Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: OB(O)c1cccnc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3cccnc3)C2=O)cc1
Yield: 93 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and pyridin-3-yl-3-boronic acid instead of phenyl boronic acid to obtain the title compound (93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>[Cu].CS(C)=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Ic1ncccn1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of copper bronze (Aldrich) (5.88 g, 92.5 mmol), DMSO (10 mL), and bromo-difluoro-acetic acid ethyl ester (Advanced Synthesis Technologies) (6.46 mL, 50.4 mmol) was evacuated and flushed with argon three times, and was then stirred at rt for 1 h. Upon standing, the supernatant was dark green. Solid 2-iodopyrimidine (8.76 g, 42.5 mmol) (J. Org. Chem. 67:6550, 2002) was then added, the flask was again evacuated and flushed with argon three times, and stirred at rt for 14 h (mild initial warming of flask spontaneously occurred). The resulting immobile dark brown paste was diluted with saturated NH4Cl (175 mL) and EtOAc (150 mL), the mixture was filtered through a pad of Celite, and the filter cake washed with EtOAc (2×50 mL). The blue aqueous layer filtrate was extracted with EtOAc (1×50 mL), and the combined filtrate clear yellow organic layers were washed with saturated NH4Cl (2×100 mL), 10% w/v EDTA trisodium (1×100 mL; saturated NaBr needed to break phases), saturated NaCl (1×50 mL), saturated NaBr (1×20 mL), dried (2×Na2SO4), and concentrated under reduced pressure. Silica flash chromatography of the greenish residue (1:1 hexanes/EtOAc eluent) provided the title compound as a nearly colorless oil with a greenish precipitate (1.75 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([CH:13]=[CH2:14])[C:10]([OH:12])=[O:11])=[O:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.S(Cl)(Cl)=O.[CH3:25]O>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([CH:13]=[CH2:14])[C:10]([O:12][CH3:25])=[O:11])=[O:7])=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: C=CC(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: C=CC(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
25 g (90.3 mmol) of 2-(4-fluoro-2-trifluoromethylbenzoylamino)but-3-enoic acid were dissolved in methanol, and 9.9 g (82.8 mmol) of thionyl chloride were added dropwise over a period of 30 min. The solution was stirred at RT for three days. Removal of the solvent gave 25.2 g of product (100% of theory) of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[C:17](Cl)(=[O:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CCOC(C)=O>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][N:5]4[N:4]=[CH:3][C:2]([Br:1])=[C:6]4[N:7]=3)[CH2:12][CH2:13]2)=[O:28])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To 2.00 g (7.09 mmol) of 3-bromo-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine dissolved in 40 mL of EtOAc at 0° C., was added 1.71 g (8.51 mmol) of 4-nitrophenyl carbonochloridate, followed by 1.97 mL (14.18 mmol) of TEA. After 5 minutes stirring at 0° C., the ice bath was removed, and stirring continued at RT for about 2 hr. It was diluted with 50 mL of 50% EtOAc/hex. The desired product was filtered out, and dried to obtain 3.17 g (100% yield) of an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: COc1ccc(I)cc1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2ccc(C)c(N3CCc4nc(N)ncc4C3)c2=O)cc1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (25 mg, 0.097 mmol), 4-methoxy-iodobenzene (23 mg, 97 mmol) N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), copper iodide (5 mg, 22 mmol), and potassium phosphate (41 mg, 0.194 mmol) in 2 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (19 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×5 mL) and NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and then concentrated in vacuo. The crude mixture was purified using the ISCO flash chromatography system using a 0-100% EtOAc gradient/100-0% Hexane gradient mixture. Following concentration of the appropriate fractions the crude solid collected was further purified by recrystallization using an Et2O/Hexane solvent mixture to give the title compound as an off white solid (13 mg, 37%). 1H NMR (DMSO) δ: 7.92 (s, 1H), 7.45-7.52 (m, 2H), 7.61 (d, J=6.7 Hz, 1H), 7.24-7.31 (m, 2H), 6.28 (s, 2H), 6.37 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.72 (s, 3H), 3.29 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([OH:19])=O)[S:15][CH:16]=3)=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C@@H:38]1([NH2:45])[CH2:43][CH2:42][CH2:41][CH2:40][C@@H:39]1[NH2:44]>CN(C)C=O>[NH2:44][C@@H:39]1[CH2:40][CH2:41][CH2:42][CH2:43][C@@H:38]1[NH:45][C:17]([C:14]1[S:15][CH:16]=[C:12]([C:9]2[N:8]3[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:6][C:7]3=[N:11][CH:10]=2)[CH:13]=1)=[O:19]
