Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=[O:31]>>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:31])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CS(C)=O
Reactant: COc1cc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc(OC)c1OC
Product: COc1cc(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)cc(OC)c1OC
Reaction time: 24 h
Yield: 33.4 %

Procedure:
A light brown solution of 3-(cyclopentylamino)-2-(3,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (330 mg, 0.865 mmol) in DMSO (100 mL) was stored for 60 days at RT. Within one day, it became a light brown solution and no precipitation was observed during these 60 days. Then, it was poured into water (1 L) and the resulting precipitate was extracted into EA (2×75 mL). The combined extracts were washed with water, brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude solid which was purified using an ISCO (40 g) column chromatography eluting with 0-70% EA in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 115 mg (33.4%) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(3,4,5-trimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as alight yellow solid. 1H NMR (400 MHz, DMSO-d6): 1.50-1.80 (br m, 8H), 3.67 (p, 1H), 3.79 (s, 3H), 3.81 (s, 6H), 7.06 (s, 2H), 7.7 (s, 1H), 8.12 (br s, 2H). LC/MS calcd. for C20H23N5O4 (m/e) 397.433, obsd. 398.3 (M+H, ES+).
Reaction SMILES: [N+:1]([C:4]1[O:19][C:7]([CH:8]=[C:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[NH:10][C:9]2=[CH:8][C:7]2[O:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Nc1cccc2c1=NC(=Cc1ccc([N+](=O)[O-])o1)N=2
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1cccc2c1NC(=Cc1ccc([N+](=O)[O-])o1)N2C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 78.4 %

Procedure:
51.2 g (0.2 moles) 2-(5-nitro-furfurylidene)-amino-benzimidazole are stirred in a mixture of 120 ml of chloroform and 80 ml of dimethylformamide, whereupon 37.6 g (0.2 moles) of powdered 3.4-dichlorophenyl-isocyanate are added. The crystalline reaction mixture is stirred at room temperature for 7 hours while a mixture of 40 ml of dimethylformamide and 60 ml of chloroform are added. The precipitated crystals are filtered off, washed with 100 ml of chloroform and dried in vacuo at 40° C. to 60° C. Thus 70 g of 1-(3',4'-dichlorophenyl-carbamoyl)-2-(5-nitro-furfurylidene)-amino-benzimidazole are obtained. Mp.: 202°-204° C.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].[H-].[Na+].S(O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)[CH:25]=1)(=O)(=O)C.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[Cl:1]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:25]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: CCN(C/C=C/Cl)Cc1cccc(O)c1
Reactant: CS(=O)(=O)OCc1cccc(-c2ccsc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C/C=C/Cl)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of 280 mg (1.24 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-hydroxybenzyiamine in 2.5 ml of tetrahydrofuran was added 74.4 mg (1.86 mmol) of 60% oily sodium hydride under ice cooling. The mixture was stirred for 20 minutes at room temperature, ice-cooled, treated with a solution of 333 mg (1.24 mmol) of 3-(3-thienyl)benzyl mesylate in 2.5 ml of dimethylformamide, and stirred for 1.5 hours at room temperature. The reaction mixture was poured into 40 ml of ethyl acetate, washed with 20 ml×2 of water and 20 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 460 mg (yield: 93%) of the above identified compound as an oil.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:5][CH:6]=[CH2:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[OH:17][CH2:16][C:15]1[CH:20]=[CH:21][C:12]([S:9]([N:8]([C@@H:4]([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:2])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: C=CC[C@@H](C(=O)OC)N(CCCCC)S(=O)(=O)c1ccc(C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](CO)N(CCCCC)S(=O)(=O)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a stirred solution of the material from Step 1 (2 g, 5.03 mmol) in THF (33.5 mL) at 0° C. was slowly added 1.0 M lithium aluminum hydride (10 mL, 10.06 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. Water (383 μL) was carefully added, followed by the slow addition of 15% NaOH (383 μL) and water (1.2 mL). The reaction mixture was vigorously stirred for 10 minutes. It was filtered through celite and washed with ether and EtOAc. The filtrate was concentrated in vacuo to afford 1.7 g of the title compound which was directly used at Step 2. LCMS (M+Na)=364.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][CH:8]([F:19])[C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1>C1COCC1>[F:7][CH:8]([F:19])[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(C(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(C(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of LAH (1.0 M in THF, 31 mL, 31 mmol) was added dropwise to a solution of Example 38A (5.82 g, 31.3 mmol) in THF (100 mL) at 0° C. The reaction was stirred for 1 hr, then quenched by careful addition of solid Na2SO4.10H2O. The mixture was warmed to ambient temperature and stirred 30 min. Celite filter aid was added and the mixture was filtered. The filtrate was concentrated in vacuo to yield 4.02 g (81%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.52 (d, J=8.2, 2H), 7.48-7.41 (m, 2H), 7.00 (t, J=56.0, 1H), 5.30 (t, J=5.7, 1H), 4.55 (d, J=5.4, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:17].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:17][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]
Reactant: COc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccnc(Nc2ccc(Cl)c(OCC=C(C)C)c2)n1
Yield: 51 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-5-(4-methoxypyrimidin-2-ylamino)phenol (54 mg, 0.22 mmol) and Cs2CO3 (70 mg, 0.22 mmol) in acetone (3 mL) was treated with 4-bromo-2-methyl-2-butene (25 μL, 0.22 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 51% yield (35 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C.C(N(CC)C(C)C)(C)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:32])=[O:33]
Reactant: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc(Cl)c(S(C)(=O)=O)c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (250 mg, 0.88 mmol) and 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanamine (300 mg, 1.28 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (700 μL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[Na].[CH2:16]([OH:19])[CH2:17][CH3:18]>CN(C=O)C>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:19][CH2:16][CH2:17][CH3:18])[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCCO
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a solution of 2,6-dinitrobenzonitrile (6 g, 31.07 mmol) in dry DMF (45 mL) at 0° C., was added a solution of sodium (815 mg, 35.42 mmol) in n-propanol (23.5 mL) dropwise over 30 minutes. After compete addition, the reaction mixture was warmed to room temperature and stirred for 2.5 hours. The reaction was poured into an ice/water mixture (250 mL), and the precipitate was collected by filtration and dried to yield 2-nitro-6-propoxybenzonitrile (4.95 g, 77%) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 1.11 (d, J=7.5 Hz, 3H), 1.93 (sext, J=7.5 Hz, 2H), 4.14 (t, J=7.0 Hz, 2H), 7.31 (d, J=8.6 Hz, 1H), 7.69 (t, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[F:1][CH:2]([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccccc1C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1C(F)F
Yield: 91.7 %

