Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]3=[N:12][C:11]=2[C:25]#[C:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[C:47](Cl)(=[O:51])[O:48][CH2:49][CH3:50]>C1COCC1>[CH2:49]([O:48][C:47]([O:1][NH:2][C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:13]3=[N:12][C:11]=2[C:25]#[C:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][N:5]=1)=[O:51])[CH3:50]
Reactant: CCOC(=O)Cl
Reactant: N=C(NO)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)ONC(=N)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
A solution of compound 42a (0.16 g, 0.33 mmol), DIEA (0.17 g, 1.3 mmol) and ethyl carbonochloridate (0.10 g, 0.93 mmol) in THF (10 mL), was stirred at rt for 2 h. The reaction was then quenched with water (50 mL). The solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain compound 42b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H26N8O4: 563.2 (M+H). Found 563.2.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>>[CH2:1]([NH:13][C:17]([NH:16][CH2:14][CH3:15])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCN=C=O
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(=O)NCC
Temperature: 50 °C

Procedure:
Dodecylamine (370 g) was placed in 80/100° fraction petroleum ether (1.5 litre) and stirred in a flask fitted with a dipping thermometer, tap funnel and reflux condenser. A mixture of ethyl isocyanate (142 g) and petroleum ether (150 ml) was run in slowly whilst external cooling was applied to the flask. The temperature was allowed to reach but not exceed 50° C. The mixture was stirred for 1 hour after the addition was complete, maintaining the temperature at about 50° C. The reaction was then allowed to cool and the copious white precipitate (which had begun to separate as soon as the isocyanate addition commenced) was filtered off, pressed well and washed with about 300 ml petroleum ether. The white mass was dried in vacuum at 50° C. to give a quantitative yield (512 g) with a melting point of 84° to 87° C. The product was not subjected to any further purification before use.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC(F)(F)F)CC1
Yield: 72.6 %

Procedure:
tert-Butyl 4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate (0.908 g, 3.22 mmol) was added to a solution of borane-tetrahydrofuran complex (8 mmol) in tetrahydrofuran (24 mL) and the reaction mixture was heated at reflux for 2 h. After cooling, 2 N hydrochloric acid (4 mL) was carefully added and the reaction mixture was stirred until gas evolution ceased and then diluted with ethyl acetate (200 mL). Aqueous sodium hydroxide (0.2 M, 75 mL) was then added and the phases were separated. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography (eluting with 20% ethyl acetate in hexanes) to give tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (0.627 g, 73%) as a white solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:46]2[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:45])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:43])[CH3:42])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]2[NH:3][C:4](=[O:7])[O:5][N:53]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:45])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:42])[CH3:43])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogen carbonate (0.54 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.063 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.053 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A stirred mixture of (4-cyano-phenyl)boronic acid (0.220 g, 0.00150 mol), 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (0.2715 g, 0.00100 mol), triethylamine (0.418 mL, 0.0030 mol), tri(O-toluyl)phosphine (0.0191 g, 0.0000628 mol) and palladium(II)acetate (0.0067 g, 0.000030 mol) in dry dimethylformamide (4.0 mL) was heated at 105° C. under nitrogen for 2 hours and allowed to cool. For convenience, allowed to stand overnight. The mixture was diluted with diethyl ether, and the resulting suspension was filtered through Celite. The Celite and filtercake were washed with additional diethyl ether then dichloromethane. The filtrate and washings were combined and washed with 0.5 M aqueous hydrochloric acid, water, 3% aqueous ammonium hydroxide, water, and brine. The organics were dried (Na2SO4) and rotary evaporated. The residue was dissolved (chloroform) and chromatographed on silica gel (35 g, 230-400 mesh), eluting with hexanes-acetone (4:1, 30×30 mL) to give 0.172 g of 4-(4′-cyano-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 149-151° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH3:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:15][CH3:16])=[C:2]([F:1])[CH:11]=2)[C:6]([O:13][CH3:14])=[CH:7][N:8]=1
Reactant: COc1cc2c(OC)c[nH]c(=O)c2cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(OC)cnc(Cl)c2cc1F
Yield: 24.3 %

