Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].C(O)(=O)C.[N:50]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[NH:45]1[C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=[N:50]1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]nnc12
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (120 mg) were added acetic acid (47 mg) and water (0.5 ml) and the suspension was stirred at ambient temperature until a clear solution was obtained. After being cooled to 5° C. a cold solution of sodium nitrite (15 mg) in water (0.3 ml) was added all at once to the solution. The reaction mixture was stirred at 5° C. for 5 minutes and then the temperature was raised to 75° C. and stirred for 10 minutes. The reaction mixture was cooled to 20° C. and the solution was stirred in an ice water bath for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and chloroform and the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(1 H-benzotriazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (81 mg) to give a powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C([O:14][C:15]([N:17]1CC(=O)[CH2:18]1)=[O:16])(C)(C)C.O.Cl.[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[CH3:28][CH2:24][CH2:25][CH2:26][N:17]([C:15]([O:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: CCCCN(C)C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
4-Fluorophenyl magnesium bromide (6.0 mL, 1.0 solution in THF, 6 mmol) was added dropwise to a solution of 3-oxo-azetidine-1-carboxylic acid t-butyl ester (514 mg, 3 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for one hour. Water was added, and the mixture was acidified with 1 N HCl solution and then extracted with ether (2×30 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a light yellow oil. This material was fractionated using preparative. HPLC. Homogeneous fractions were combined and concentrated to give the intermediate carbamate a colorless oil, (564 mg, 70% yield).
Reaction SMILES: [CH2:1]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=O>>[CH2:1]([S:8](/[CH:11]=[CH:12]/[C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccccc1
Reactant: O=Cc1ccccc1Cl
Product: O=S(=O)(/C=C/c1ccccc1Cl)Cc1ccccc1
Yield: 72 %

Procedure:
A solution of benzyl sulfonylacetic acid (0.01 mol) and 2-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 72% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[N+:11]([C:14]1[CH:18]=[CH:17][NH:16][N:15]=1)([O-:13])=[O:12].C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH:17]=[CH:18][C:14]([N+:11]([O-:13])=[O:12])=[N:15]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc([N+](=O)[O-])n2)ccc1Br
Temperature: 95 °C
Yield: 60.5 %

Procedure:
A mixture of 1-bromo-4-iodo-2-methoxybenzene (3.99 g, 12.75 mmol), 3-nitro-1H-pyrazole (1.730 g, 15.30 mmol), Salicylaldoxime (0.350 g, 2.55 mmol), Cu2O (0.146 g, 1.020 mmol) and Cs2CO3 (6.23 g, 19.13 mmol) in DMF (13 mL) was degassed with N2 and heated at 95° C. overnight. After cooling to RT, the mixture was filtered through celite and rinsed with EtOAc. The filtrate was washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in 5% MeOH/DCM, and the precipitate filtered, rinsed with 5% MeOH/DCM, and dried to give 2.3 g of 1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole as a white solid. The filtrate from the above work up was purified by silica gel chromatography (EtOAc/Heptane=10:90 to 50:50) to give an additional 760 mg of 1-(4-bromo-3-methoxyphenyl)-3-nitro-1H-pyrazole as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14]C(O)=O)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])C=CC=CC=1.C1C=CC=CC=1.C([N:49]([CH2:52]C)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:49]=[C:52]=[O:31])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: Cn1c(CC(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cn1c(CN=C=O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C

