Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18].C[O-].[Na+].S(OC)(O[CH3:26])(=O)=O>CN(C)C=O>[CH3:26][N:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18]
Reactant: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCC2(CCC(=O)c3ccccc32)C1=O
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
To 24.3 grams (0.1 M) of 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione in 100 milliliters of dry dimethylformamide was added with stirring 5.4 grams (0.1 M) of sodium methoxide. This was followed by 17.0 milliliters of dimethyl sulfate. The reaction mixture became clear and was slightly exothermic. After stirring for 15 minutes, 50 milliliters of solvent was removed at reduced pressure on a steam bath. The resulting solution was cooled and added to 1 liter of ice water. The resulting precipitate was collected and washed with 5 per cent sodium hydroxide solution and finally with water. Recrystallization from butanone-petroleum ether (70°-90°) and then from aqueous ethanol gave 18.4 grams (17.5%) of 1'-methyl-2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 136°-137.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](Cl)=[O:13]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:13])[CH:11]=[C:10]([CH3:15])[CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1cccc(Br)c1
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of Nail (4.15 g, 173 mmol, 60% in oil) in 50 ml of THF was cannulated a solution of 20.322 g (118 mmol) of 3-bromo-aniline in 50 ml of THF. The resulting mixture was stirred at 0° C. for 45 min and warmed to room temperature over a period of 15 min. To this solution was added through cannulation 13.123 g (173 mmol) of 3,3-dimethylacryloyl chloride. The mixture was stirred at room temperature for 24 h and thereafter slowly poured into ice water. The resulting mixture was extracted with methylene chloride (twice), dried over MgSO4 and concentrated to yield a solid. The solid was purified by recrystallization in hexane/EtOAc (2:1) to give the title compound as a light brown solid. PNMR (CDCl3) d 7.83 (1H, b), 7.30 (4H, m), 5.68 (1H, s), 2.22 (3H, s), 1.90 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].ClC1C=CC=CC=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=1
Reactant: CCOC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2ccc([N+](=O)[O-])c(F)c2)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
After adding 3-fluoro-4-nitrophenol (24.7 g) and chlorobenzene (7.0 ml) to ethyl 4-chloropyridine-2-carboxylate (19.4 g), the mixture was heated and stirred for 4 hours at 120° C. under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature. Ethyl acetate (400 ml) and saturated aqueous sodium carbonate (400 ml) were added thereto and the mixture was stirred for 27 hours at room temperature. The stirring was paused and the aqueous layer was separated. Saturated aqueous sodium carbonate was again added to the organic layer, and the mixture was stirred at room temperature for 2 days. The stirring was again paused and the aqueous layer was separated. The aqueous layer was then extracted with ethyl acetate (300 ml). The organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1 to 1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the title compound (12.9 g, 40.2%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[C:39]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=3)[CH:40]=[CH:41][C:42]=2[OH:43])=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:43][C:42]2[CH:41]=[CH:40][C:39]([C:44]3[CH:45]=[CH:46][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:48][CH:49]=3)=[CH:38][C:37]=2[C:34]2[CH:35]=[CH:36][N:31]=[N:32][CH:33]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Yield: 101 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-pyrimidin-2-yl-benzenesulfonamide (Preparation 13, 216 mg, 0.47 mmol), 3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-ol (Preparation 8, 150 mg, 0.47 mmol) and potassium carbonate (196 mg, 1.42 mmol) were stirred in dimethylsulfoxide (3 mL) at room temperature for 18 hours. A 1M aqueous solution of sodium hydroxide was added to the reaction mixture whereupon a precipitate was observed. The precipitate was collected by filtration and dissolved in ethyl acetate. The ethyl acetate was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a solid (357 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19]C)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.P(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[OH:19])/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: COc1ccc(/C=C/c2nc3ccccc3s2)cc1N
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1cc(/C=C/c2nc3ccccc3s2)ccc1O
