Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[NH2:32])=[CH:20][CH:19]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:32][C:26]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=3[S:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Product: COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(CC(C)C)ccc23)cc1

Procedure:
The product from Example 12d (60 mg, 0.271 mmol) was reacted with the product from Example 50b (66 mg, 0.271 mmol) for 25 h giving following the procedure from Example 1g the crude title compound that was triturated with 3:1 ether/THF providing the title compound as a hydrochloride salt (121 mg, 96%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J=6.62 Hz, 6H) 2.24 (m, J=6.62 Hz, 1 H) 2.34 (s, 3 H) 2.89 (d, J=7.35 Hz, 2 H) 3.72 (s, 3 H) 6.27 (d, J=6.99 Hz, 1 H) 6.84 (d, J=8.46 Hz, 2 H) 7.10 (d, J=8.09 Hz, 1 H) 7.23-7.32 (m, 4 H) 7.81 (d, J=8.46 Hz, 1 H) 8.41 (d, J=6.99 Hz, 1 H) 9.07 (d, J=8.46 Hz, 1 H) 11.09 (br s, 1 H) 14.40 (br s, 1 H); MS (ESI+) m/z 430 (M−Cl)+; (ESI−) m/z 428 (M−HCl)−.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:10]1([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:2]1=[O:1])[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1C(Cc2cnccn2)c2ccccc2N1c1ccccc1
Product: CCOC(=O)CCCC1(Cc2cnccn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 80 %

Procedure:
By substituting 2,3-dihydro-2-oxo-1-phenyl-3-(2-pyrazinylmethyl)-1H-indole and ethyl 4-bromobutyrate in Example 1, the desired product was obtained in 80% yield as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[NH2:31]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:31][C:30]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:28]([CH3:27])[CH:29]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:5]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: Cc1cc(C)cc(N)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C)cc(Nc2nc(Cl)nc(Nc3ccc(P(C)(C)=O)cc3)n2)c1

Procedure:
To a solution of 4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 3,5-dimethylaniline (24 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19]C3C=CC(Cl)=CC=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](OCC)=O)=[CH:30][CH:29]=1.F[C:41]1C=CC(CC(OCC)=O)=CC=1.C(N)CC1C=CC=CC=1.ClC1C=CC(N)=CC=1>>[C:2]1([CH3:41])[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(F)cc2)c[nH]c2ccnc(Nc3ccc(Cl)cc3)c12
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(F)cc1
Agent: NCCc1ccccc1
Agent: Nc1ccc(Cl)cc1
Product: Cc1ccc(-c2c[nH]c3ccnc(NCCc4ccccc4)c3c2=O)cc1

Procedure:
3-(4-Fluorophenyl)-1,4-dihydro-4-oxo-5-(4-chlorophenylamino)-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that ethyl (4-chlorophenyl)acetate was replaced with ethyl (4-fluorophenyl)acetate and phenethylamine was replaced with 4-chloroaniline. MS 366 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][OH:24])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Reactant: C#CCCCO
Product: Cc1cn(C(=O)OC(C)(C)C)c2ccc(C#CCCCO)cc12

Procedure:
In analogy to example 7.2, 5-Bromo-3-methyl-indole-1-carboxylic acid tert-butyl ester and 4-pentynol were converted to yield 5-(5-Hydroxy-pent-1-ynyl)-3-methyl-indole-1-carboxylic acid tert-butyl ester as brown gum, MS: 313 (M).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[CH:3]=2)[N:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1ccc2cc(C#C[Si](C)(C)C)ccc2n1
Yield: 83.5 %

Procedure:
In a sealed tube were introduced 6-bromo-2-methyl-quinoline (4.6 g, 21 mmol, 1 eq), PdCl2(PPh3)3 (727 mg, 1 mmol, 5% mol), copper iodide (197 mg, 1 mmol, 5% mol), and triphenylphosphine (1.1 g, 4.1 mmol, 20% mol). Then, DMF (35 mL) was added followed by diethylamine (6 mL, 62 mmol, 5 eq) and trimethylsilylacetylene (3.2 mL, 23 mmol, 1.1 eq). The mixture was refluxed overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-AcOEt 95/5) and obtained as a white solid (4.2 g, 83%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:28]=1.C(N(CC)CC)C>CS(C)=O.O>[F:22][C:20]([F:23])([F:21])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:9]=[C:8]([CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:4]2[CH2:5][CH2:6][N:1]([C:34]([NH:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:2][CH2:3]2)=[N:13][CH:14]=1
Reactant: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.6 %