Procedure:
To a mixture of 6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinoline acetic acid (Reference Example 9 Step 2) (330 mg), diphenylphosphoryl azide (0.29 ml) and benzene (20 ml) was added dropwise triethylamine (0.14 ml) while stirring at room temperature. This mixture was stirred for one hour at room temperature, then for 30 minutes by heating under reflux {in the reaction mixture, (6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl)methyl isocyanate was produced}, to which was then added 3-isopropoxyaniline (180 mg). The mixture was heated for 30 minutes under reflux. The solvent was distilled off. To the residue was added ethyl acetate. This mixture was washed with water, dilute hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried (Na2SO4), followed by distilling off the solvent to give the title compound as colorless crystals (390 mg). The physico-chemical data of this product were in agreement with those of the compound obtained in Method A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[N+:16]([O-])([OH:18])=[O:17].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([C:12]([F:13])([F:14])[F:15])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of the acetamide from step (a) above (8.46 g, 30 mmol) in concentrated sulfuric acid (32.5 mL) was added dropwise concentrated HNO3 (4.1 mL, 90%. J. T. Baker) with stirring at 0° C. The resulting solution was stirred at room temperature for 3 h and poured into crushed ice (80 mL). The mixture was carefully neutralized with solid NaHCO3 and extracted with EtOAc (3×200 mL).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][N:16]1[C:20]2([CH2:24][CH2:23][NH:22][CH2:21]2)[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][N:16]1[C:20]2([CH2:24][CH2:23][N:22]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=3)[CH2:21]2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCCC12CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(N2CCC3(CCCN3C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of 1.42 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 1.0 g of 1-methyl-1,7-diazaspiro[4,4]nonane and 1.48 g of potassium carbonate in 10 ml of DMSO is stirred at ambient temperature overnight. The mixture is diluted with 160 ml of water and extracted three times with 100 ml of ethyl acetate. The organic phases are dried over magnesium sulfate and concentrated under vacuum. The yellow oily residue is purified on silica, with an elution gradient with dichloromethane/methanol (100/0 then 90/10), so as to obtain 160 mg of 1-methyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in the form of an orangey-coloured oil.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[C:7]2[O:12][C:13]([CH3:17])([CH3:16])[O:14][CH2:15][C:6]=12.[H][H].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[C:22]([CH2:21][S:3][CH2:4][C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[C:7]2[O:12][C:13]([CH3:17])([CH3:16])[O:14][CH2:15][C:6]=12)([O:24][CH2:25][CH3:26])=[O:23]
Reactant: [H][H]
Reactant: CCOC(=O)CBr
Reactant: Cc1ncc(CS)c2c1OC(C)(C)OC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSCc1cnc(C)c2c1COC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.01 mole of sodium hydride in 50 ml. dry dimethylformamide under nitrogen at 0.5° is added dropwise a solution of 0.01 mole of 5-mercaptomethyl-2,2,8-trimethyl-4H-1,3-dioxino[4,5-C]pyridine in 10 ml. of dimethylformamide. When the evolution of hydrogen has ceased, 0.011 mole of ethyl bromoacetate is added. The reaction mixture is allowed to stir overnight at room temperature and then poured into a mixture of benzene-ice water. The organic layer is separated and washed well with water, dried and concentrated in vacuo. Chromatography on silica gel and elution with ether petroleum ether (10-75%) gives 5-carboethoxymethylthiomethyl-2,2,8-trimethyl-4H-1,3-dioxino[4,5-C]pyridine.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:11]=1[CH2:12][C:13](=[O:20])[CH2:14]2.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1.CCOCC>[O:20]([C:13]1[CH2:14][C:15]2[C:11]([CH:12]=1)=[C:10]([CH3:9])[CH:18]=[CH:17][C:16]=2[CH3:19])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(C)c2c1CC(=O)C2
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C)c2c1C=C(O[Si](C)(C)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyldimethylchlorosilane (2.85 g, 18.9 mmol) and 4,7-dimethyl-2-indanone (2.53 g, 15.8 mmol, obtained by oxidation of 4,7-dimethylindene) in benzene (30 mL) was added DBU (3.13 g, 20.5 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The mixture was diluted with Et2O (50 mL), washed with water (2×50 mL), 5% HCl (50 mL) water (2×50 mL) and dried over sodium sulphate. Evaporation of the solvents left a dark oil that was dissolved in pentane (30 mL). The unreacted starting materials were crystallized at −15° C. and removed by filtration. Evaporation of the solvent gave 3.03 g (69.9%) of fairly pure title compound as an orange oil. 1H NMR (CDCl3, δ): 6.94 (dq, 3J=7.7 Hz, 4J=0.3 Hz, 1H),; 6.78 (dq, 3J=7.7 Hz, 4J=0.3 Hz, 1H); 5.84 (t, 4J=1.1 Hz, 1H); 3.20 (m, 2H); 2.30 (s, 3H); 2.25 (s, 3H); 1.00 (s, 9H); 0.27 (s, 6H); 13C NMR (CDCl3, δ): 162.08; 143.39; 134.89; 129.45; 127.78; 125.49; 123.84; 105.28; 38.80; 25.65; 18.29; 18.21; −4.57.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]([CH:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)=[O:19]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Agent: Cl
Product: O=C(c1ccc(F)cc1F)C1CCNCC1
Yield: 85 %

