Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])C=CC=CC=1.[CH3:29][C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[C:38]=1[CH:39]=O>>[CH3:29][C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[C:38]=1[CH:39]=[CH:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: C[Si](C)(C)CCOC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc2ccccn2c1C=O
Agent: [Cl-]
Product: Cc1nc2ccccn2c1C=COCC[Si](C)(C)C
Yield: 96 %

Procedure:
Following procedures analogous to those described in Example 6 and use triphenyl-(2-trimethylsilanyl-ethoxymethyl)phosphonium chloride, 2-methyl-imidazo[1,2-a]pyridine-3-carbaldehyde was converted into 2-methyl-3-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-imidazo[1,2-a]pyridine (96% yield).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:14][C:13]3[CH:23]=[N:24][NH:25][C:12]=3[C:11]=2[CH:10]=1)=[O:6]>O.CO>[C:5]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:14][C:13]3[CH:23]=[N:24][NH:25][C:12]=3[C:11]=2[CH:10]=1)([OH:6])=[O:4]
Reactant: CCC(=O)N1Cc2cn[nH]c2-c2cc(OCC(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(=O)N1Cc2cn[nH]c2-c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
A solution of sodium hydroxide (0.32 g) in water (4 ml) was added to a mixture of 4,5-dihydro-8-methoxycarbonylmethoxy-5-propionyl-1H-pyrazolo-[4,3-c]quinoline (1.26 g) in methanol (20 ml). After being stirred at room temperature for 1.5 hours, the solution was evaporated in vacuo and the residue was dissolved in an aqueous solution of sodium bicarbonate. The solution was washed with ethyl acetate and acidified with 10% hydrochloric acid under ice cooling and stirring. The resulting precipitates were collected by filtration, washed with water, and recrystallized for methanol to give 8-carboxymethoxy-4,5-dihydro-5-propionyl-1H-pyrazolo[4,3-c]quinoline (1.05 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O.Cl(O)(=O)(=O)=O.N>>[CH3:8][C:9]1([CH3:11])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: CC(C)=O
Reactant: OCC(CO)CO
Agent: N
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC1(C)OCC(CO)CO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 85.8 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (4.09 g, 38.5 mmol), acetone (130 ml, 1768 mmol) and 70% perchloric acid (1.37 g, 9.55 mmol) was stirred at room temperature for 21 hours. After the pH of the reaction mixture was adjusted with concentrated aqueous ammonia to 9, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel: 100 g, elution solvent: heptane, heptane/ethyl acetate=1/3) to obtain the title compound (4.83 g, yield: 85.8%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:26][P:27]([O:31]CC)[O:28][CH2:29][CH3:30])[CH3:25]>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][P:27]([O:28][CH2:29][CH3:30])([O:26][CH2:24][CH3:25])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)c1ccccc1CBr
Product: CCOP(=O)(Cc1ccccc1C(=O)N1C(=O)CC[C@H]1C(=O)OC(C)(C)C)OCC
Temperature: 70 °C
Yield: 82.7 %

Procedure:
A mixture of (S)-1-(2-bromomethyl-benzoyl)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (898 mg, 2.4 mmol) and triethylphosphite (432 mg, 2.4 mmol) was heated at 70° C. for 4 h. After cooling, the residue was purified by flash chromatography (ethyl acetate) to afford the title compound as a clear viscous oil (872 mg, 84%): 1H NMR (400 MHz, CDCl3) δ 1.17 (3H, t, J 7.0 Hz), 1.26 (3H, t, J 7.0 Hz), 1.53 (9H, s), 2.07-2.14 (1H, m), 2.43-2.69 (3H, m), 3.12 (1H, dd, J 22.4, 15.0 Hz), 3.62 (1H, dd, J 22.1, 15.0 Hz), 3.84-4.06 (4H, m), 4.87 (1H, dd, J 8.9, 4.8 Hz), 7.31-7.46 (4H, m). Method L:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]([CH3:21])[C:16]([O:18]CC)=[O:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9]([CH3:14])([CH3:13])[CH:8]=[CH:7]2.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9]([CH3:14])([CH3:13])[CH:8]=[CH:7]2
Reactant: CCOC(=O)C(C)c1cc(Cl)c2c(c1)C=CC(C)(C)N2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1cc(Cl)c2c(c1)C=CC(C)(C)N2C
Yield: 84.4 %

