degassed and filled with argon. The reaction is heated at 105-110° C. for 20 h. After cooling to rt, ethyl acetate (10 mL) is added to each reaction vial. The organic phase is filtered through a pat of celite and then is evaporated to give a residue that is purified by silica gel column chromatography (1-3% 2N NH3 in MeOH/DCM) to give the title compound as a light yellow solid (90 mg, yield, 69.8%). 1H NMR (300 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.60 (d, J=4.8 Hz), 7.58 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.12 (m, 4H), 2.50 (m, 4H), 2.36 (q, J=6.9, 2H), 1.04 (t, J=6.9 Hz, 3H); LCMS-ESI (m/z): calcd for C24H27N7O, 429; [M+H]+ found, 430.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][CH2:8][CH2:9]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:13]>>[Cl-:13].[CH:1]1([CH2:6][NH2+:7][CH2:8][CH2:9][Cl:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCNCC1CCCC1
Product: ClCC[NH2+]CC1CCCC1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][C:17]#N)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br.Cl.[O:26]1CCCC1>[Zn]>[CH3:19][O:20][C:21](=[O:24])[CH2:22][C:17](=[O:26])[CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]/[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:7]=1
Reactant: C1CCOC1
Reactant: COC(=O)CBr
Reactant: N#CCCC/C=C/c1cccc(-c2ccsc2)c1
Agent: Cl
Agent: [Zn]
Product: COC(=O)CC(=O)CCC/C=C/c1cccc(-c2ccsc2)c1

Procedure:
3.64 g of the above nitrile compound and 3.92 g of activated zinc powder are added to 50 ml of tetrahydrofuran, 4.54 ml of bromoacetic acid methyl ester is added dropwise to this mixture over a period of 1 hour under reflux with heating and stirring, and the mixture is further stirred under reflux for 1 hour. 100 ml of 10% hydrochloric acid is added to the reaction solution, the mixture is stirred at room temperature for 30 minutes, tetrahydrofuran is distilled off under reduced pressure, and methylene chloride is added to the residual solution for extraction. The extract is washed with saturated saline and post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 100 g; hexane/ethyl acetate=4/1] to obtain 2.33 g of (E)-8-[3-(3-thienyl)phenyl]-3-oxo-7-octenoic acid methyl ester as colorless oil.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[C:20]([O:24][C:25](=[O:26])[NH:27][CH2:28][C:29](=[O:30])[N:17]1[CH2:18][CH2:19][CH:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)[CH2:16]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
To a mixture of 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (preparation #7) (3.0 g, 9.90 mmol), tert-butoxycarbonylamino-acetic acid (1.73 g, 9.90 mmol) and EDC (1.90, 9.90 mmol) in DCM (60 mL) was added Et3N (5.5 mL, 39.6 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. DCM was added and the organic layer was washed with water and saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using 5% MeOH/EtOAc as the mobile phase to afford {2-oxo-2-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethyl}-carbamic acid tert-butyl ester (1.47 g, 38% yield). RP-HPLC (Table 1, Method b) Rt 1.54 min; m/z: (M+H)+ 388.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:18])=[CH:20][CH:21]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCCCC3)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (50 mg, 0.16 mmol) obtained in Example 21 and piperidine (0.021 ml, 0.21 mmol) in methylene chloride (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol), and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was purified by a silica gel column chromatography (hexane:ethyl acetate=1:2) to yield the title compound (30 mg, 0.08 mmol, yield 50%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.O[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][O:1][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[CH2:10][CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CN1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(CCCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
N-[3-(4-Methyl-1-piperazinyl)propoxy]phthalimide may be obtained in the following manner: a solution of 1-(3-hydroxypropyl)-4-methylpiperazine (8.4 g), N-hydroxyphthalimide (8.2 g) and triphenylphosphine (13.1 g) in tetrahydrofuran (120 cc) is cooled to a temperature in the region of 0° C. and ethyl azodicarboxylate (10.1 g) is added in the course of 30 minutes. The solution obtained is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 60° C. The crude oil obtained is chromatographed on a column 5 cm in diameter containing silica (0.063-0.2 mm) (400 g). The column is eluted with mixtures of ethyl acetate and methanol, collecting 500-cc fractions. The first 5 fractions originating from elution with pure ethyl acetate and the next 5 fractions originating from elution with a mixture of ethyl acetate and methanol (70:30 by volume) are discarded. The next fraction originating from elution with a mixture of ethyl acetate and methanol (70:30 by volume), the next 5 fractions originating from elution with a mixture of ethyl acetate and methanol (50:50 by volume) and the next 2 fractions originating from elution with pure methanol are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 60° C. N-[3-(4-Methyl-1-piperazinyl)propoxy]phthalimide (11.4 g) is thereby obtained in the form of a red oil (Rf=0.2; thin-layer chromatography on silica, eluent: ethyl acetate/methanol, 50:50 by volume).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH:21]1([C:24]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:25])[CH2:23][CH2:22]1
Reactant: O=C(O)C1CC1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 0.063 ml cyclopropylcarboxylic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight at ambient temperature. The reaction mixture is evaporated. The residue is then purified by silica gel chromatography. 91 mg of the title compound are obtained.