Procedure:
A solution of 7-fluoro-4,6-dimethoxyisoquinolin-1(2H)-one (7.6 g, 34.1 mmol) in POCl3 (50 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2 g, 24.3%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.88-7.85 (d, J=12 Hz, 1H), 7.75 (s, 1H), 7.54-7.52 (d, J=8 Hz, 1H), 4.05 (s, 3H); MS: MS m/z 242.0 (M++1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:15]=2[OH:33])=[CH:3][CH:2]=1.C(Cl)Cl.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>O>[C:44]([O:33][C:15]1[CH:16]=[CH:17][C:18]([C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:19][C:14]=1[C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1)(=[O:47])[CH:45]=[CH2:46]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(-c2cccc3c2oc2ccccc23)cc1-c1cccc2c1oc1ccccc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(-c2cccc3c2oc2ccccc23)cc1-c1cccc2c1oc1ccccc12
Reaction time: 0.5 h
Yield: 79 %

Procedure:
1.89 g of the thus obtained 2,4-bis(4-dibenzofuranyl)phenol is placed in a round bottom flask; 20 mL of methylene chloride is added to form a transparent solution; after ice cooling the flask, 0.54 g of triethylamine is added; 0.48 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=90/10 (volume ratio)) to concentrate a component having an Rf of 0.20, thereby obtaining 1.69 g (yield: 79%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.66 (dd=1.2 & 10.8 Hz, 1H), 5.98 (dd=10.8 & 17.2 Hz, 1H), 6.28 (dd=1.2 & 17.2 Hz, 1H), 7.34 to 7.38 (m, 2H), 7.41 to 7.46 (m, 4H), 7.51 to 7.61 (m, 4H), 7.66 to 7.68 (m, 1H), 7.95 to 7.98 (m, 4H), 7.99 to 8.00 (m, 1H), 8.05 to 8.06 (m, 1H)
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C=O.[C:13]([BH3-])#[N:14].[Na+].[C:17](O)(=O)C>CC#N>[CH3:17][N:14]([CH3:13])[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Nc1ccc2occc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc2occc2c1

Procedure:
To a stirred solution of 5-aminobenzo[b]furan in CH3CN is added 37% aqueous formaldehyde followed by sodium cyanoborohydride and glacial acetic acid to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[CH3:5].[H-].[Na+].ClC[CH2:34][O:35][CH3:36]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[N:9]([CH2:34][O:35][CH3:36])[C:8]=2[CH2:7]1)[CH3:5]
Reactant: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(C(=O)OC)S(=O)(=O)c1ccccc1)C2
Reaction time: 2 h