Procedure:
3.0 g of ethyl 2-(8-chloro-1,2-dihydro-1,2,2-trimethylquinolin-6-yl)propionate (Compound 18) were added to a mixture of 40 ml of ethanol and 10% aqueous solution of sodium hydroxide. The solution was heated and refluxed for 4 hours. Ethanol was distilled off and the reaction mixture was diluted with water and washed with ether. The water layer was made weakly acidic by the addition of hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from hexane to give 2.3 g of 2-(8-chloro-1,2-dihydro-1,2,2-trimethylquinolin-6-yl)propionic acid (Compound 34).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33](Cl)[CH:32]=1>C(O)C.CN(C1C=CN=CC=1)C>[Cl:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:32]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Cl)c(C#N)cn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.00 g (10.9 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 7.59 mL (43.6 mmol) DIPEA were placed in 90 mL ethanol. 1.89 g (10.9 mmol) 4,6-dichloro-nicotinonitrile and 3 spatula tips of DMAP were added and the reaction mixture was stirred for 4 h at RT. The precipitated solid was suction filtered and dried.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)C.[CH2:23]1[CH2:29][S:26](=[O:28])(=[O:27])[O:25][CH2:24]1>C(OCC)C>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[CH:19][C:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][N:4]([CH2:24][CH2:23][CH2:29][S:26]([OH:28])(=[O:27])=[O:25])[CH2:3][CH2:2]2)=[CH:10][CH:11]=1)=[O:14])[CH3:17]
Reactant: O=S1(=O)CCCO1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CCN2CCN(CCCS(=O)(=O)O)CC2)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 10.25 g. (39 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate and 70 ml. anhydrous ethanol, there are added 4.76 g. (39 mmole) 1,3-propanesultone, followed by stirring at 20° C. After standing overnight, the ethanol is stripped off and the residue is treated with diethyl ether and ligroin. After suction filtration, it is recrystallised from ethanol to give 11.2 g. (75% of theory) of the desired compound; m.p. 235°-236° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][NH2:11])=[CH:4][C:3]=1[CH3:12].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][NH:11][C:20](=[O:22])[CH3:21])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(=O)Cl
Reactant: Cc1cc(CCN)cc(C)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cc(C)c(Br)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-(4-bromo-3,5-dimethylphenyl)ethanamine (100 mg) and triethylamine (68 μL) in dichloromethane (3 mL) is added acetyl chloride (31 μL). The mixture is stirred for 2 hours at 0° C. Then the mixture is partitioned between dichloromethane and water. The organic phase is separated and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 25 mg; LC (method 7): tR=0.98 min; Mass spectrum (ESI+): m/z=270 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].CS(C)=O.O[Li].O>O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:1][C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=2[C:7]#[N:8])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Cc1cc(C#N)c(N)s1
