Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>C(O)C>[CH:1](=[C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 0.67 M solution of the benzaldehyde (20.0 mmol) and cyclohexanone (10.0 mmol) in ethanol (15 ml) is added 10 ml 40% KOH at 10° C. After stirring for 12-24 hr at room temperature, the solution is diluted and filtered. The precipitate is recrystallized from ethanol to afford 2,6-dibenzalcyclohexanone and its derivatives. VIII. 2,6-DIBENZYLIDENECYCLOPENTANONE Derivatives
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[F:13][CH:14]([F:18])[C:15](O)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[N:12]=[C:15]([CH:14]([F:18])[F:13])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C(O)C(F)F
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)c2nc(C(F)F)[nH]c2c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a 100 mL round bottomed flask was added 3-bromo-5-nitrobenzene-1,2-diamine (5.5 g, 23.70 mmol) and 2,2-difluoroacetic acid (4.46 mL, 71.1 mmol) in Toluene (55 mL). The stirred solution was heated to 105° C. and monitored by LC/MS. After stirring at 105° C. for 2 hr the reaction was allowed to cool to rt, was diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated in-vacuo then taken up in EtOAc, washed several times with sat'd NaHCO3 soln, brine and then dried over Na2SO4 and concentrated to provide crude 4-bromo-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (6.7 g, 22.94 mmol, 97% yield) as a brown solid. LC/MS: MS (ES+) m/e 293.7 [M+H]+.
Reaction SMILES: OOS([O-])=O.[K+].[C:7]([C:11]1[N:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:7]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]=2)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)c1ncc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)cn1
Reaction time: 0.25 h

Procedure:
16.9 g (55 mmol) of oxone [70693-62-8] are added in portions with stirring at 10° C. to a solution of 16.4 g (100 mmol) of 2-tert-butylpyrimidine-5-carboxaldehyde [104461-06-5] and 11.9 g (110 mmol) of 1,2-diaminobenzene in a mixture of 100 ml of DMF and 3 ml of water, and the mixture is subsequently stirred at room temperature until conversion of the aldehyde is complete (about 2 h). The reaction mixture is stirred into a solution of 40 g of potassium carbonate solution in 2000 ml of water, stirred for a further 15 min., the solid formed is filtered off with suction, washed three times with 100 ml of water each time and dried in vacuo. The solid is dissolved in about 50 ml of hot ethyl acetate, and, during cooling, diethyl ether is added until slightly cloudy, the mixture is stirred for a further 12 h, the crystals are filtered off with suction, washed once with 50 ml of diethyl ether and dried in vacuo. Yield: 16.6 g (66 mmol), 66%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1([CH:21]([CH3:26])[C:22](OC)=[O:23])[CH:20]=[N:19][CH:18]=[N:17]1>O1CCCC1>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:23])[CH:21]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)n1cncn1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(n1cncn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 4-trifluoromethoxybromobenzene (9.3 g) in dry tetrahydrofuran (40 cm3)was added dropwise to a stirred mixture of magnesium turnings (0.93 g), dry tetrahydrofuran (15 cm3) and a crystal of iodine under a nitrogen atmosphere and at the ambient temperature. The reaction was observed to have commenced after 4 cm3 of the solution had been added. After the addition was complete the mixture was stirred for a further 2 hours. A solution of methyl 2-(1,2,4-1H-triazol-1-yl)propionate (3.0 g) in dry tetrahydrofuran (5.0 cm3) was added dropwise to the mixture and after stirring for a further two hours at the ambient temperature the mixture was warmed to 40° C. for 3 hours. The mixture was then quenched with water, acidified with dilute hydrochloric acid and extracted with diethyl ether. The ethereal extract was washed with water (three times) and dried over anhydrous magnesium sulphate. The residual oil remaining after removal of the solvent by evaporation under reduced pressure was subjected to purification by hplc using a silica gel column eluted with a mixture of dichloromethane (3 parts by volume) and ethyl acetate (2 parts by volume) to give 1,1-bis(4-trifluoromethoxyphenyl)-2-(1,2,4-1H-triazol-1-yl)propanol (1.0 l g) as a solid residue.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15]I.O>O1CCCC1>[CH:3]1([CH2:9][P:10]([CH3:15])(=[O:14])[O:11][CH2:12][CH3:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CI
Reactant: CCO[PH](=O)CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(C)(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.25 g of sodium hydride (55% dispersion in oil) in 10 ml of anhydrous tetrahydrofuran is cooled to 0° under an inert atmosphere. A solution of 8.9 g of ethyl (cyclohexylmethyl)phosphinate in 10 ml of anhydrous tetrahydrofuran is added dropwise maintaining the temperature at between 0°-5°. After the addition is complete the suspension is warmed to room temperature and stirred for 30 minutes before re-cooling to 0° C. A solution of 19.87 g of methyl iodide in 10 ml of anhydrous tetrahydrofuran is added slowly--very exothermic! After warming to room temperature, the reaction mixture is stirred for 45 minutes, re-cooled to 0° and carefully treated with water. Removal of the organic phase, drying and concentration affords a yellow oil. Chromatography on silica gel gives ethyl P-cyclohexylmethyl-P-methylphosphinate as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=4.04 (2H, m, CH2OP), 1.94-1.57 (7H, m, 3×CH2 +CH), 1.45 (3H, d, J=15 Hz, P--CH3), 1.36-0.95 (9H, m, 3×CH2 +CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCCCn1c(C)nc2c(N)nc3ccccc3c21
Yield: 6.4 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with ethanesulfonyl chloride (2.11 mL, 22.3 mmol) to provide 85 mg of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ethanesulfonamide as an off-white solid, m.p. 210.7-211.6° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH:18](Br)[C:17]=1O)=[O:15])[CH3:12]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([O:13][C:14]([CH:16]1[C:17]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:3][CH2:2][F:1])[C:18]=2[CH2:19][CH2:20][CH2:21]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Reactant: FCCNc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCOC(=O)C1CCCc2c1c1ccccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of (2-fluoro-ethyl)-phenyl-amine (24; prepared according to Example 4(a)) (560 mg, 4.0 mmol) and 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (29) (500 mg, 2.0 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (4 mL) and dry zinc chloride (820 mg, 6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The product was dissolved in ethyl acetate/ether (30 mL/150 mL) and washed with 2 N HCl (40 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated to afford 447 mg (91%) of 9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (30) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 14.3, 20.4, 21.7, 26.4, 38.5, 43.1 (d, TCF=15 Hz), 60.6, 76.6, 77.0, 77.4, 82.1 (d, JCF=173 Hz), 106.9, 108.5, 118.9, 119.4, 121.1, 127.1, 136.2, 136.7, 174.9.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CS(C)=O>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(Cl)c4)c3)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1cccc(Cl)c1
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(3-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (34.0 mg, 0.073 mmol) (from Example 10 supra) in methyl sulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. The solvent was removed in vacuum and the residue was treated with MeOH (2 mL). The resulting white precipitate was filtered, washed with cold MeOH and dried to give 3-[3-(3-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 25.7 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)([O:6][CH3:7])=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: COC(=O)c1cccc(N)c1Br
Product: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Br
Temperature: 125 °C
Yield: 92.5 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125° C. under a stream of nitrogen for 4 h. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) δ 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm−1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.C(OCC)C>[Si:32]([O:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reaction time: 2 h