Procedure:
To a solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(2,2,2-trifluoroethoxy)pyridine (0.14 g, 0.38 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (0.082 g, 0.38 mmol) followed by triethylamine (0.235 mL, 1.692 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% acetone, 70% hexane) to give the title compound (0.13 g, 70%). 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.30 (d, J=7.2 Hz, 1H), 8.22 (d, J=4.4 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.32 (m, 4H), 7.02 (d, J=7.5 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 4.33 (q, J=7.8 Hz, 2H), 3.65 (m, 2H), 3.55 (m, 2H), 2.60 (m, 2H), 2.47 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 158.96, 154.56, 154.45, 150.43, 143.12, 140.48, 138.89, 137.80, 136.56, 134.41, 129.49, 127.96, 125.08, 124.74, 123.80, 121.02, 118.77, 112.57, 67.33, 67.05, 45.75, 44.70, 35.74, 29.16; m/z (485.1, M+ H+); HPLC: 93.6%.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].C(=O)(OC)[O:16][C:17]1[CH:22]=[C:21]([N:23]=[C:24]=[O:25])[C:20]([F:26])=[CH:19][C:18]=1[Cl:27].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O.O>[Cl:27][C:18]1[C:17]([OH:16])=[CH:22][C:21]([N:23]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:24]2=[O:25])=[C:20]([F:26])[CH:19]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COC(=O)Oc1cc(N=C=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4.67 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 15 ml of toluene is added dropwise while stirring at 0° C. during 20 minutes to a suspension of 1.11 g of a 55% sodium hydride dispersion in 30 ml of absolute dimethylformamide, and the mixture is stirred at 0° C. for 15 minutes. The reaction mixture is subsequently cooled to -40° C. and a solution of 6.24 g of 2-chloro-4-fluoro-5-isocyanatophenyl methyl carbonate in 30 ml of toluene is added dropwise during 5 minutes. The reaction mixture is stirred at room temperature for 1 hour and stirred for a further 30 minutes with a solution of 5.40 g of sodium carbonate in 100 ml of water. The aqueous phase is separated. extracted twice with 50 ml of diethyl ether each time and adjusted to pH 1 with 8 ml of 2N hydrochloric acid. The mixture is extracted twice with 100 ml of diethyl ether each time and the organic phases are washed with water. dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 223°-225° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[C:10]1[C:18]2[O:17][CH:16](NC)[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH:21]([N:24]([CH:27](C)C)CC)(C)[CH3:22].C(OC(=O)C)(=[O:32])C>C(Cl)Cl>[Cl:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=1[C:10]1[C:18]2[O:17][CH:16]([CH2:27][NH:24][C:21](=[O:32])[CH3:22])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CNC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Reactant: CC(=O)OC(C)=O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(=O)NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
[7-(2,6-Dichloro-phenyl)-2,3-dihydro-benzofuran-2-yl]-methylamine hydrochloride (0.050 g, 0.17 mmol) was suspended in 5.0 mL of methylene chloride and diisopropylethylamine (0.072 g, 0.56 mmol) and acetic anhydride (0.029 g, 0.28 mmol) added. The mixture was stirred at room temperature for 30 min, diluted to 100 mL with methylene chloride, washed with 50 mL portions of 2 N HCl (aqueous), saturated aqueous sodium bicarbonate and saturated brine. The solution was dried over sodium sulfate, filtered and concentrated in vacuum to give 0.038 g of the title compound as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.C[O-].[Na+].[C:13]([C:16]1[C:21](=[O:22])[CH:20]=[CH:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:17]=1)(=O)[CH3:14].[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OC)(C)(C)C.C1COCC1.Cl.CC(O)=O>[C:33]1([N:39]2[C:13]([C:16]3[C:21](=[O:22])[CH:20]=[CH:19][N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[N:17]=3)=[CH:14][C:3]([C:2]([F:1])([F:8])[F:9])=[N:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 2 %