Agent: [Li]O
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])s1
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Stir in a 3 neck 500 mL round bottom flask, 2-amino-5-methyl-thiophene-3-carbonitrile (124.11 g, 0.898 mol, 1 eauiv.), 1,4-dichloro-2-nitro-benzene (174.15 g, 0.907 mol, 1.01 equiv), and DMSO (1.6 L, 13 vol)) for 15 min. (dark solution). Charge in one portion, LiOH H2O (75.37 g, 1.796 mol, 2 equiv). Began to exotherm from 20.4° C. to 25.5° C. over 10 minutes. After 30 minutes temp reaches 28.1° C. and at 1 hour 30.4° C. Place tap water in the bath around the flask to control the exotherm. Check HPLC at 23 h, which shows 81.2% of desired product. Let continue to stir at ambient temperature for greater reaction conversion. Check HPLC at 39 h, which shows 83.5% of one product. Let stir 40 hours total. Cool with ice/water bath to 17° C. Begin pH adjustment by slowly adding 1 N HCl (1020 mL) to reach pH=7.1. Keep exotherm is at 15-22° C. during the addition. Workup includes: pouring reaction mixture into 22 L bottom outlet flask, rinsing in with CH2Cl2 (5.6 L) and 5% LiCl solution (3.6 L), stirring about 10 min., and allowing layers to separate. The lower layer might be darker than upper layer. Back-extract the aqueous layer with CH2Cl2 (1.5 L). Combine organic layers and wash with 5% LiCl solution (3×1.3 L). Dry organic layer with Na2SO4 (800 g) allowing it to stir 1 hour, filter and evaporate to dryness. Wt.=376 g. Back-extract the combined aqueous layers with CH2Cl2 (0.5 L). Check aq layer by HPLC ˜2 mL aq layer in 15 mL of eluent for product in aq layer. Wash the organic phase with brine (2×500 mL) and finally with 5% LiCl (500 mL). Dry over the weekend with NaSO4 (80 g). Filter and add to other organic layer. For Chromatography, dissolve crude material in methylene chloride (950 g) and charge to a silica gel 60 (2.8 kg pre wetted with heptane) bed on fritted funnel. Some product might crash out on top of silica cake. Rinse flask and add to top of cake with CH2Cl2 (0.3 L) until all of the precipitate is dissolve and onto the column. Elute with heptane (˜16 L), then 25% CH2Cl2 in heptane (˜8 L), then 37.5% CH2Cl2 in heptane (˜8 L), follow by 50% CH2Cl2 in heptane and 100% CH2Cl2. Early Fractions might contain no product. Identify mix fractions containing product and rundown separately until virtually all methylene chloride is gone leaving the product in heptane, cool to 0° C. and filter. Filtrate analysis shows 5% product by area % integration. Combine product only fractions and evaporate to dryness. Add cake from mixed fractions. Combined dry weight=197.4 g. HPLC area percent=97.0% NMR is consistent with desired procduct: Yield 74.8%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4].C(N(CC)CC)C.ClCCl.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O.Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH:11][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:10]=1)=[O:4]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cc2)c1
Yield: 101.4 %

