Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CCC(CC)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (156 mg, 1.0 mmol) and dry DCM (10 ml) was added 4-methoxyphenyl chloroformate (190 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×20 ml) and water (3×20 ml) and dried (MgSO4). The organic solution was concentrated to yield an oil that was dissolved in a 0.5 N HCl solution (30 ml). The acidic solution was washed with diethyl ether (2×20 ml) and 4 N NaOH was added until pH 11. The resulting mixture was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried (MgSO4). The solvent was evaporated to give an oil that crystallized on standing. This afforded 185 mg (60%) of the title compound as a solid. M.p. 52–54° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O.C(O)C>O.Cl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:12]([C:18]([CH3:20])=[CH:17][C:16](=[O:21])[O:15]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(NCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Product: Cc1cc(=O)oc2cc(NCc3ccccc3)ccc12

Procedure:
7-Benzylamino-4-methylcoumarin was synthesized from 3-benzylaminophenol and ethyl acetoacetate by the usual Peckmann reaction (anhydrous zinc chloride, absolute ethanol). Recrystallization from ethanol gave flat needles, m.p. 174.5°-175.5° C. The fluorescence maximum in water was 455 nm (excited 355 nm), in 10-2N HCl 458 nm. 1H nmr (60 MHz, CDCl3), δ2.36 (s, 3H, C--CH3), 4.45 (d, 2H, --CH2NH--, J=~5.5 Hz, collapses to a singlet when D2O added), 4.7-5 (1H, NH), 6.03 (s, 1H, H3), 6.57 (d, 1H H8), 6.63 (dd, 1H, H6, J56 =~9 Hz, J68 =~2 Hz), 7.45 (s, 5H, C6H5), 7.45 (d, 1H, H5, J56 =~9 Hz).
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].Cl>O>[CH2:21]([NH:25][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCNC1=CCC(C)n2c1ncc(C(=O)O)c2=O
Reaction time: 72 h
Yield: 31 %

Procedure:
14.35 g. (0.05 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 100 ml. of anhydrous chloroform. To the solution 15.0 ml. (0.15 mole) of n-butyl amine are added. The reaction mixture is allowed to stand for 3 days at room temperature, whereafter 70 ml. of water are added. The pH-value of the aqueous layer is adjusted under vigorous stirring to 2 by adding 10% by W/V hydrochloric acid solution. The organic layer is separated and the aqueous layer is shaken out with 2×50 ml. of chloroform. The combined organic layers are dried above calcinated sodium sulfate, finally the solvent is distilled off at reduced pressure. The residue is crystallized from methanol. 4.3 g. (31%) of 9-(n-butyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained. Melting point: 13.5°-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]2=[O:16].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH2:17]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=2[O:1][C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[C:7]1=[O:16])[CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(O)c2c(c1)C(=O)N(CC(C)C)CC2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(CC(C)C)CC2
Temperature: 100 °C