Reactant: COc1cc(-c2ccccc2)cc2ncc(-c3csc(C(=O)O)c3)n12
Reactant: N[C@@H]1CCCC[C@@H]1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2)cc2ncc(-c3csc(C(=O)N[C@H]4CCCC[C@H]4N)c3)n12

Procedure:
To a solution of 4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxylic acid (10.0 mg, 0.029 mmol) in N,N-dimethylformamide (1 ml) was added 1,1′-carbonyldiimidazole (7.0 mg, 0.043 mmol). After 20 minutes cis-1,2-cyclohexanediamine (0.034 ml, 0.29 mmol) was added. After 10 minutes the reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give N-[(1S,2R)-2-aminocyclohexyl]-4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxamide. 1H NMR (600 MHz, DMSO-d6) δ 8.13 (s, 1H); 7.85 (d, 2H); 7.74 (d, 1H); 7.59 (s, 1H); 7.54 (d, 1H); 7.47-7.49 (m, 2H); 7.38-7.41 (m, 1H); 6.66 (d, 1H); 3.99 (s, 3H); 1.50-1.72 (m, 7H); 1.29-1.36 (m, 3H). LRMS (ESI) calculated for C25H27N4O2S [M+H]+, 447.2 found 447.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reaction time: 24 h

Procedure:
A solution of 183 mg of 2,3-dimethylpyridine 1-oxide in 0.6 ml of concentrated sulfuric acid was treated while cooling with ice with 0.2 ml of 65% nitric acid (d=1.4). The reaction mixture was stirred at 90° for 24 hours and poured on to a mixture of ice and sodium carbonate, whereupon the resulting mixture was extracted with methylene chloride and the methylene chloride phase was dried and evaporated. The residue, crystallized from ethanol/n-pentane, gave 2,3-dimethyl-4-nitropyridine 1-oxide of melting point 99°-102°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccncc3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine (0.32 g, 0.83 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.64 mmol) in dichloromethane (50 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (0.096 mL, 1.24 mmol). After 1 hour, warm to ambient temperature. Again cool in an ice bath and add N,N-diisopropylethylamine (0.23 mL, 1.32 mmol) followed by methanesulfonyl chloride (0.096 ml, 1.24 mmol). After 1 hour, dilute the reaction mixture with dichloromethane and extract with a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.24 (silica gel, 5% methanol/dichloromethane/0.1% concentrated aqueous ammonia).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)=O>>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:37][CH:36]=1
Reactant: Cc1ccc(C(=O)CBr)cn1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1ccc(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)cn1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 58 mg (0.269 mmol) of 2-bromo-1-(6-methylpyridin-3-yl)ethanone were reacted according to the General Method 3. Yield: 18 mg (15% of theory)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([F:9])=[C:6]([F:8])[F:7].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:9][C:5](=[C:6]([F:8])[F:7])[CH2:4][CH2:3][N:2]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: NCCC(F)=C(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)=C(F)CCN=C=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 0.4 gram (0.0027 mole) of 4-amino-1,1,2-trifluoro-1-butene hydrochloride in 15 ml of chloroform was added 0.3 gram (0.003 mole) of thiophosgene, followed by 0.7 ml (0.009 mole) of triethylamine. Upon completion of addition the reaction mixture was stirred at ambient temperature for three hours. The reaction mixture was then washed in succession with one 25 ml portion of water, two 25 ml portions of aqueous 5% sodium hydroxide, and, finally, one 25 ml portion of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 0.3 gram of (3,4,4-trifluoro-3-butenyl) isothiocyanate as an oil. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:11]=[N-:12])=[CH:6][CH:5]=1.[S:24]1[CH2:28][C@@H:27]([C:29]([OH:31])=[O:30])[NH:26][CH2:25]1.C(N(CC)CC)C.C(O)=O>CN(C)C=O>[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([N:26]2[C@H:27]([C:29]([OH:31])=[O:30])[CH2:28][S:24][CH2:25]2)=[O:23])=[CH:9][CH:8]=1)=[N+:11]=[N-:12]