Procedure:
5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (0.10 g, 2.49 mmol) and triethylamine (6.75 g, 7.47 mmol) were added to dichloromethane (40 mL) and stirred under nitrogen atmosphere. Isobutyryl chloride (0.318 g, 2.98 mmol) was added slowly, and the reaction mixture was stirred for 2.5 hours at room temperature. The mixture was diluted with water and 1N aqueous HCl, and the organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.786 g of 5-isobutyrylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[SH:10][C:11]1[N:15]=[CH:14]N[N:12]=1.N>ClCCl>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[CH:14]=[N:15][C:11]([S:10][Si:4]([CH3:7])([CH3:6])[CH3:5])=[N:12]1
Reactant: Sc1nc[nH]n1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Solvent: ClCCl
Product: C[Si](C)(C)Sc1ncn([Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 134.4 %

Procedure:
1-trimethylsilyl-3-trimethylsilylthio-1H-1,2,4-triazole was prepared by adding 29.2 ml (140 mmoles) of hexamethyldisilazane to a refluxing suspension of 9.70 g (96 mmoles) of 3-mercapto-1H-1,2,4-triazole and 100 mg (0.25 mmole) of di-4-nitrophenyl-N-(4-toluenesulfonyl)-phosphoramidate in 200 ml of dichloromethane and the calculated amount of ammonia was evolved after refluxing for 75 minutes. Refluxing was continued for 30 minutes and then the clear solution obtained was evaporated to dryness to obtain 23.1 g (98% yield) of 1-trimethylsilyl-3-trimethylsilylthio-1H-1,2,4-triazole melting at 90°-94° C.
Reaction SMILES: C=O.[CH3:3][C:4]1[C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17](N)[CH2:16][CH2:15]2)=[CH:11][C:10]([CH3:21])=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.[C:22]([BH3-])#[N:23].[Na+].[C:26](O)(=O)C>>[CH3:3][C:4]1[C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:23]([CH3:22])[CH3:26])[CH2:16][CH2:15]2)=[CH:11][C:10]([CH3:21])=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Cc1c(O[C@H]2CC[C@@H](N)CC2)cc(C)c2[nH]ncc12
Agent: C=O
Agent: [Na+]
Product: Cc1c(O[C@H]2CC[C@@H](N(C)C)CC2)cc(C)c2[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A 36% aqueous formalin solution (161 μl, 1.93 mmol) was added to a methanolic solution (2 ml) of the cis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.386 mmol) obtained in Example 658, and the resulting mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (51 mg, 0.771 mmol) and acetic acid (110 μl, 1.92 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 18 hours. The methanol was removed by the use of nitrogen gas and chloroform-1N-aqueous sodium hydroxide solution was added to the residue, followed by extraction with chloroform. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was purified by a preparative thin-layer silica gel chromatography (chloroform/methanol/aqueous ammonia=7:1:0.1) to obtain cis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine (77 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Yield: 7.7 %

Procedure:
A mixture of 7-amino-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (0.154 g, 0.49 mmol), acetic anhydride (0.14 mL, 1.5 mmol), triethylamine (0.14 mL, 1.0 mmol) and a catalytic amount of 4-(N,N-dimethylamino)pyridine are stirred under N2 at room temperature for 18 h. The reaction is then quenched by addition of ice water. The dark precipitate is collected by Buchner filtration and is purified by preparative tlc (Rf=0.25, 7% MeOH/CHCl3). Recrystallization from EtOH gives 7-acetylamino-4-(3-bromoanilino)pyrido[4,3-d]-pyrimidine (13.5 mg, 7.7). 1H NMR (DMSO) δ 10.92 (1H, s), 10.22 (1H, s), 9.64 (1H, s), 8.70 (1H, s), 8.28 (1H, s), 8.21 (1H, s), 7.88 (1H, d, J=7.7 Hz) 7.41-7.34 (3H, m), 2.16 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Reactant: OB(O)c1ccc(Cl)cc1
Product: Nc1c(C(=O)NC2CCC2)nnc2c(-c3ccc(Cl)cc3)cccc12
Yield: 70.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 4-chlorophenyl boronic acid (176 mg) were reacted to afford the title compound (112 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.31 (d, 1H), 8.43 (d, 1H), 7.86 (m, 1H), 7.79 (m, 1H), 7.73 (m, 2H), 7.54 (m, 2H), 4.52 (m, 1H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=353 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13]3=[C:14]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=N[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:12]3[C:11]3[CH:10]=[CH:9][C:8]([Cl:27])=[CH:7][C:6]=3[S:5]2)[CH:15]=1.[CH:28](=O)C1C=CC=CC=1>>[CH2:19]([C:17]1[C:16](=[O:26])[C:14]2[CH:15]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:13]=2[N:12]([CH:18]=1)[C:11]1[CH:10]=[CH:9][C:8]([Cl:27])=[CH:7][C:6]=1[S:5]3)[C:20]1[CH:21]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(Cl)cc13)Sc1cc(Cl)ccc1-2
Reactant: O=Cc1ccccc1
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(Cl)cc13)Sc1cc(Cl)ccc1-2
Yield: 60 %