Procedure:
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.096 g, 0.29 mmol) was dissolved in DMF (1 mL) with 1H-imidazole (0.026 g, 0.38 mmol) and tert-butylchlorodimethylsilane (0.053 g, 0.35 mmol). The reaction was stirred 2 hrs, diluted with diethyl ether and washed twice with water and once with brine. The organic layer was dried over magnesium sulfate and concentrated to furnish the title compound, which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:5][O:6][CH:7]([CH2:9][OH:10])[CH3:8])[CH3:4].[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Zr+4].C(=O)([O-])[O-].O>[C:11]([O:10][CH2:9][CH:7]([CH3:8])[O:6][CH2:5][CH:3]([O:2][CH3:1])[CH3:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(C)COC(C)CO
Reactant: O=C(O)c1ccccc1
Agent: [Zr+4]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(C)COC(C)COC(=O)c1ccccc1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
Dipropylene glycol monomethyl ether (444.6 grams; 3.0 mol), benzoic acid (373.7 grams; 3.06 mol), toluene (50 ml) and zirconium carbonate (2.0 grams) were placed into a 200 ml, 3-necked round bottom flask equipped with stirrer, thermometer, heating mantle, Dean Stark water trap, condenser and 10" Vigneux column. The reaction temperature was 180° C. at the beginning of the reaction and 217° C. after 6.5 hours with stirring. During that time, water (44 mls) was removed. The reaction was continued the next day for 2.5 hours at 224°-226° C. with the removal of water (56 mls.). The reaction mixture was washed at 95°-100° C. three times with sodium carbonate (15%) and then washed with water (400 ml). Then additional water (200 ml) was added and the product separated and dried at 125°, cooled to 100° C. and filtered. The desired product (694.6 grams) was obtained representing a yield of 91.8%. It assayed 99.5% with the following properties:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4]([CH3:15])=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH:23]=[CH2:24]>CN(C)C=O>[CH2:24]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4]([CH3:15])=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2)[CH:23]=[CH2:22]
Reactant: C=CCI
Reactant: Cc1c(C)c2c(O)ccc(C)c2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2[nH]c(=O)c(C)c(C)c12
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
5-Hydroxy-3,4,8-trimethylcarbostyril (3.30 g, 16.3 mmol) was dissolved in N,N-dimethylformamide (100 ml), to which potassium carbonate (2.70 g, 19.6 mmol) and allyl iodide (2.91 g, 17.9 mmol) were added. The mixture was stirred in a bath of 75° C. for 8 hours. The reaction mixture was cooled, and the insoluble matter was removed by filtration. The filtrate was subjected to distillation under reduced pressure for removing the solvent. The residue was recrystallized from chloroform--n-hexane. As a result, 2.84 g of the title compound was obtained as pale yellow needles (71.7%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([N:18]1[C:22]([C:23](=[O:25])[CH3:24])=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1>[CH2:11]([N:18]1[C:22]([C:23]([OH:25])([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:24])=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)c1cncn1Cc1ccccc1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)(CCc1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
1.0 g of magnesium turnings are covered with 5 ml of dry tetrahydrofuran. To the mixture is added 7.8 g of (2-bromoethyl)benzene in 30 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. The mixture is then heated under reflux for one hour. After being cooled to room temperature, 3.0 g of 1-(3-benzyl-3H-imidazol-4-yl)-ethanone in 20 ml of tetrahyrofuran is added dropwise to the Grignard reagent and the reaction mixture is refluxed for one hour. The cooled reaction mixture is poured into a cold dilute hydrochloric acid solution. Work-up of the mixture gives the crude product, which is recrystallized from ethyl acetate. The yield is 3.3 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:32][CH2:31]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:36]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)(=[O:38])=[O:37])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)N2CCN(C)CC2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 43 %

