Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])=[C:27]([O:45][CH3:46])[CH:26]=1.Cl>O.CN(C)C=O>[CH3:46][O:45][C:27]1[CH:26]=[C:25]([CH:44]=[CH:43][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:24][N:14]1[C:15]2[CH:3]=[CH:4][CH:5]=[C:6]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])[C:7]=2[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cn2c3ccccc3c3c(OC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
302 mg of sodium hydride (60%) was added to N,N-dimethylformamide (30 mL) solution of 924 mg of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid, stirred at room temperature for 20 minutes. Thereafter, 1.31 g of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, adjusted to pH3 with 1 N hydrochloric acid, and extracted twice with ethyl acetate. The combined extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (chloroform:methanol=50:1), and 1.88 g of the subject compound was prepared as pale yellow powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=4)[N:15]=[CH:14][CH:13]=3)=[CH:10][C:2]1=2.[CH3:25][C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC([N+]([O-])=O)=CC=2)[CH:27]=1.C(N(CC)CC)C>C1COCC1>[OH:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][C:9]3[CH:8]=[CH:7][C:3]4[N:4]([C:32]([NH:31][C:28]5[CH:27]=[C:26]([CH3:25])[O:30][N:29]=5)=[O:33])[CH2:5][CH2:6][O:1][C:2]=4[CH:10]=3)=[CH:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(Oc3ccc4c(c3)OCCN4)ccnc2cc1O
Reactant: Cc1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)no1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc4c(c3)OCCN4C(=O)Nc3cc(C)on3)ccnc2cc1O
Temperature: 50 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
A 25-mL round bottomed flask was charged with 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yloxy)-6-methoxyquinolin-7-ol (0.124 g, 0.38 mmol), 4-nitrophenyl 5-methylisoxazol-3-ylcarbamate (0.11 g, 0.40 mmol), and THF (5.0 mL). Triethylamine (0.160 mL, 1.1 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated and the residue was purified via column chromatography on silica gel (RediSep 40 g column, 100% ethyl acetate for 10 min, followed by 5% methanol/dichloromethane for 20 min) to afford 7-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-(5-methylisoxazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxamide (0.026 g, 15% yield) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 4 h
Yield: 19.7 %

Procedure:
Under a nitrogen atmosphere, 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 2.3 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (0.64 mL, 4.6 mmol) using mild heat and vigorous stirring. The solution was chilled in an ice-water bath and 4-morpholinecarbonyl chloride (0.27 mL, 2.3 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for an additional 4 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (25 mL). The phases were separated and the organic layer was washed with water (3×25 ml), brine (25 mL), dried (Na2SO4), filtered and concentrated to yield a yellow foam. The product was recrystallized from dichloromethane and ethyl acetate. The crystals were triturated with ether (2×5 mL) to remove residual solvent. The final product was dried in a vacuum oven to provide 200 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide as a tan crystalline solid, m.p. 164-166° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>N1C=CC=CC=1.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1)([O-:10])=[O:9]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1N1CCC2(CC1)OCCO2
Yield: 81.3 %