Procedure:
A mixture of methyl 2-(difluoromethyl)benzoate 52 (7 g, 38 mmol) and 10% aq. NaOH (100 mL) in MeOH (50 mL) was heated at reflux for 30 min. The pH was adjusted to 4 by the addition of 3N HCl. The resulting solid was collected by filtration, rinsed with H2O and dried to give 53 (6 g, 93% yield).
Reaction SMILES: CC(S([NH:7][C:8]1([CH:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:19]=2)[CH2:13][CH3:14])[CH2:11][O:10][CH2:9]1)=O)(C)C.Cl.C(=O)([O-])O.[Na+]>CO.O1CCOCC1>[F:30][C:27]([F:28])([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:15]([CH:12]([C:8]3([NH2:7])[CH2:9][O:10][CH2:11]3)[CH2:13][CH3:14])[NH:16][CH:17]=2)=[CH:21][CH:22]=1
Reactant: CCC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(NS(=O)C(C)(C)C)COC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(N)COC1
Reaction time: 4 h
Yield: 44.7 %

Procedure:
To a solution of 2-methyl-N-[3-(1-{4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}-propyl)oxetan-3-yl]propane-2-sulfinamide (Preparation 10, 0.450 g, 1.01 mmol) in methanol (5 mL) at 0° C. was added 4M hydrogen chloride in 1,4-dioxane (1 mL) and the reaction left to stir for 4 hours. Solid sodium hydrogen carbonate was added to the reaction, followed by a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.154 g, 45% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](I)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43]([Si:45]([CH3:48])([CH3:47])[CH3:46])#[CH:44]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12]([C:44]#[C:43][Si:45]([CH3:48])([CH3:47])[CH3:46])=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(C#C[Si](C)(C)C)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (300 mg, 0.5 mmol), Cu(I)I (5 mg, 0.02 mmol), PdCl2(PPh3)2 (18 mg, 0.02 mmol), and triethylamine (0.3 mL, 2.5 mmol) were placed in THF (4 mL) and de-gassed under argon. Ethynyltrimethylsilane (0.2 mL, 1.5 mmol) was then added, and the reaction was stirred at room temperature overnight. The reaction was then concentrated to dryness to give the crude product tert-butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (280 mg, 98% yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([OH:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1.[CH3:22][C:23]([CH3:27])([CH3:26])[CH2:24]O>>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:22][C:23]([CH3:27])([CH3:26])[CH3:24])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CC(C)(C)CO
Reactant: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2O)cc1
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCC(C)(C)C)cc1