Procedure:
2-(2-Aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) was dissolved in a mixture of chloroform (dried over alumina) (20 ml) and triethylamine (2 ml) and the mixture stirred at room temperature. 4-Methyl-1-piperazinylsulphonyl chloride (0.25 g) was added in one portion and the mixture stirred at room temperature for 17 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium carbonate and methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated to give 0.3 g of a colourless oil, which was dissolved in diisopropyl ether (15 ml) and kept in a refrigerator for 14 days. The resultant crystals were collected by filtration to afford the title compound (0.1 g), m.p. 137°-139° C. Found: C, 52.58; H, 6.18; N, 9.81%. C25H35ClN4O7S requires C, 53.03; H, 6.14; N, 9.20%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[N:13]=[N:12]1.N1CCCCC1>CCO>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2[nH]nnc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]nnc2c1
Temperature: 90 °C
Yield: 74.8 %

Procedure:
A scintillation vial was charged with indolin-2-one (101 mg, 0.760 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (123 mg, 0.836 mmol), piperidine (7.5 uL, 0.076 mmol) and EtOH (4 mL). The reaction was then heated to 90° C. for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more EtOH (5 mL). The yellow solid was then filtered and washed with EtOH (20 mL) giving 149 mg, 75% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 15.94 (s, 1H), 10.65 (s, 1H), 8.27 (bs, 1H), 8.05 (bs, 1H), 7.80 (s, 1H), 7.77 (bs, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.09.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:25][CH2:26]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c(C)c1
Temperature: 25 °C
Yield: 102.7 %

Procedure:
4-Nitrobenzoic acid (2 g), 1-(2,4-dimethylphenyl)piperazine (2.28 g), and 1-hydroxybenzotriazole 1 hydrate (1.62 g) were dissolved in N,N-dimethylformamide (30 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.31 g) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate/diisopropyl ether and the insoluble material was collected by filtration to give [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g). Then, ammonium chloride (3.71 g) and iron (2.68 g) were added to a solution of ethanol (61 mL) and water (17 mL), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g) was added with stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was filtered off, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (4.17 g). To the obtained crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1 g) were added itaconic acid (0.42 g), water (5 mL), 1,2-dimethoxyethane (2 mL) and acetic acid (5 mL), and the mixture was stirred with heating under reflux for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate, and the precipitate was collected by filtration to give the title compound (508 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>CO>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CN(C)CCCCl
Solvent: O
Solvent: CO
Product: CN(C)CCCOc1ccc(C(=O)c2ccc(OCCCN(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of bis-(4-hydroxy-phenyl)-methanone (7.00 g) in methanol (130 mL) was added at room temperature t-Bu3OK (14.7 g) followed by (3-chloro-propyl)-dimethyl-amine (10.3 g). The reaction mixture was heated under reflux for 18 h and was allowed to cool down to room temperature. Water (50 mL) was added and the solvent was removed in vacuo. Methylene chloride (650 mL) was added and the organic layer was washed with water (2×150 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The crude products were separated and purified by flash chromatography on silica gel (chloroform/2 M ammonia in methanol) to give the title compound bis-[4-(3-dimethylamino-propoxy)-phenyl]-methanone as a colorless residue (250 mg). 1H NMR (400 MHz, CD3OD): 7.78 (d, 4 H), 7.09 (d, 4 H), 4.22 (t, 4 H), 3.37-3.40 (m, 4 H), 2.96 (s, 12 H), 2.24-2.31 (m, 4 H). And title compound [4-(3-dimethylamino-propoxy)-phenyl]-(4-hydroxy-phenyl)-methanone as a colorless residue (150 mg). 1H NMR (400 MHz, CD3OD): 7.88-7.99 (m, 4 H), 7.25-7.29 (m, 2 H), 7.08-7.13 (m, 2 h), 4.48 (t, 2 H), 2.69-2.76 (m, 2 H), 2.56 (s, 6 H), 2.23-2.30 (m, 2 H).