Procedure:
A mixture of methyl 5-hydroxy-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (250 mg, 0.90 mmol), 4-fluorophenyl methyl sulfone (236 mg, 1.35 mmol), Cs2CO3 (441 mg, 1.35 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the ether (312 mg, 78%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.78 Hz, 6 H) 1.94-2.16 (m, 1 H) 2.94 (t, J=6.59 Hz, 2 H) 3.04-3.16 (m, 3 H) 3.41 (d, J=7.54 Hz, 2 H) 3.55 (t, J=6.59 Hz, 2 H) 3.87-4.01 (m, 3 H) 7.00-7.11 (m, 2 H) 7.80 (d, J=1.70 Hz, 1 H) 7.88-8.00 (m, 2H) 8.66 (d, J=1.51 Hz, 1 H); MS (ESI, pos): 432.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[S:29][CH:30]=[C:31]([P:41]([O:46][CH2:47][CH3:48])([O:43][CH2:44][CH3:45])=[O:42])[C:32]=1[P:33]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:34])CCC>C1COCC1.[Cu]Cl>[CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1[C:28]1[S:29][CH:30]=[C:31]([P:41]([O:43][CH2:44][CH3:45])([O:46][CH2:47][CH3:48])=[O:42])[C:32]=1[P:33]([O:35][CH2:36][CH3:37])([O:38][CH2:39][CH3:40])=[O:34])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1csc(I)c1P(=O)(OCC)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1csc(-c2scc(P(=O)(OCC)OCC)c2P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
In THF, 0.037 g (0.076 mmols) of the 2-iodo-3,4-bis(diethoxyphosphoryl)thiophene obtained in Example 4 and 0.049 g (0.076 mmols) of the 2-tributylstannyl-3,4-bis(diethoxyphosphoryl)thiophene obtained in Example 5 were dissolved, to which 0.009 g (0.091 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated and stirred for 4 hours under reflex. After the reaction, the reaction mixture was cooled down to room temperature and the resulting solid was removed by celite filtration. The filtrate was distilled off under reduced pressure to remove the solvent, and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1 to ethyl acetate:methanol=5:1) to obtain the specified substance in the form of a transparent oil at a yield of 0.049 g (yield: 91%).
Reaction SMILES: [C:1]([N:5]1[CH2:14][C:13]2[C:8](=[N:9][C:10](S(C)(=O)=O)=[N:11][CH:12]=2)[N:7]([CH3:19])[C:6]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23]([CH2:34][CH3:35])[CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:22]>>[C:1]([N:5]1[CH2:14][C:13]2[C:8](=[N:9][C:10]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:23]([CH2:34][CH3:35])[CH2:21][CH3:22])=[CH:33][CH:32]=3)=[N:11][CH:12]=2)[N:7]([CH3:19])[C:6]1=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(C(C)(C)C)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(C(C)(C)C)C3)cc1
Temperature: 180 °C
Yield: 19.8 %

Procedure:
A mixture of 250 ml (0.83 mmol) of 3-tert.butyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 600 mg (2.9 mmol) of 4-(2-(diethylamino)ethoxy)aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 30 ml of dichloromethane. The solution was washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered off and dried to give 70 mg (21%) of 3-tert.butyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Fc1ccc(I)c(Br)c1
Product: Fc1ccc(Sc2ccc(Cl)cc2)c(Br)c1

Procedure:
Prepared from 4-chloro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:2]([Cl:16])=[N:3][CH:4]=[N:5][C:6]=1[CH3:13]
Reactant: COC(=O)Cc1c(C)ncnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c(C)ncnc1Cl
Yield: 81.8 %

Procedure:
A suspension of methyl (4-hydroxy-6-methyl-5-pyrimidinyl)-acetate (116 g, 0.64 mol) in toluene (200 ml) and phosphorous oxychloride (94 ml, 1.0 mol) is refluxed for three hours. The solvent is removed under reduced pressure and the resulting oil is poured onto crushed ice with stirring. The pH is adjusted to 9 by adding potassium carbonate. Extraction with ether, drying and destillation under high vacuum gives methyl(4-chloro-6-methyl-5-pyrimidinyl)-acetate as a yellowish oil (105 g, 82 %). b.p./l torr 88°-91° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CCO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reaction time: 16 h
Yield: 127.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-1-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70° C. for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgSO4 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 m/z 309.0 (M+H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:28]1[N:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[N:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: Cc1cnc(Br)nc1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5-methyl-pyrimidine in dimethylsulfoxide at 100° C. in the presence of potassium carbonate. LC (method 4): tR=0.81 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([O:8][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
A solution of ethyl 3,5-dihydroxyphenylacetate (4.0 g, 20.39 mmol), benzyl bromide (4.85 ml, 6.97 g, 40.77 mmol, 2 eq) and 5.64 g (40.77 mmol, 2 eq) of K2CO3 in 100 ml of acetone is refluxed overnight. The mixture is concentrated in vacuo, then partitioned between EtOAc and H2O. The organics are dried (MgSO4) and concentrated in vacuo. This is then passed through a flash silica gel column that is slurry packed with hexanes and eluted with 10% EtOAc in hexanes. Concentration of desired fractions gives ethyl 3,5-dibenzyloxyphenylacetate which is confirmed by NMR and used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:21])[C:14]([OH:20])=[CH:15][N:16]2[CH3:19])=[CH:11][CH:10]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:20][C:14]1[C:13](=[O:21])[C:12]2[C:17](=[CH:18][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]([CH3:19])[CH:15]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(Cl)cc21

