Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(COC)OC.B([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])(O)O.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([NH:26][C:20]1[CH:19]=[CH:24][C:23]([CH3:25])=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(B(O)O)c1
Reactant: CSc1nccc(Cl)n1
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1nccc(-c2cc(C)ccc2NC(=O)C(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
A mixture of 16 g (0.1 mol) 4-chloro-2-(methylthio)pyrimidine, 0.150 g palladium bis(triphenylphosphine) dichloride, and 30 mL dimethoxyethane was stirred under nitrogen for 20 min, 25.8 g (0.11 mol) N-(2-borono-4-methyl phenyl)-2,2-dimethylpropanamide and a solution of 26 g sodium bicarbonate in 300 mL water was added, and the resulting mixture was heated to reflux for 5 h. After cooling to 50° C., 50 mL ethyl acetate was added and the reaction mixture was stirred until it reached room temperature. The reaction mixture was diluted with 300 mL ethyl acetate and washed successively with water and brine. The organic extracts were dried over magnesium sulfate, faltered, and evaporated to dryness. The crude product was purified by chromatography on silica gel using 40:1 chlorobutane/ethyl acetate mixture as eluent to yield 25.2 g of the title compound as white crystals melting at 119°-20° C. 1H NMR (CDCl3): δ 1.28 (s,9H), 2.38 (s,3H), 2.60 (s,3H) 7.30-8.6 (5H), 11.3(s,1H,NH).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:46]1[S:50][C:49]([CH3:51])=[N:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@@H:11]2[CH2:10][O:9][C:3]2[C:2]([C:46]3[S:50][C:49]([CH3:51])=[N:48][CH:47]=3)=[CH:7][N:6]=[C:5]([CH3:8])[N:4]=2)=[N:15][CH:16]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Reactant: Cc1ncc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cnc(C)s2)nc1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-2-methylpyrimidine (MM3) (35 mg, 0.10 mmol), bis(pinacolato)diboron (27.9 mg, 0.11 mmol), potassium acetate (39 mg, 0.40 mmol) and PdCl2(dppf) (14.6 mg, 0.020 mmol) in dioxane (0.6 mL) under N2 was heated at 120° C. for 2 hours. A solution of 5-bromo-2-methyl-1,3-thiazole (26.7 mg, 0.15 mmol) in dioxane (0.2 mL) was added followed by aqueous cesium carbonate (2 M, 0.15 mL, 0.30 mmol). The resulting mixture was heated at 120° C. for 14 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white, gummy solid. 1H NMR (500 MHz, DMSO): δ 8.83 (s, 1 H), 8.20 (s, 1 H), 8.14 (d, J=2.9 Hz, 1 H), 7.31-7.25 (m, 2 H), 4.56 (dd, J=11.2, 6.9 Hz, 1 H), 4.37 (dd, J=11.2, 7.6 Hz, 1 H), 3.78 (s, 3 H), 2.62 (s, 3 H), 2.54 (s, 3 H), 2.22 (dt, J=8.6, 4.6 Hz, 1 H), 1.78 (s, 1 H), 1.24-1.18 (m, 1 H), 1.11-1.05 (m, 1 H); HRMS m/z (M+H) 369.1386 found, 369.1380 required.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[OH:31][C:27]1[C:28]([CH3:30])=[CH:29][C:24]([C:14]2([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:15]2=[O:23])=[CH:25][C:26]=1[CH3:39]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3ccccc3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.6 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.816 g, 1.36 mmol), phenylboronic acid (0.330 g, 2.71 mmol), copper (II) acetate (0.25 g, 1.36 mmol), triethylamine (0.38 mL, 2.71 mmol), 4 angstrom molecular sieves, and dichloromethane (20 mL). Stir at room temperature for 72 h under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound in (0.446 g, 0.655 mmol), Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.64 mL). Stir for 1 h. Add 1N aqueous HCl (10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers, and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.236 g (39%) of the title compound: mass spectrum (FAB): m/z=450(M+1); 1H NMR(DMSO-d6): δ8.24 (s, 2H), 7.58-7.54 (m, 2H), 7.48-7.41 (m, 3H), 7.32 (dd, 1H), 7.22 (td, 1H), 7.10 (td, 1H), 6.77 (d, 1H), 6.74 (s, 4H), 2.07 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]4[NH:27][N:26]=[CH:25][CH:24]=4)=[CH:18][C:17]=3[Cl:28])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:38][C:39]([OH:43])([C:41]#[CH:42])[CH3:40]>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[Cl:28][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:42]#[C:41][C:39]([OH:43])([CH3:40])[CH3:38])[CH:30]=[CH:29][C:5]=2[N:6]=1
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(O)C#Cc1ccc2nc(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)c3cc[nH]c(=O)c3c2c1
Temperature: 75 °C