Procedure:
1-acetyl-4-(2,4-difluorobenzoyl)piperidine (5.6 g, 20.9 mmol) is added to 19 ml of 6N Hydrochloric acid and reflux for 5 hours. The mixture is evaporated to dryness under reduced pressure. The residue is added 20 ml of isopropanol, stirred, filtered, and dried to obtain 4.67 g of a product, with a yield of 85%.
Reaction SMILES: C(OC1C=[C:11]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29]C(F)=CC=2)N=NC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:39][C:40]1[N:41]=[N:42][C:43](Cl)=[CH:44][C:45]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(CNC)CC1>>[CH2:47]([O:46][C:45]1[CH:44]=[C:43]([N:23]([CH2:24][CH:25]2[CH2:30][CH2:29]2)[CH3:11])[N:42]=[N:41][C:40]=1[O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1ccc(CNc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: CNCC1CC1
Product: CN(CC1CC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 17 %

Procedure:
Prepared as described for 5,6-bis(benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin-3-amine (Intermediate 45) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-cyclopropyl-N-methylmethanamine in 17% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:16]I.O>CO>[CH3:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccccc2)cc1

Procedure:
To a solution of 4-hydroxy-1,1'-biphenyl (34 g, 0.2 mol) and potassium hydroxide (20 g, 0.36 mol) in methanol (400 ml) and H20 (200 ml), methyl iodide (28.4 g, 0.2 mol) was added, and the resultant mixture was stirred for 4 hours under reflux. After cooling, the mixture was poured into H2O (1 l), the resultant precipitate was filtered, washed with H20 and recrystallized from ethanol to give the title compound as white crystals; yield;: 26.5 g; mp. 87.3°-87.7° C. ##STR41##
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][CH2:2][N+:17]2[CH:18]=[CH:19][C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=3[CH:16]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(C#CCCBr)cc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CC#N
Product: CCCCc1ccc(C#CCC[n+]2ccc3c(c2)CCCC3)cc1
Product: [Br-]
Yield: 68 %

Procedure:
1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solution of tetrahyroisoquinoline (2 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no tetrahyroisoquinoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (68%). 1HNMR (300 MHz, CDCl3, ppm), 9.30 (s, 1H), 9.04 (d, J=6.3, 2H), 7.62 (d, J=6.3, 1H), 7.18 (d, J=8.4, 2H), 7.06 (d, J=8.4, 2H), 5.10 (t, J=6.0, 3.21 (t, J=6.0, 2H), 2.94-2.96 (m, 2H), 2.56 (t, J=8.1, 2H), 1.81-1.87 (m, 2H), 1.49-1.56 (m, 2H), 1.27-1.34 (m, 2H), 0.89 (t, J=7.2, 3H); 13CNMR, 158.51, 144.59, 143.95, 140.93, 138.61, 131.55, 128.71, 127.57, 119.46, 85.97, 83.23, 59.58, 35.86, 33.69, 31.01, 26.70, 23.12, 22.63, 21.37, 14.28.
Reaction SMILES: OC[C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](CNC)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[C:20]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:20][C:11]1[C:16]2[C:15](=[CH:10][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: CNCc1c2ccccc2c(CO)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc2cc3ccccc3cc12
Yield: 103.4 %