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: [N-]=[N+]=Nc1ccc(COC(=O)N2CSC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 92 %

Procedure:
4-Azidobenzyl (4-nitrophenyl) carbonate prepared by a method known in the literature (Bioconjugate Chem. 2008, 19, 714) (3.50 g, 11.1 mmol) was added to a solution of (R)-thiazolidine-4-carboxylic acid (H-Thz-OH) (Compound SP609) (1.48 g, 11.1 mmol) and triethylamine (Et3N) (4.66 ml, 33.4 mmol) in Dimethylformamide (DMF) (11.0 ml) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 19 hours. Formic acid (2.1 ml) was added to the reaction solution, and the mixture was purified by reverse-phase silica gel chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-3-(((4-azidobenzyl)oxy)carbonyl)thiazolidine-4-carboxylic acid (Acbz-Thz-OH) (Compound SP610) (3.17 g, 92%).
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](=[N:16]O)C(O)=O)([O-:4])=[O:3]>C(O)(=O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]#[N:16])([O-:4])=[O:3]
Reactant: O=C(O)C(Cc1ccccc1[N+](=O)[O-])=NO
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (50,000 ml), 2,940 ml of glacial acetic acid and (22.22 moles) of 2-nitrophenylpyruvic acid oxime were charged into a 20 gallon reactor. The stirred suspension was heated over two hours under nitrogen atmosphere to 90° and this temperature was maintained for 2 hours. The dark solution was allowed to cool slowly and was stirred overnight at ambient temperature. The suspension was extracted with 5×4,000 ml of methylene chloride, washed with 3×3,000 ml of water, dried over magnesium sulfate and filtered. The filtrate was treated with activated carbon, filtered and the solvent was removed under reduced pressure. The solid residue was recrystallized from 1,000 ml of isopropanol to give 2-nitrophenylacetonitrile, m.p. 82°-84°.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[OH:45])=[CH:40][CH:39]=1.Cl[CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71](=[O:73])[CH3:72])=[CH:67][C:66]=1[O:74][CH3:75].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C(O)(=O)C(O)=O>C(O)CCC>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:59][O:58][C:55]1[CH:54]=[CH:53][C:52]([C:44]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)([OH:45])[CH:46]2[CH2:51][CH2:50][N:49]([CH2:61][CH2:62][CH2:63][O:64][C:65]3[CH:70]=[CH:69][C:68]([C:71](=[O:73])[CH3:72])=[CH:67][C:66]=3[O:74][CH3:75])[CH2:48][CH2:47]2)=[CH:57][CH:56]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCN(CCCOc3ccc(C(C)=O)cc3OC)CC2)cc1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.2 g (0.01 mole) of α,α-bis(4-methoxypenyl)-4-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by columm chromatography on 100 g of Florisil®. Fractions eluted with 5-40% acetone in benzene were combined and concentrated under reduced pressure to give a brown glass as residue. The glass was converted to the oxalic acid salt. The solid was recrystallized from absolute ethanol yield 3.3 g (53%) of the title compound as a white solid, mp 139°-142° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[CH2:27]1[O:36][C:35]2[C:29](=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[O:28]1.[ClH:37]>C(O)(C)C>[ClH:1].[ClH:37].[ClH:1].[CH2:27]1[O:36][C:35]2[C:29](=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:9][C:10]=3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:5]=[CH:4][N:3]=2)[O:28]1
Reactant: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Cl)c23)CC1
Reactant: Nc1cccc2c1OCO2
Agent: Cl
Solvent: CC(C)O
Product: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Nc4cccc5c4OCO5)c23)CC1