Procedure:
A solution of 9-bromo-5-{[2,6-dichloro-4-(1H-pyrazol-5-yl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (125 mg, 0.25 mmol) in DMF (3 mL) was degassed with nitrogen. Triethylamine (0.07 ml, 0.50 mmol), 2-methylbut-3-yn-2-ol (42.0 mg, 0.499 mmol), Pd(Ph3P)4 (28.8 mg, 0.025 mmol) and copper(I) iodide (9.50 mg, 0.050 mmol) were added and the reaction was heated to 75° C. for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[N+](C1C=CC=CC=1)([O-])=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of 4-bromo-benzoyl chloride (3.3 g, 15 mmol) and AlCl3 (2.6 g, 20 mmol) in nitrobenzene (20 mL) was added a solution of methoxy-benzene (1.5 g, 14.5 mmol) in nitrobenzene (5 mL) slowly at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 16 h. The mixture was poured onto 150 mL ice-water solution and extracted with CH2Cl2 (5×100 mL). The combined organic layers were washed with water (2×100 mL) and brine (50 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by recrystallization from cyclohexane to yield the title product (4.0 g, 91%) as a solid; 1H NMR (500 MHz, CDCl3); δ3.90 (s, 3H), 6.97 (d, J=8.5, 2H), 7.63 (d, J=2.0, 4H), 7.79 (d, J=9.0, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:22][CH:21]=3)=[N:16][C:17]#[N:18])[N:8]=[C:7]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:6]=2[CH:43]=1.O.FC(F)(F)C(O)=[O:48]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14]/[C:15](/[NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[CH:22][CH:21]=3)=[N:16]/[C:17]([NH2:18])=[O:48])[N:8]=[C:7]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:6]=2[CH:43]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1C(=O)C(NC(=NC#N)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C(N/C(=N/C(N)=O)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 40.8 %

Procedure:
A mixture of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N″-cyano-N′-[4-(4-morpholinyl)-1-naphthalenyl]guanidine (EXAMPLE 10) (21.9 mg, 35.8 μmol), water (4.6 μL, 260 μmol) and trifluoroacetic acid (19.8 μL, 257 μmol) in THF (3 mL) was heated to reflux for 43 h. The reaction was concentrated in vacuo, and the residue was purified by reverse phase HPLC (gradient 20-70% CH3CN in H2O) to provide the title compound (0.0092 g, 35%) as its TFA salt. 1H-NMR (CD3OD): δ 8.37 (br s, 1H), 8.06 (br s, 1H), 7.75-7.41 (br m, 9H), 7.26 (br s, 1H), 7.04 (br s, 1H), 5.66 (br s, 1H), 4.00 (br s, 4H), 3.58 (br s, 3H), 3.17 (br s, 4H). HRMS calculated for (C32H29Cl2N7O3+H) (M+H)+: 630.1787. Found (ESI): 630.1800.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:24]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:28])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:24]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:28])[CH:16]=3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
A mixture of methyl 4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin 3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoate (50 mg, 0.10 mmol) and lithium hydroxide (13 mg, 0.31 mmol) in THF (10 mL) and H2O (10 mL) was stirred at 50° C. for 3 h. The mixture was diluted with EtOAc (100 mL), washed with HCl (2.0 M, 20 mL), brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the target product (50 mg) as oil which was used in the next step without further purification. LCMS (ESI) m/z: 466.1 [M+H]+.
Reaction SMILES: [CH:1](O)=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].CSC.B>C1COCC1.CO>[CH3:1][NH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=CO
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CC(=O)OC(C)=O
Product: CNc1cccc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of formic acid (106 mL) and acetic anhydride (53.0 mL) was stirred at room temperature for 1 h. Methyl 3-aminobenzoate (8.50 g, 56.2 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure to give a solid. The solid was dissolved in THF (50.0 mL) and this solution was cooled to 0° C. Borane dimethylsulfide (10.7 mL, 112 mmol) was added slowly and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then cooled to 0° C. and MeOH (10 mL) was added slowly. This mixture was stirred for 3 hours and then concentrated under reduced pressure to give the title compound, which was used without any further purification.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 41 mg, 1.03 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (247 mg, 1.02 mmol) in THF (4 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester (1.23 mmol, crude, prepared as in Example 69, step 4) in THF (3 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 30 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30%→50% EtOAc/CH2Cl2, gradient) afforded 122 mg (31%) of the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[CH3:16][C:17]1([CH3:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]1.O>ClCCl>[CH3:16][C:17]1([CH3:29])[CH2:18][CH2:19][C:20]([CH3:28])([CH3:27])[C:21]2[CH:22]=[C:23]([C:13](=[O:14])[CH2:12][C:9]3[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][CH:8]=3)[CH:24]=[CH:25][C:26]1=2
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Cc3ccc(Br)cc3)ccc21
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Aluminium trichloride (4.33 g, 32.5 mmol) and 4-bromophenylacetyl chloride (5.55 g, 23.2 mmol) are added successively at −30° C. to a solution of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.36 g, 23.2 mmol) in 300 ml of dichloromethane. The temperature is allowed to rise to 0° C. in 30 minutes, the reaction mixture is poured over 400 ml of a volume to volume mixture of ice and water and this is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated. The raw product is purified by crystallisation in hexane to obtain 5.69 g of a white solid, 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-oxo-2-ethyl]bromobenzene (yield=63%).
Reaction SMILES: C1(N=C=O)C2C(=CC=CC=2)C=CC=1.CN.NC(N)=O.C(CC(O)=O)#N.N([O-])=O.[Na+].NC1[N:36]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:35](=[O:47])[N:34](C)[C:33](=O)C=1.[H][H].NC1C(=O)N(C)C(=O)N(C2C3C(=CC=CC=3)C=CC=2)C=1N>>[CH3:33][NH:34][C:35]([NH:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)=[O:47]
Reactant: Cn1c(=O)cc(N)n(-c2cccc3ccccc23)c1=O
Reactant: [H][H]
Agent: CN
Agent: Cn1c(=O)c(N)c(N)n(-c2cccc3ccccc23)c1=O
Agent: N#CCC(=O)O
Product: CNC(=O)Nc1cccc2ccccc12