Procedure:
A solution of 2-fluoronitrobenzene (10 g, 70.9 mmol) and 1,4-dioxa-8-aza-spiro[4.5]decane (10 g, 69.8 mmol) in pyridine (70 mL) was heated at 70° C. for 1 day, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, and filtered. The solvent was removed under reduced pressure to give the title compound (15 g) as a red oil; 1H NMR (300 MHz, CDCl3) δ 1.88 (t, J=5.6 Hz, 4H), 3.16 (t, J=5.6 Hz, 4H), 4.00 (s, 4H), 7.03 (dd, J=8.2, 8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.40 (ddd, J=8.2, 8.2, 1.7 Hz, 1H), 7.77 (dd, J=8.4, 1.7Hz, 1H); MS (ES) m/z: 265.1 (MH+); HRMS Calcd. for C13H17N2O4 (MH+): 265.1188. Found: 265.1164.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)=[CH:21][CH:20]=1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccc(C(F)(F)F)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 29.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-trifluoromethylphenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 g, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 12 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (15 mg, 0.038 mmol) as a yellow solid. MS: [M+H]+=394.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([F:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[F:23][C:4]1[CH:3]=[C:2]([NH:1][CH3:24])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2F)CCN1C(=O)OC(C)(C)C
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(F)c1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-2-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D66) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to addition of sodium borohydride and for 24 h after addition. δH (CDCl3, 400 MHz) 7.11 (1H, t), 6.35 (1H, dd), 6.27 (1H, dd), 4.17 (1H, br.s), 3.78 (2H, m), 3.44 (2H, m), 3.07 (1H, td), 2.82 (3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.14 (1H, dd), 1.99 (1H, m), 1.44 (9H, s), 1.21 (3H, d).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[C:15]2C=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2O)=[C:9]([F:25])[CH:8]=1.Cl>N1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14](=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:5]=3[O:4][C:2]2=[O:3])=[C:9]([F:25])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(=O)n(-c3ccc(Cl)cc3F)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloroformate (0.1 mL, 1.2 mmole) was added dropwise to a stirred solution of compound 2a (0.295 g, 1 mmole) in dry pyridine (8 mL) at 0° C. The mixture was refluxed for 2 hr. After 16 hr stirring at room temperature, the pH of the reaction mixture was adjusted to pH=6 from 1 M HCl(aq). The resulting white mixture was cooled to obtain solid compound. The product was filtered off and recrystallized from hot ethanol. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[O:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:31]2[CH2:32][CH2:33][C:28]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (5 g), potassium carbonate (10 g) and N,N-dimethylformamide (50 mL), 1,4-dioxa-8-azaspiro[4.5]decane (5 g) was added and stirred overnight at 70° C. The reaction mixture was diluted with water (150 mL), and the precipitated solid was collected by filtration and washed with diethyl ether to give 8-(3-methoxy-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (7.86 g) as a light-yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11](=[N:2][OH:3])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: NO
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(=NO)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of hydroxylamine hydrochloride (10.2 g, 147 mmol) was added to a suspension of 4,4'-dinitrobenzophenone (19 g, 70 mmol) in 100 ml of ethanol. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, and the solid collected by filtration. Recrystallization from ethanol provided the title compound (14.0 g, 70%) as pale yellow crystals. mp 194° C.; 1H NMR (D6 -DMSO) 12.25 (s, 1H), 8.35 (d, 2H), 8.20 (d, 2H), 7.60 (d, 4H). 4,4'-Dinitrobenzophenone Oxime Boc-Asp(OcHex)-2-aminomethylphenylacetate
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8].C(OCC)C.[CH3:45][NH2:46]>C(Cl)Cl>[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34](=[O:36])[NH:46][CH3:45])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8]
Reactant: CN
Reactant: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)O)cc34)cc2OC)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)NC)cc34)cc2OC)cn1

Procedure:
Oxalyl chloride (0.142 ml) was added to a mixture of N-(1-ethylpyrazol-4-yl)-2-[4-(6-carboxyquinolin-4-yloxy)-2-methoxyphenyl]acetamide (0.15 g) and methylene chloride (6 ml) and the resultant mixture was stirred at ambient temperature for 10 minutes. Diethyl ether (10 ml) was added and the resultant precipitate was recovered and dried under vacuum. The material so obtained was suspended in methylene chloride and methylamine gas was passed into the suspension until a clear solution was obtained. The solvent was evaporated and the residue was purified by column chromatography on silica using a gradient of 100:0 to 19:1 of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.102 g); 1H NMR: (DMSOd6) 1.33 (t, 3H), 2.85 (d, 3H), 3.61 (s, 2H), 3.78 (s, 3H), 4.07 (q, 2H), 6.7 (d, 1H), 6.87 (m, 1H), 7.01 (d, 1H), 7.37 (d, 1H), 7.42 (s, 1H), 7.88 (s, 1H), 8.08 (d, 1H), 8.24 (m, 1H), 8.77 (d, 1H), 8.82 (q, 1H), 8.87 (d, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([NH:34][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: NCCc1ccccc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)NCCc3ccccc3)cc2)=C(C)C1=O
Yield: 65.5 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and phenethylamine (91 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (170 mg, 0.38 mmol, yield 65%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH3:64][N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1.O>ClCCl>[OH:48][CH:29]([CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44]([N:68]1[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]1)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH:27]([CH:12]1[O:13][C:14](=[O:26])[C:15]([O:24][CH3:25])=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]([CH3:22])[CH:20]([OH:21])[CH:3]([CH2:1][CH3:2])[CH:4]([OH:53])[CH:5]([CH3:52])[CH2:6][C:7]([CH3:51])=[CH:8][CH:9]=[CH:10][CH:11]1[O:49][CH3:50])[CH3:28]
Reactant: CN1CCNCC1
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCN(C)CC1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCN(C)CC1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min, N-methyl-piperazine (1.5 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated. The reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[CH:23]=[C:22]3[C:25]4[C:30]([CH:31]=[C:21]3[NH:20][C:19]=2[C:18]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]2)=[CH:29][CH:28]=[CH:27][CH:26]=4.[C:42](O[Na])(C)(C)C.CI>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[CH:23]=[C:22]3[C:25]4[C:30]([CH:31]=[C:21]3[N:20]([CH3:42])[C:19]=2[C:18]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]2)=[CH:29][CH:28]=[CH:27][CH:26]=4
Reactant: CC(C)(C)O[Na]
Reactant: c1ccc2cc(-c3c4ccccc4c(-c4ccc5ccccc5c4)c4[nH]c5cc6ccccc6c-5cc34)ccc2c1
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c2cc3ccccc3c-2cc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c21
Reaction time: 0.5 h