Procedure:
To a solution of ethyl trifluoroacetate (0.139 mL, 1.17 mmol) in methyl tert-butyl ether (1 mL) was added NaOMe (28% in MeOH, 245 mg, 1.27 mmol) at room temperature. To the mixture was added a solution of 3-acetyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (300 mg, 1.06 mmol) in THF (1.5 mL) and methyl tert-butyl ether (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 days. The mixture was diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. To the residue were added phenylhydrazine (0.209 mL, 2.12 mmol) and AcOH (3.5 mL). The mixture was heated to reflux for 90 min. The mixture was diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with NaHCO3 aqueous solution, dried over MgSO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=50/50 to 0/100), crystallized with AcOEt/hexane and purified by HPLC to yield the title compound (9.6 mg, 2% yield) as a white solid: mp 190-191° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.73 (1H, d, J=7.9 Hz), 7.37-7.81 (10H, m), 8.97 (1H, d, J=8.3 Hz). Anal. Calcd for C1H12F6N4O: C, 56.01; H, 2.69; N, 12.44. Found: C, 55.70; H, 2.81; N, 12.23.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc2[nH]nnc2c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.3 %

Procedure:
Methanesulphonyl chloride (9.3 ml, 0.12 mol) in toluene (30 ml) was added dropwise to a solution of benzotriazole (11.9 g, 0.1 mol) and pyridine (12 ml, 0.16 mol) in toluene (120 ml). The reaction was stirred at room temperature for 20 h, diluted with ethyl acetate (150 ml), washed with water (2×100 ml), brine (150 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum to give 1-(methylsulphonyl)-1H-benzotriazole (19 g). NMR: δH CDCl3 8.17, (1H, m), 8.02, (1H, m), 7.69, (1H, m), 7.55, (1H, m), 3.52, (3H, s).
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:35][C:36]#[N:37])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)C1C=CC=CC=1.[OH-].[Na+].C(CC(COCCCCCCCCCCCCCCCC)CO)#N>CO.O1CCCC1>[C:36]([CH2:35][CH:11]([CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][OH:9])#[N:37]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)COC(=O)c1ccccc1
Agent: CCCCCCCCCCCCCCCCOCC(CO)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC#N
Yield: 81.3 %

Procedure:
A mixture of 1.49 g (2.96 mM) of 2-cyanomethyl-3-n-octadecylcarbamoyloxypropyl benzoate n5', 1.66 ml (3.32 mM) of 2N aqueous sodium hydroxide in 15 ml of methanol and 15 ml of tetrahydrofuran is allowed to react by the same procedure as described in (137) and 966 mg (76.8% yield) of the titled compound Vn2 is obtained.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH2:10][CH:11]=O)[CH:5]=[CH:6][CH:7]=2)[O:2]1.[CH2:13]1OC2C(=C(C=CC=2)C=O)[O:14]1>>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH2:10][CH2:11][CH:13]=[O:14])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: O=CCc1cccc2c1OCO2
Product: O=CCCc1cccc2c1OCO2

Procedure:
Following essentially the same procedure, but substituting 2-(2,3-methylenedioxyphenyl)acetaldehyde for the 2,3-methylenedioxybenzaldehyde, results in the formation of 3-(2,3-methylenedioxyphenyl)propionaldehyde.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]#[C:5][CH2:6][CH3:7].[Br:10][C:11]1[CH:12]=[C:13]([O:17][CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:14]=[N:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([O:17][CH:18]([CH2:22][CH3:23])[C:19]([NH:2][C:3]([CH3:9])([C:4]#[C:5][CH2:6][CH3:7])[CH3:8])=[O:20])[CH:14]=[N:15][CH:16]=1
Reactant: CCC#CC(C)(C)N
Reactant: CCC(Oc1cncc(Br)c1)C(=O)O
Agent: Cl
Product: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Br)c1

Procedure:
This compound was prepared using a similar procedure to that described in Stage 3 of Example 1 except that 5-amino-5-methylhex-3-yne hydrochloride was used in place of 4-amino-4-methylpent-2-yne hydrochloride and 2-(5-bromo-3-pyridyloxy)butyric acid was used in place of 2-(5-chloro-3-pyridyloxy)butyric acid. The compound was characterised as follows: colourless solid, m.p. 90–92° C.; 1H NMR (CDCl3) δ: 1.02–1.06 (3H, t); 1.10–1.14 (3H, t); 1.62 (6H, s); 1.96–2.02 (2H, m); 2.16–2.22 (2H, m); 4.424.46 (1H, m); 6.30 (1H, br s); 7.40 (1H, m); 8.30 (1H, d); 8.36 (1H, d).
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][Cl:30])[CH2:23][CH2:22]3)=[CH:18][CH:19]=[CH:20][C:13]1=2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[ClH:30].[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][O:1][C:2]4[N:3]=[CH:4][C:5]5[C:10]([CH:11]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:25][CH2:26]3)=[CH:18][CH:19]=[CH:20][C:13]1=2
Reactant: Oc1cc2ccccc2cn1
Reactant: ClCCCN1CCN(c2cccc3sccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: c1ccc2cc(OCCCN3CCN(c4cccc5sccc45)CC3)ncc2c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 36.4 %