Procedure:
350 mg (0.81 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester (from example 3) in 10 mL of THF at 0° C., were treated with 39 mg (0.89 mmol, 1.1 eq) of NaH (55% in oil) portionwise within 30 min. 0.10 mL (1.22 mmol, 1.5 eq) of 1-chloro-2-methoxy-ethane was added and the ice bath removed. After 2 hours, the reaction was quenched by addition of aqueous NH4Cl sat., extracted with EtOAc and the organic phases dried over Na2SO4. Evaporation of the solvent afforded (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazol-2yl)-propionic acid methyl ester as yellow solid, MS: 493 (MNH4′). The crude material was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].C([Li:23])CCC>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH-:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[Li+:23]
Reactant: CC(C)C1=Cc2c(cccc2-c2ccccc2)C1
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1cc2c(-c3ccccc3)cccc2[cH-]1
Product: [Li+]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a toluene solution (25 ml) of 2-isopropyl-4-phenylindene (3.34 g, 14.25 mmol), in a glovebox filled with argon, was added n-butyl lithium (5.500 ml, 13.75 mmol). The mixture was stirred at room temperature overnight. The toluene was removed under reduced pressure. Hexane (20 ml) was added and removed under reduced pressure then added again (50 ml). The mixture was stirred for 1 h then filtered, washed with about 15 ml hexane and the filtrate dried under vacuum. The lithium indenide product (3.09 g) was obtained as an orange-brown powder. This material was stored in the glovebox until needed.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.C(N(CC)CC)C>CC#N>[NH2:24][C:19]1[N:20]=[C:21]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[CH2:11]2)[CH:22]=[C:17]([Cl:16])[N:18]=1
Reactant: O=C(NC1CCCCC1)[C@H]1CCCNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)NC3CCCCC3)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To (3S)—N-cyclohexyl-3-piperidinecarboxamide (446 mg, 2.12 mmol) in CH3CN (10 mL) was added 4,6-dichloro-2-pyrimidinamine (382 mg, 2.332 mmol) and triethylamine (0.591 mL, 4.24 mmol), and the reaction mixture was stirred overnight at 50° C. LCMS show no starting material after 3 hours. The reaction was concentrated, and 3 mL of EtOAc was added until solid dissolved. Then 15 mL of hexane was added and solid crashed out of the solution. The solid was isolated by filtration to afford the title compound (430 mg) as a white solid. LC-MS (ES) m/z=338 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1.[N+](C1C=C(O)C=CC=1)([O-])=O.[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38]>C1(C)C=CC=CC=1>[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH:17]=2)=[O:47])=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38]
Reactant: COc1cc2nccc(Oc3cccc([N+](=O)[O-])c3)c2cc1OC
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: O=[N+]([O-])c1cccc(O)c1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(=O)Nc2cccc(Oc3ccnc4cc(OC)c(OC)cc34)c2)cc1
Yield: 32 %

Procedure:
6,7-Dimethoxy-4-(3-aminophenoxy)quinoline (51 mg), which was obtained, analogously to Example 49, by reducing 6,7-dimethoxy-4-(3-nitrophenoxy)quinoline obtained in the same manner as described in Example 48, except that 3-nitrophenol was used in place of 4-nitrophenol, was dissolved in toluene (3 ml) with heat, 4-n-butylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 50 minutes. The resulting residue was purified by chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 26 mg of the title compound (yield: 32%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH:22]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:25][CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: COc1cccc(C=O)c1OCC1CCC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OCC1CCC1
Yield: 46.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-cyclobutylmethoxy-3-methoxybenzaldehyde (368 mg, 1.603 mmol) in the presence of sodium ethoxide (163 mg, 2.411 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 310 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.80-1.86 (m, 5H), 1.98-2.04 (m, 2H), 3.77 (s, 3H), 3.82 (d, J=6.9 Hz, 2H), 6.87-7.00 (m, 4H), 7.51 (d, J=7.5 Hz, 1H), 7.59 (d, J=7.8 Hz, 2H), 7.84 (d, J=7.8 Hz, 2H), 8.01 (d, J=4.8 Hz, 1H) 8.14 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 513.30 (M+H)+.
Reaction SMILES: C1([C:4]2[NH:5][C:6]3[C:11]([C:12](=[O:17])[C:13]=2[C:14]([OH:16])=[O:15])=[CH:10][C:9]([F:18])=[C:8]([N:19]2[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][CH2:20]2)[C:7]=3[C:31]([F:34])([F:33])[F:32])CC1.O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.Cl.C(N=C=N[CH2:50][CH2:51][CH2:52]N(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH3:5].[O:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][O:16][C:14]([C:13]2[C:12](=[O:17])[C:11]3[C:6](=[C:7]([C:31]([F:34])([F:32])[F:33])[C:8]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[C:9]([F:18])[CH:10]=3)[N:5]([CH:51]3[CH2:52][CH2:50]3)[CH:4]=2)=[O:15])[CH2:39][CH2:40]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1c(C2CC2)[nH]c2c(C(F)(F)F)c(N3CCN(c4ccccn4)CC3)c(F)cc2c1=O
Reactant: OCCN1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: N
Product: O=C(OCCN1CCOCC1)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCN(c4ccccn4)CC3)c(F)cc2c1=O
Reaction time: 168 h
Yield: 28 %
Yield: 96.9 %