Procedure:
7.4 g (14.2 mmol) of 6,11-di(2-naphthyl)-12-H-12-aza-indeno[1,2-b]anthracene was dissolved with 70 ml of THF in a 250 ml flask, and 1.64 g (17.0 mmol) of t-BuONa was added thereto and then, 2.4 ml (17.0 mmol) of CH3I was slowly added thereto at room temperature. After 30 minutes, a solvent was removed to obtain a solid, and the solid was hot filtered twice using dichlorobenzene, and re-crystallized three times using dichlorobenzene. Then, the resultant solid was dried under reduced pressure, thereby producing 6,11-di(2-naphthyl)-12-methyl-12-aza indeno[1,2-b]anthracene (3.5 g, 46%) that was white yellow.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:42](=[O:43])[CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][CH3:33])[CH2:15][CH2:14]3)[N:10]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Fc1ccc(-c2nc(C3CCNCC3)n(-c3ncccn3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CC(=O)N1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of INTERMEDIATE 9 HCl salt (15.0 mg, 0.035 mmol) and triethylamine (22.9 mg, 0.23 mmol) in DMF (0.25 ml) was added (2-methoxyphenyl)acetic acid (7.8 mg, 0.045 mmol), followed by addition of HATU (17.2 mg, 0.045 mmol). After stirring at ambient temperature for 1.5 hour, the reaction mixture was quenched with 2 mL of a mixture of 1,4-dioxane and water (1:1). The mixture was purified by RP-HPLC (10 to 100% ACN/Water, both containing 0.1% TEA) to give the title compound as a white powder after lyophilization. LC-MS (m/z): 473.11 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([O:18]C)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].S(=O)(=O)(O)O>CC(C)=O.O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Temperature: 70 °C
Yield: 76.6 %

Procedure:
A solution of 6-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman (74.11 g, 266.25 mmol), and concentrated sulfuric acid (2.5 mL) in a mixture of acetone (375 mL) and water 300 mL) was added to a distillation apparatus and warmed at reflux. Distillant was collected until the still head temperature reached 92° C. (about 1.5 h). The slurry was allowed to cool to 70° C. and 240 mL of acetone was added. The resulting mixture was allowed to cool to ambient temperature and the solid that formed was collected filtration. The solid was recrystallized from acetone and dried in a vacuum oven at 60° C. to afford 53.9 g (76.7% yield) of the desired product as a tan solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH:24][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[CH3:23])=[CH:18][CH:17]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Product: COc1cccc2c(N[C@H](C)c3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 41. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and (R)-1-(4-chloro-phenyl)ethylamine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].F[C:24](F)(F)C(O)=O.C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCCC1.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:24][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: COc1nc2nc(OC3CCCC3)[nH]c(N)c-2n1
Agent: ClCCCCBr
Product: COc1nc2c(N)nc(OC3CCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclopentyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][OH:19])=[N:13][C:12]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:11]2.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([NH:20][C:12]2[N:13]=[C:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3[C:10]([CH:11]=2)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=3)=[N:22]1)(=[O:4])=[O:3]
Reactant: COc1ccc2c(CO)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
MsCl (1.0 g) in 20 mL CH2Cl2 was added slowly to a mixture of [6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-methanol (11.0 g) and Et3N (1.42 g) in 50 mL CH2Cl2 at 0° C. The reaction mixture was stirred at r.t. for 3 h, and then washed with saturated NaHCO3 (aq) and NaCl(aq). The organic layer was dried over Na2SO4, and concentrated to give the crude product.