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 282 mg of 2-(trans-3-amino-4-methoxystyryl)benzothiazole dissolved in 30 ml of dichloromethane was added 380 mg of phosphorous tribromide at 70° C., and the mixture was gradually returned to room temperature and stirred overnight. After an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture to make it weakly alkaline, the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give 260 mg (yield 97%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[CH:2].I[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]Cl>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=3)[CH:22]=2)[CH:18]=[N:19]1
Reactant: C#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: Cl[Cu]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 4-ethynyl-2-nitro-phenylamine (1.306 g, 8.05 mmol), 6-iodo-1H-indazole (1.965 g, 8.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (122 mg, 0.24 mmol) and copper(I) chloride (54.4 mg, 0.28 mmol) in THF (8 mL) and triethyl amine (8 mL) was stirred at room temperature overnight. Purification by column chromatography on silica gel gave 4-(1H-indazol-6-ylethynyl)-2-nitrophenylamine as red solid (777 mg, 2.79 mmol, yield 35%). LC-MS m/z: 279 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:12]Br.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)c(C#N)cc1Br
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Compound 2-fluoro-4-methoxybenzonitrile (2.97 g, 19.0 mmol) in CHCl3 (30 mL) was added Br2 (2 mL), and the mixture was stirred at ambient temperature for 4 days. The mixture was diluted by DCM and washed with saturated NaHCO3, water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with fast column chromatograph to give 5-bromo-2-fluoro-4-methoxybenzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 7.76 (d, J=7.2 Hz, 1H), 6.73 (d, J=10.5 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:14][C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:47]([O:51][NH2:52])([CH3:50])([CH3:49])[CH3:48].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:47]([O:51][NH:52][C:15](=[O:17])[CH2:14][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccc3ccccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetic acid hydrochloride (1.49 g, 3.35 mmol), 1-hydroxybenzotriazole (0.539 g, 3.52 mmol), 4-methylmorpholine (1.55 mL, 14.9 mmol), and O-t-butylhydroxyl amine hydrochloride (0.464 g, 3.70 mmol) are dissolved in methylene chloride (50.0 mL), and the reaction is cooled to 0° C. To this solution is added N- [dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.35 g, 7.04 mmol), and the reaction is allowed to warm up to room temperature and stir overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with saturated sodium bicarbonate, brine, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (1% methanol/methylene chloride) to give N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH:3]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CC1(O)CC1)OC1CCCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(CC1(O)CC1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol (1.0 g, 4.63 mmol) and triethylamine (1 mL, 7.4 mmol, Shantou Xilong chemical factory) in 30 mL of CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.64 g, 5.6 mmol, Shanghai Haiqu chemical Ltd.) via a syringe. The reaction mixture was stirred at 0° C. for 1 hr and then quenched with 5 mL of ice-water. The resulted mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to furnish 3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate as yellow oil (used in the next step immediately without further purification).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]1)=[O:7].O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[CH2:11][CH:10]([C:24]2[O:26][N:34]=[C:29]([CH2:30][CH2:31][O:32][CH3:33])[N:28]=2)[CH2:9]1)=[O:7]
Reactant: COCCC(N)=NO
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CCOC)no2)C1

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 78 mg (0.497 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 22 mg (17% of theory)
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=2)=[N:14]1.CN(C=O)C.C(Cl)Cl>O>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[C:24]([F:26])[C:21]([C:22]#[N:23])=[C:20]([Cl:27])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1c[nH]c(Br)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]c(Br)n1
Yield: 1.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid (4.31 mmol, 0.822 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (3.59 mmol, 1 g) using DMF (10 ml) as the solvent. DCM and water was added to the mixture, the layers were separated and the water phase was extracted with DCM. The combined organics were washed three times with water. The DCM phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 30.5 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.10 (d, 3H), 4.24-4.49 (m, 3H), 7.00 (d, 1H), 7.62 (s, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.96 (s, 1H), 8.11 (d, 1H), 13.23 (bs, 1H).