Procedure:
N-Methyl-N'-(1-naphthyl)urea was prepared preliminarily from 1-naphthyl isocyanate and methylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring in the obtained 6-amino-3-methyl-1-(1-naphthyl)uracil and then reduced with hydrogen gas to prepare 5,6-diamino-3-methyl-1-(1-naphthyl)uracil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1I)=[O:5])[CH3:2].[CH2:12]([Sn](CCCC)(CCCC)C#C)[CH2:13]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(OCC)(=O)C>CN1CCCC1=O.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:12]#[CH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncsc1I
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C#Cc1scnc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
4-Ethoxycarbonyl-5-iodothiazole (1.45 g) was dissolved in 25 ml of N-methyl-2-pyrrolidinone. Tri-n-butylethynyltin (1.78 ml), 143 mg of tri(2-furyl)phosphine, 143 mg of tris(dibenzylideneacetone)dipalladium(0), and 1.43 g of zinc chloride were added to the solution under an argon atmosphere, and the mixture was stirred at room temperature for 40 min. Brine and ethyl acetate were added to the reaction solution. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 750 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][CH:17]([CH3:19])[CH2:16][N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([CH:21]=[CH:20][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1
Reactant: C=Cc1ccncc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=Cc4ccncc4)cc3c21
Temperature: 100 °C
Yield: 65.1 %

Procedure:
Nitrogen was bubbled through a solution of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine (3.0 g, 9.4 mmol), 4-vinylpyridine (2.0 mL, 19 mmol), triphenylphosphine (246 mg, 0.94 mmol), and triethylamine (2.7 mL, 19 mmol) in acetonitrile (50 mL) for 15 minutes. Palladium (II) acetate (105 mg, 0.47 mmol) was added, and the reaction was heated at 100° C. for three days. The solvent was removed under reduced pressure, and the residue was adjusted to pH 2 with the addition of concentrated hydrochloric acid. Water was added, and the mixture was filtered through a layer of CELITE filter aid. Aqueous sodium carbonate (2 N) was added to the filtrate to adjust the solution to pH 10. The solution was then extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 95:5 to 80:20) to provide 2.1 g of 1-(2-methylpropyl)-8-(2-pyridin-4-ylvinyl)-1H-imidazo[4,5-c]-quinolin-4-amine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]([N:23]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:29]4[C:24]3=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:21][CH:22]=2)O1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.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>[Br:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:17][CH:18]=[C:19]([N:23]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[C:30]4[C:35]3=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Reactant: Brc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c1

Procedure:
Step3. 1,3-Dibromobenzene (16 g, 64.9 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole b(6.0 g, 11.6 mmol), potassium acetate (saturated solution of 6.6 g in water) and tetrakis(triphenylphosphine)palladium (0) (380 mg) are heated to reflux in 150 mL of toluene overnight under nitrogen atmosphere. After cooling down, evaporation and column chromatography 9-(3′-bromo-[1,1′-biphenyl]-3-yl)-9H-carbazole (5.8 g) is obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][CH:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ccnc23)c1F
Yield: 10.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine (Intermediate-25, 100 mg, 0.33 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 190 mg, 0.66 mmol), oxalyl chloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (128 mg, 0.99 mmol) in CH2Cl2 (6 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.35 (s, 1H), 8.73-8.71 (d, J=7.2 Hz, 1H), 8.52 (d, 1H), 8.17 (m, 2H), 7.71-7.62 (m, 4H), 7.48-7.36 (m, 3H), 7.14 (m, 1H), 4.31 (d, 2H), 1.14 (s, 9H); MS (m/z): 573.36 (M+H)+.