Procedure:
10-(hydroxymethyl)-9-((methylamino)methyl)anthracene (0.800 g, 3.18 mmol) and K2CO3 (0.56 g, 4.05 mmol) were taken up in 15 mL acetonitrile. A solution of 2,2-dimethylpropane-1,3-diyl(o-(bromomethyl)phenyl)boronate 3 (1.00 g, 3.44 mmol) in 5 mL acetonitrile was added and the mixture was refluxed under nitrogen for 24 h. The mixture was filtered hot on a sintered-glass frit and upon cooling, a yellow solid precipitated. The resulting solid was triturated with acetonitrile/water (4:1, v/v), filtered on a sintered-glass frit and vacuum dried to yield 11 as a bright yellow solid (0.632 g, 51.6% yield): 1H NMR (300.13 MHz, CD3OD) δ 2.58 (s, 3H), 4.58 (s, 2H), 5.22 (s, 2H), 5.61 (s, 2H), 7.62 (m, 6H), 7.80 (m, 2H), 8.18 (m, 2H), 8.58 (m, 2H); 13C—{1H} NMR (75.4 MHz, CD3OD) δ 136.9, 136.2, 135.9, 132.9, 132.7, 131.4, 129.9, 128.3, 127.1, 126.8, 126.5, 124.9, 124.1, 63.8, 57.1, 50.9, 40.7.
Reaction SMILES: Cl.[C:2]1([CH3:17])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[C:11]([CH3:16])=[N:12][NH:13][C:14]=1[NH2:15].[C:18]([C:20](=[C:26](OCC)[CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>CO>[NH2:19][C:18]1[N:13]2[N:12]=[C:11]([CH3:16])[C:10]([C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:17])=[C:14]2[N:15]=[C:26]([CH3:27])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1N
Yield: 20.4 %

Procedure:
Concentrated hydrochloric acid (0.1 mL) was added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (2.5 g, 11.61 mmol) and ethyl 2-cyano-3-ethoxy-2-butenoate (2.13 g, 11.61 mmol) in methanol (30 mL), followed by heating under reflux for 18 hours. The reaction mixture was evaporated as it was. Then, water was added and a 5N aqueous solution of sodium hydroxide was added under ice-cooling, to neutralize. Further, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane), to give the title compound (835 mg).
Reaction SMILES: [N:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[C:19]([NH2:24])[C:18]3[N:25]=[C:26]([CH2:31][O:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[C:17]=3[C:16]=2[CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[ClH:9].[NH2:24][C:19]1[C:18]2[N:25]=[C:26]([CH2:31][O:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[C:17]=2[C:16]2[CH:15]=[C:14]([O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCN)cc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNC(=O)N4CCOCC4)cc3c21
Product: Cl
Yield: 25 %

Procedure:
4-Morpholinecarbonyl chloride (0.177 mL, 1.52 mmol) was added dropwise to a solution of 8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.46 mmol) in dichloromethane, and the reaction was stirred for ten minutes. Triethylamine (0.418 mL, 3.00 mmol) was then added, and the reaction was stirred for 16 hours. Aqueous sodium hydroxide (50%) was added, and the mixture was stirred for 30 minutes and then diluted with dichloromethane (100 mL). The organic layer was separated, washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was then treated with concentrated hydrochloric acid and water. A precipitate formed and was isolated by filtration, washed with water and diethyl ether, and dried in a vacuum oven at 60° C. to provide 0.180 g of N-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)morpholine-4-carboxamide hydrochloride as a white solid, mp 200-202° C. 1H NMR (300 MHz, DMSO-d6) δ 13.47 (s, 1H), 8.71 (bs, 2H), 7.79 (d, J=9.4 Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.40 (dd, J=9.3, 2.5 Hz, 1H), 6.84 (t, J=5.4 Hz, 1H), 4.84 (s, 2H), 4.65 (t, J=7.8 Hz, 2H), 4.19 (t, J=6.1 Hz, 2H), 3.59 (q, J=7.0 Hz, 2H), 3.52 (t, J=4.7 Hz, 4H), 3.50-3.40 (m, 2H), 3.26 (t, J=4.9 Hz, 4H), 1.90 (sextet, J=7.4 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H), 1.03 (t, J=7.3 Hz, 3H);
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:16]=[CH:17][C:18]=2[Cl:19])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:29])[CH3:30])[CH:23]=3)[CH:16]=[CH:17][C:18]=1[Cl:19])[N:10]=2
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc(N)cn3)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(N)sc4n3)c2)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Potassium thiocyanate (1.33 g, 13.7 mmol) was suspended in acetic acid (30 mL), and the mixture was stirred at room m temperature for 10 min. N-{3-[(5-Aminopyridin-2-yl)oxy]-4-chlorophenyl}-3-(1-cyano-1-methylethyl)benzamide (1.40 g, 3.44 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (576 mg, 3.61 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL×2), water (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (1.58 g, 99%) as a yellow amorphous substance.