Reaction SMILES: NCCCCN.C(O)(=O)CCCCCCC/C=C\C/C=C\C/C=C\CC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH:63][CH2:64][CH:65]=[CH:66][CH2:67][CH:68]=[CH:69][CH2:70][CH3:71])=[O:47])[CH:32]=[CH:33][C:34]=1[O:35]COCCOC.O1CCOCC1CC(O)=O.O>O1CCCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:72])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH:63][CH2:64][CH:65]=[CH:66][CH2:67][CH:68]=[CH:69][CH2:70][CH3:71])=[O:47])[CH:32]=[CH:33][C:34]=1[OH:35]
Reactant: CCC=CCC=CCC=CCCCCCCCC(=O)NCCCCNC(=O)C=CC=Cc1ccc(OCOCCOC)c(OC)c1
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: NCCCCN
Agent: O=C(O)CC1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CCC=CCC=CCC=CCCCCCCCC(=O)NCCCCNC(=O)C=CC=Cc1ccc(O)c(OC)c1

Procedure:
To a solution fo 880 mg (10 mmol) of 1,4-diaminobutane in tetrahydrofuran (20 ml) was added in an argon atmosphere a solutin fo 410 mg (1 mmol) of N-{5-(3-methoxy-4-β-methoxyethoxymethoxyphenyl)-2,4-pentadienoyl}-2-thiothiazolidine in tetrahydrofuran (10 ml) at room temperature over 30 min. The mixture was treated in the same way as in Example 3 to react with 390 mg (1.05 mmol) of α-linolenic acid thiazolidinethionamide. The reaction product was treated in the same way as in Example 3 to hydrolyze N-{5-(3-methoxy-4-β-methoxyethoxymethoxyphenyl)-2,4-pentadienoyl}-N'-9,12,15-octadecatrieneo yl-1,4-diaminobutane with 1,4-dioxane - acetic acid-water (5:4:1). The reaction product was treated in the same way as in Example 3 to give 195 mg (0.35 mmol) of N-{5-(3-methoxy-4-hydroxyphenyl)-2,4-pentadienoyl}-N'- 9,12,15-octadecatrienoyl-1,4-diaminobutane. Spectrophotometric data of the product support the structure shown below. ##STR31##
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[N:32]=2)[CH2:27][CH2:26]1)C1C=CC=CC=1.Cl>>[CH3:37][C:35]1[CH:34]=[C:33]([CH3:38])[N:32]=[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:17]3[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=3[OH:15])[CH2:30][CH2:29]2)[CH:36]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3OCc3ccccc3)CC2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3O)CC2)c1
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Trifluoroacetic acid (5 mL) was added to 1-(2-benzyloxy-4-nitro-phenyl)-4-(4,6-dimethyl-pyridin-2-yl)-piperazine (720 mg, 1.72 mmol) at between 0 and 5° C. followed by concentrated hydrochloric acid (2 mL). The mixture was heated at reflux overnight then cooled to between 0 and 5° C. and quenched with saturated sodium bicarbonate solution (30 mL). Chloroform (30 mL) was added and the mixture stirred for 15 min. The organic phase was separated and the aqueous phase was extracted with chloroform (30 mL). The combined organic phases were washed successively with water (2×30 mL) then brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. Trituration with petroleum ether afforded 2-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-5-nitro-phenol (510 mg, 90%) as a brownish-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18](=O)[NH:17][CH:16]=2)=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH2:29][CH3:30].O>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[CH2:28][CH2:29][CH3:30])=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CCCI
Reactant: N#Cc1cc(-c2ccc(=O)[nH]c2)c(-c2ccco2)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccncc1-c1cc(C#N)c(N)nc1-c1ccco1
Temperature: 70 °C
Reaction time: 18 h
Yield: 11.9 %

Procedure:
2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile (20 mg, 0.072 mmol) and potassium carbonate (30 mg, 0.22 mmol) were introduced into a reaction vessel, dissolved in N,N-dimethylformamide (1 mL). Propyl iodide (52 mg, 0.31 mmol) was added thereto, followed by stirring at 70° C. for 18 hours. After the reaction was finished, water was added thereto, and it was extracted with ethyl acetate. After removing the aqueous layer, the organic layer was concentrated and purified by high performance liquid chromatography, to give the title product as a yellow solid (2.6 mg, 11%; 1.8 mg, 7.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.N[C:18]1C(=O)NC(=S)N(CC2CCCCC2)C=1N.C(OCC)(OCC)OCC>[Pt].O1CCCC1.O.C(O)C>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][N:7]1[C:2]2[N:1]=[CH:18][NH:15][C:3]=2[C:4](=[O:14])[NH:5][C:6]1=[S:13]