Procedure:
According to Example 1<step 4>, the compound (30 mg) produced in Example 5<step 3 >was reacted with benzaldehyde (15 μl) to obtain the title compound (23 mg; 60%).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7](=[O:31])[C:6]=2[C:5]([OH:32])=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:43])[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[CH3:33][N:34]([CH3:43])[C:35]1[CH:42]=[CH:41][C:38]([CH:39]2[N:27]([CH2:26][CH2:25][NH:24][C:9]3[C:8]4[C:7](=[O:31])[C:6]5[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=5[OH:32])[C:14](=[O:16])[C:13]=4[C:12]([NH:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH:39]4[C:38]4[CH:41]=[CH:42][C:35]([N:34]([CH3:43])[CH3:33])=[CH:36][CH:37]=4)=[CH:11][CH:10]=3)[CH2:28][CH2:29][O:30]2)=[CH:37][CH:36]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C2OCCN2CCNc2ccc(NCCN3CCOC3c3ccc(N(C)C)cc3)c3c2C(=O)c2c(O)ccc(O)c2C3=O)cc1

Procedure:
A suspension of 3.11 g. of 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethylamino)ethyl]amino]anthraquinone [prepared as described in Example 1(A)] in 60 ml. of toluene containing 3.13 g. of p-dimethylaminobenzaldehyde is stirred and heated at reflux for 5 hours by the procedure of Example 1(B). The hot reaction solution is filtered and is allowed to stand for several days. The crystallized product is collected by filtration and washed with toluene to yield 4.34 g. of the product of the Example as dark-blue crystals, m.p. 150°-154° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[N:35]=[C:36]=[O:37].O>CN(C)C=O.C(OCC)(=O)C>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[NH:35][C:36]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:37]
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)Nc4ccc(F)cc4F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
After dissolving 4-(1H-indol-5-yloxy)-6,7-dimethoxyquinoline (40 mg, 0.1249 mmol, described in WO9717329) in N,N-dimethylformamide (0.7 ml), sodium hydride (10 mg,) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Difluorophenyl isocyanate (0.018 ml, 0.1561 mmol) was further added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the filtrate was distilled off under reduced pressure. The obtained crystals were suspended in diethyl ether:ethanol=10:1 and diluted with hexane, and then the crystals were filtered out, washed with diethyl ether:ethanol=10:1 and dried by aspiration to obtain the title compound (35 mg, 0.0736 mmol, 58.94%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(O)(C(F)(F)F)=O.O=[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[CH:21]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Nc2cnc3ccccc3c2)c(C(=O)O)c1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc3c(c2)CCCC3)c(C(=O)O)c1
Yield: 0.1 %

Procedure:
A solution of 5-methyl-2-(quinolin-3-ylamino)benzoic acid (Example 16) (1.08 mmol, 0.30 g) in TFA (2.5 ml) was hydrogenated under pressure (58 psi) with PtO2 (0.11 mmol, 0.028 g) as catalyst until all starting material disappeared. After that the reaction mixture was filtered, concentrated and redissolved in water. The pH was adjusted to 4-5 by addition of 2N NaOH and a solid was formed. This yellow solid formed was the desired compound (0.249 mg, 79% of yield).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([O:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[C:11]=1[OH:17])[CH:7]=[CH2:8].[C:18]([O-])(O)=[O:19].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:6]([O:9][C:10]1[CH:16]=[CH:15][C:14]([CH:18]=[O:19])=[C:12]([OH:13])[C:11]=1[OH:17])[CH:7]=[CH2:8]
Reactant: C=CCOc1cccc(O)c1O
Reactant: O=C([O-])O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(C=O)c(O)c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tin tetrachloride (0.31 g, 0.14 mL, 1.32 mmol) was added to a solution of 39 (0.20 g, 1.20 mmol) and αα′-dichloromethyl methyl ether (0.15 g, 0.12 mL, 1.32 mmol) in CH2Cl2 at −78° C. The pale brown reaction mixture was stirred at this temperature for 1.5 h, then poured into an excess of saturated NaHCO3 aq. cooled at 0° C. The mixture was stirred for 15 min, acidified to pH 5 by the addition of 5% w/v citric acid then extracted with CH2Cl2 (3×). The organic phase was dried (Na2SO4) and evaporated to dryness to give 40 compound (0.18 g, 76%) which was used as such in the next step.