Procedure:
To 5 ml of methylene chloride were added 100 mg (0.21 mmole) of 2-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7-[4-(2-pyridyl)piperazin-1-yl]quinoline-3-carboxylic acid, 0-055 g (0.42 mmole) of 4-(2-hydroxyethyl)morpholine, 0.045 g (0.37 mmole) of 4-dimethylaminopyridine and 0.091 g (0.48 mmole) of 1-ethyl-3-(3-dimethyaminopropyl)carbodiimide hydrochloride, the mixture was left to stand at room temperature for 7 days, and then the solvent was removed by evaporation under reduced pressure. The residue was applied to column chromatography (eluent; a chloroform:methanol:28% aqueous ammonia=40:9:1 mixed solution) to obtain 60 mg of 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7-[4-(2-pyridyl)piperazin-1-yl]quinoline-3-carboxylic acid 2-morpholinoethyl ester as pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:33]=1)[O:8][CH2:9][C@H:10]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1C=CC=CC=1)=[O:13])#[N:2].[C:35]([NH:38][C:39](=[CH2:44])[C:40]([O:42][CH3:43])=[O:41])(=[O:37])[CH3:36].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:35]([NH:38][C:39](=[CH:44][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][C:7]=1[O:8][CH2:9][C@H:10]([NH:22][C:23](=[O:32])[C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:40]([O:42][CH3:43])=[O:41])(=[O:37])[CH3:36]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: N#Cc1ccc(C(=O)N[C@@H](COc2cc(C#N)ccc2I)CC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C[C@H](COc1cc(C#N)ccc1C=C(NC(C)=O)C(=O)OC)NC(=O)c1ccc(C#N)cc1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
1.28 g (2.27 mmol) of benzyl (3R)-4-(5-cyano-2-iodophenoxy)-3-(4-cyanobenzoylamino)butanoate, 975 mg (6.81 mmol) of methyl 2-acetamidoacrylate, 415 mg (1.36 mmol) of tris(2-methylphenyl)phosphine, 0.95 ml (6.81 mmol) of triethylamine and 0.5 ml of dimethylformamide were dissolved in 8.0 ml of acetonitrile. 56 mg (0.23 mmol) of palladium acetate was added to the solution at room temperature, and they were stirred at 90° C. for 12 hours. The solvent was distilled off, and the residue was purified by the silica gel column chromatography (volume ratio of chloroform:methanol=30:1) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](C)([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[CH3:15]C(C1C=CC=C(O)C=1)=O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(C)(O)c1cccc(O)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CCCCCC(O)c1cccc(O)c1

Procedure:
1-(3-hydroxyphenyl)-1-methyl-1-pentanol (using 3-hydroxyphenyl methyl ketone in lieu of the aldehyde); and
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:32])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:32].[ClH:32].[Cl:32][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:24]=[C:23]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3cc(Cl)ccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Fc1ccccc1-c1nc(NC2CCNCC2)nc2ccc(Cl)cc12

Procedure:
A solution of 4-[6-chloro-4-(2-fluoro-phenyl)-quinazolin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.66 g, 1.44 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 356.9 [M+H]+.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC([C:23]([NH2:25])=[O:24])=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.[C:32]([O:36][C:37](=[O:69])[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:58](=[O:59])[C:57]4[C:52](=[CH:53][C:54]([O:61][CH3:62])=[C:55](Br)[CH:56]=4)[O:51][C:50]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:69])[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:58](=[O:59])[C:57]4[C:52](=[CH:53][C:54]([O:61][CH3:62])=[C:55]([C:23](=[O:24])[NH2:25])[CH:56]=4)[O:51][C:50]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1Br
Reactant: NC(=O)c1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C(N)=O
Yield: 37 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-4-oxo-2-phenyl-4H-chromene-7-carboxylic acid amide, {1-[4-(6-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (115 mg, 0.20 mmol) was reacted to give the title compound (40 mg, 37%). LCMS (Method B): RT=4.58 min, [M+H]+=541.