Reactant: Nc1c(N)n(CC2CCCCC2)c(=S)[nH]c1=O
Reactant: COCCCn1c(N)c(N=O)c(=O)[nH]c1=S
Agent: [Pt]
Solvent: O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: COCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Reaction time: 2 h
Yield: 6.2 %

Procedure:
Platinum on carbon (0.5 g) was added to a solution of the crude 6-amino-1-(3-methoxypropyl)-5-nitroso 2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.80 g, 7.38 mmol) in tetrahydrofuran (80 mL) and water (20 mL) and the reaction mixture was hydrogenated at atmospheric pressure for 2 h. The catalyst was filtered off and the pale brown filtrate was co-evaporated with ethanol (250 mL). The resulting brown solid, 1.6 g, was used in the next step without further purification. 5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.6 g, 12.2 mmol) was dissolved in ethanol (10 mL) and triethyl orthoformate (10 mL) and the reaction mixture was refluxed for 2.5 h. The solvents were evaporated off and the resulting brown solid was purified by flash chromatography (heptane/ethyl acetate, 4:1-1:1) to give the title compound (110 mg, 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].P(Cl)(Cl)([Cl:18])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl

Procedure:
7-Chloro-6-nitro-quinazolin-4-one (1.002 g, 4.44mmol), phosphorous oxychloride (11.5 g, 7.51 mmol) and phosphorous pentachloride (1.62 g, 7.74 mmol) were refluxed for 2 hours and the reaction mixture was concentrated in vacuo to a residue which was triturated with toluene and then again with chloroform and dried in vacuo to afford crude 4,7-dichloro-6-nitro-quinazoline. This was dissolved in 35 mL of isopropyl alcohol and 3-ethynylaniline (639 mg, 5.45 mmol) and refluxed for 3 hours. The cooled reaction mixture was filtered to afford the title product as a solid which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 1.055 g (66%); mp 230.8°-232.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[H][H]>C1C=CC=CC=1.C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[NH2:19]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Agent: O=[Pt]=O
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Yield: 60.1 %

Procedure:
3-Chloro-4-(2-naphthyloxy)nitrobenzene (14.8 g) and platinum dioxide (0.1 g) were suspended in a mixture of benzene and ethanol (1:1) (200 ml), and hydrogenation was carried out until 3.2 liters of hydrogen were absorbed. After removal of the solvent from the reaction mixture by distillation under reduced pressure, the residue was distilled in vacuo to give 3-chloro-4-(2-naphthyloxy)aniline (8 g) as a fraction boiling at 173° to 198° C./0.2 to 0.3 mmHg. M.P., 67°-69° C.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17](O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: O=C(O)c1ccccc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3ccccc3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
1,3-dipropyl-5,6-diaminouracil (0.01 mol) was dissolved in 30 ml methanol, followed by 0.01 mol of benzoic acid and then 0.01 mol of DICD. The solution was stirred for 30 min at room temperature, filtered, and washed with a small amount of methanol. The solid was boiled for ten minutes in 2.5N KOH, filtered hot, and the liquid neutralized with concentrated HCl. The solid was collcted by filtration, washed with water, redissolved in 100 ml with a minimum amount of KOH, precipitated by neutralization with HCl, filtered, washed with water, and dried. The product was identified by chemical ionization mass spectrometry and elemental Analysis. Yield 77%.