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.11 g) was reacted with 2,3-methylenedioxyaniline (0.045 g) in the presence of a 6M solution of hydrogen chloride in isopropanol to give the title compound, as a trihydrochloride salt (0.105 g), a portion of which was converted into the free base using an analogous procedure to that described in Example 3. The free base gave the following characterising data: NMR Spectrum: (CDCl3) 1.78 (br s, 4H), 2.3 (s, 3H), 2.5 (m, 2H), 2.6 (br s, 4H), 2.8 (d, 2H), 2.95 (m, 4H), 3.08 (d, 2H), 4.18 (m, 2H), 5.98 (s, 2H), 6.6 (d, 1H), 6.86 (m, 1H), 6.94 (s, 1H), 8.06 (d, 1H), 8.5 (s, 1H), 11.8 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (1 mL) were added potassium carbonate (0.145 g; 1.047 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g; 0.0013 mmol) and 3-pyridinylboronic acid (0.064 g; 0.524 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:17][CH2:18][N:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=2)[C:20]1=[O:33]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:18][N:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[C:20]2=[O:33])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(CCBr)c(=O)c2c1
Reactant: COc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(CCOc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxyphenol (74 mg, 0.59 mmol) in THF (2.5 mL) was added potassium tert-butoxide (52 mg, 0.46 mmol). The reaction mixture was stirred at rt for 3 h, then methyl 2-(2-bromoethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (80 mg, 0.26 mmol) in DMF (2.5 mL) was added and the resulting mixture was stirred at rt overnight. The mixture was then concentrated to afford methyl 2-[2-(4-methoxyphenoxy)ethyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate. LC-MS: (FA) ES+354.
Reaction SMILES: [Cl-].[Li+].[C:3]1(=[O:18])[O:17][C@@H:6](/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:4]1.[Cl-].Cl[Si](C)(C)C.C(OCC)(=O)C>O1CCCC1.[Cu](I)I>[C:3]1(=[O:18])[O:17][C@@H:6](/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5][CH2:4]1
Reactant: CCCCCCCC/C=C\[C@H]1C=CC(=O)O1
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\[C@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
In an argon atmosphere, 10 ml of anhydrous tetrahydrofuran were added to 570 mg (3.0 mmol) of purified copper iodide (CuI) and 318 mg (7.5 mmol) of lithium chloride (LiCl) dried at a reduced pressure and 130° C., and the resultant solution was stirred at room temperature for about 30 minutes. The resultant transparent solution was cooled to about -60° C., a solution obtained by dissolving 336 mg (1.511 mmol) of the compound (17) obtained in step h in 3.5 ml of tetrahydrofuran was added to the above transparent solution, and 0.81 ml (6 mmol) of chlorotrimethylsilane chloride immediate after distillation were added to the above solution. The resultant mixture was stirred for 10 minutes, and 1.5 ml (5.5 mmol) of distilled and purified n-Bu3SnH were added thereto in a small amount each time over 5 minutes. Thereafter, cooling was stopped, and the temperature of the reaction solution was raised to 0° C. at room temperature over about 30 minutes. 20 ml of a 10% aqueous potassium fluoride solution were added to this reaction solution, and the mixture was stirred. The produced precipitate was filtered. This filtrate was extracted with tetrahydrofuran and concentrated, 30 ml of a 10% aqueous potassium fluoride solution were added to the residue, and the solution was stirred for 15 minutes. 30 ml of ether were further added to the above solution, and the resultant solution was stirred for 15 minutes. The stirred solution was filtered, the filtrate was separated, and the water layer thereof was extracted with ether. The extracted solution was collected and sequentially washed with water and brine solution and was dried with anhydrous magnesium sulfate. Then, the crude product obtained by concentrating the extracted solution was purified by chromatography using silica gel (270-400 meshes, 10 g, developing solution of hexane: ethyl acetate at a mixing ratio of 98:2 to 96:4), thereby obtaining 265 mg of a compound (18) (yield:78%). The IR and NMR spectra of the resultant compound (18) coincided with the reported data [References: Y. Nishida, et al, Agric. Biol. Chem., 51, 635 (1987) (to be referred to as reference 1 hereinafter) and R. E. Dolitle, et al, J. Chem. Ecol., 6, 473 (1980) (to be referred to as reference 2 hereinafter)]. Other physical data were as follows.