Procedure:
Triethylamine (3 ml) was added to a stirred mixture of 7-chloro-3-hydroxy-1-methyl-4-quinolone (2.31g), methanesulphonyl chloride (1.3 ml) and dichloromethane (70 ml) and the resultant solution stirred for 90 minutes. The solvent was removed by distillation and the residue crystallised from industrial methylated spirit (30 ml) and the solid triturated with diethyl ether (50 ml) to give the novel compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 157°-158°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]([CH2:36][OH:37])[CH2:38][CH:39]([CH3:40])[CH3:41])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)C[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (S)-2-bromo-N-(1-hydroxy-4-methylpentan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H25FN4O3S, 444.16; m/z found, 445.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.29 (d, J=1.4, 1H), 8.16-8.12 (m, 1H), 7.98-7.92 (m, 1H), 7.68-7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.40-7.28 (m, 3H), 3.41-3.34 (m, 1H), 3.29-3.22 (m, 2H), 1.59-1.47 (m, 1H), 1.35-1.17 (m, 2H), 0.81 (d, J=6.7, 3H), 0.73 (d, J=6.5, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(pyrrolidin-1-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H27N3O3
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:38]([C:34]2[O:33][CH:37]=[CH:36][CH:35]=2)=[O:39])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Reactant: O=C(Cl)c1ccco1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)c2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (25 mg, 0.057), 2-furancarbonyl chloride (5.8 μL, 0.059 mmol) and DIEA (49 μL, 0.282 mmol) was combined in anhydrous DMF (1.5 mL). After stirring under nitrogen at ambient temperature for 0.5 hrs, the reaction mixture was evaporated in vacuo and partitioned between EtOAc and 1N NaHSO4. The aqueous layer was separated and back-extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The product was crystallized from MeOH/Et2O and collected by filtration providing a white solid: ES+ MS: 537 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:27]([O-])([N+]([O-])=O)=[O:28]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:27]=[O:28])[C:5]([N:7]([CH2:19][CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 76.8 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-ethyl-3-D-glucopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-ethyl-3-D-glucopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)CCC.[OH-].[Na+]>[OH2:14].[CH3:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=3)=[CH:4][NH:5][C:6]=2[N:7]=1.[CH3:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=3)=[CH:4][NH:5][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: Cc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2n1

Procedure:
A mixture of 3.0 g of ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate (prepared according to U.S. Pat. No. 3,786,043) and 1.42 g of phenylhydrazine in 30 ml of n-butanol is refluxed for 18 hours. The mixture is chilled in an ice bath and filtered to give a solid which is taken up in 50 ml of 1N sodium hydroxide and sufficient water to dissolve. The resulting solution is filtered to remove insoluble, washed with ether and neutralized with 3.0 g of ammonium chloride. The resulting mixture is filtered collecting a solid which is washed with water and dried to yield 7-methyl-2-phenylpyrazolo[4,3-c][1,8]naphthyridin-3(5H)-one hemihydrate, m.p. 305°-308°.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([NH:15][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])[C:6]=1[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30]>CN(C=O)C.CC(OC)(C)C>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([NH:15][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])[C:6]=1[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30]
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COc1nc(Cl)c(-c2c(F)cc(F)cc2F)c(N[C@@H](C)C(F)(F)F)n1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
294 mg (1.30 mmol) of sodium methoxide (90% in methanol) were added to a solution of 282 mg (0.65 mmol) of sulfone 1 in 4 ml of anhydrous DMF. The mixture was stirred at 20-25° C. for 16 hours and then diluted with MTBE, washed with water and dried. Distillative removal of the solvent and chromatography on silica gel gave 0.14 g of the title compound of m.p. 121-129° C.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:29][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccc4ccccc4c3)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccc4ccccc4c3)c2c1

Procedure:
A mixed solution of 2.2 g of the above-mentioned 2-tert-butyl-9-(naphthalene-2-yl)anthracene, 3.7 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under nitrogen gas stream at room temperature for 1 hour. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-(naphthalene-2-yl)anthracene.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1Cl

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3,4-dichlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 370.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (s, 1H); 8.43 (d, J=5.0 Hz, 1H); 8.01 (br s, 1H); 7.85 (d, J=8.7 Hz, 1H); 7.52 (d, J=1.6 Hz, 1H); 7.25 (m, 1H); 6.87 (d, J=5.5 Hz, 1H); 6.00 (br s, 1H); 4.71 (d, H=6.0 Hz, 2H).