Procedure:
3-Hydroxyisoquinoline (170 mg, 1.17 mmol), 1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (290 mg, 1.0 mmol), and potassium carbonate (200 mg, 1.45 mmol) were added to dimethylformamide (8 ml), followed by stirring at 80° C. for 7 hours. The reaction mixture was cooled to room temperature, then water was added thereto and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure after filtration. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=9:1), and concentrated under reduced pressure. The resulting residue was dissolved in ethanol (2 ml), and 1N-HCl-ethanol solution (0.5 ml) was added thereto. Insoluble matters produced were filtered out and dried to obtain 3-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]isoquinoline hydrochloride (160 mg, yield: 37%) as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[S:8])[CH3:2].[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O>C(O)C>[Cl:16][CH2:17][C:18]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[S:8][CH:20]=1
Reactant: O=C(CCl)CCl
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Solvent: CCO
Product: CCOc1ccc(-c2nc(CCl)cs2)cc1OCC
Temperature: 25 °C
Yield: 67.9 %

Procedure:
3,4-diethoxythiobenzamide (30.0 g, 133 mmol) was suspended in ethanol (300 ml), and 1,3-dichloroacetone (12.8 ml, 135 mmol) was added, followed by heating under reflux for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, and the residue was recrystallized from an ethyl acetate/n-hexane mixed solvent, to thereby obtain 26.9 g (yield: 68%) of 4-chloromethyl-2-(3,4-diethoxyphenyl)thiazole as yellow prisms.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[I-].[K+].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(Cl)(Cl)Cl>[OH2:6].[ClH:1].[ClH:1].[N:29]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:20]=[CH:19][C:18]3[S:17][C:16]4[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)=[O:6])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1S2
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1S2

Procedure:
A mixture of 40.7 g (0.10 mole) of 2,7-bis(4-chlorobutyryl)-thioxanthene, 1 g of potassium iodide and 200 ml of piperidine was stirred and heated on a steam bath for 72 hours. Upon cooling the solution was poured into 1 liter of water. The oily product obtained was dissolved in chloroform, washed with water then saturated NaCl solution, dried over magnesium sulfate and filtered. The filtrate was evaporated to a small volume, cooled, acidified to Congo Red with ethereal HCl and filtered. The resulting solid was recrystallized several times from ethanol to give the desired product. M.P. 229°-231°C.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH2:9][CH2:8][C:7]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[CH2:18][CH2:17]1)=[O:15])=[CH:6]2.[C:35](OCC)(=[O:37])[CH3:36].[C:41](OC(=O)C)(=[O:43])[CH3:42].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52]>C(OCC)C.C(O)C.C(N(CC)CC)C>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[C:35]([O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:41](=[O:43])[CH3:42])[CH2:9][CH2:8][C:7]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[CH2:18][CH2:17]1)=[O:15])=[CH:6]2)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Reactant: COc1cc(CN2CCN(C(=O)C3=Cc4cc(O)c(O)cc4CC3)CC2)cc(OC)c1OC
Agent: Br
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(CN2CCN(C(=O)C3=Cc4cc(OC(C)=O)c(OC(C)=O)cc4CC3)CC2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
A mixture of 1-(6,7-dihydroxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrobromide (0.3 g), ethyl acetate (20 ml), triethylamine (0.5 ml) and acetic anhydride (0.5 ml) is left standing at room temperature overnight. Ethanol (5 ml) is added to the mixture. The whole mixture is left standing for one hour and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) to give an oily product. This product is dissolved in ethyl ether. An ethyl ether solution (50 ml) of fumaric acid (0.1 g) is added to the solution. The mixture is diluted with petroleum ether, whereupon colorless powder precipitates out. The precipitates are collected by filtration to give 1-(6,7-diacetyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine fumarate (0.25 g) as colorless powder.