Procedure:
The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted with 2,2-dimethylpropanol to provide 2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the method of Example 90D.
Reaction SMILES: C[O:2][C:3](=[O:57])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:56])[C@@H:17]([NH:42][S:43]([C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:47]=2)(=[O:45])=[O:44])[CH2:18][CH2:19][CH2:20][NH:21]/[C:22](/[NH2:41])=[N:23]/[S:24]([C:27]2[C:28]([CH3:40])=[C:29]([CH3:39])[C:30]3[O:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]=3[C:37]=2[CH3:38])(=[O:26])=[O:25])[CH2:12][CH2:11]1)=[O:9].[Li+].[OH-]>C1COCC1.O>[NH2:41]/[C:22](/[NH:21][CH2:20][CH2:19][CH2:18][C@H:17]([NH:42][S:43]([C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)(=[O:45])=[O:44])[C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:57])=[O:2])[CH2:15][CH2:14]1)=[O:56])=[N:23]\[S:24]([C:27]1[C:28]([CH3:40])=[C:29]([CH3:39])[C:30]2[O:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]=2[C:37]=1[CH3:38])(=[O:25])=[O:26]
Reactant: COC(=O)CCCCC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NS(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(C(=O)CCCCC(=O)O)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of compound O (2.1 g, 2.08 mmol) in THF (5 mL), H2O (5 mL) was added 2 M aq LiOH (6 mL). The reaction mixture was stirred at room temperature for 2 h. Solvents were removed in vacuo, then the residue was dissolved in water (˜50 mL), acidified with saturated aqueous NaHSO4 (˜100 ml) and extracted with EtOAc (2×100 ml). The organic layer was dried over Na2SO4 and removal of the solvent gave compound P (1.72 g, 2.08 mmol). LC-MS [M+H] 813.5 (C39H52N6O9S2+H, calc: 813.3). Compound P was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccccc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
24.5 g of O-methylanisole and 20.0 g of succinic anhydride were dissolved in 230 ml of methylene chloride. Holding the temperature of the reaction solution below 5° C., 84 g of aluminum chloride were slowly added. After the addition was complete, the reaction mixture was stirred for 1 hour at a temperature below 5° C. and for an additional 5 hours at room temperature. It was then allowed to stand for one day and overnight at room temperature, after which the reaction mixture was poured into ice-cooled dilute hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed and then dissolved in ethanol. This solution was dried by azeotropic distillation and then evaporated to dryness. 4.16 g of the title compound were obtained as an oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9](OC)=[C:10]([CH2:14][C@H:15]([NH:29][C:30]([C:32]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)=[O:31])[B:16]2[O:24]C3C(C)(C4CC(C3)C4(C)C)[O:17]2)[CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:24][B:16]1[C@@H:15]([NH:29][C:30]([C:32]2([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)=[O:31])[CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([OH:5])=[O:7])[C:9]=2[O:17]1
Reactant: COc1c(C[C@H](NC(=O)C2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C(O)c1cccc2c1OB(O)[C@@H](NC(=O)C1(c3ccccc3)CCNCC1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
To a solution of the product from step 1 (460 mg, 0.64 mmol) in anhydrous CH2Cl2 (15 mL) at −78° C. was added BCl3 (5.0 mL, 1M in DCM, 5.0 mmol), and the reaction mixture was stirred at same temperature for 1 hr, at which time the reaction mixture was warmed up to 0° C. and stirred at same temperature for additional 1 hr. The reaction was quenched by addition of water (5 mL) at 0° C. After the phase separation, the product in aqueous phase was purified by reverse phase preparative HPLC [Phenomenex Luna, 5 μm, 30×75 mm, 5-100% AcCN:H2O (with 0.1% TFA)] and dried using lyophilization to afford the product (10 mg) as while solid. ESI-MS m/z 395 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Temperature: 110 °C
Reaction time: 36 h
Yield: 25.5 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol) in DMSO (3.0 mL) was added [6-(trifluoromethyl)pyridin-3-yl]boronic acid (0.078 g, 0.40 mmol), K2CO3 (0.112 g, 0.81 mmol) and tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol). The reaction mass was stirred at 110° C. for 24-48 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 4-5% EA:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.38-7.48 (m, 1H), 7.61-7.63 (m, 1H), 7.88-7.99 (m, 4H), 8.01-8.17 (m, 2H), 8.41 (d, J=7.8 Hz, 1H), 9.14 (s, 1H), 12.60 (br s, 1H). MS (m/z): 435.25 (M+H)+.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5](O)[C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O.[OH-].[NH4+]>CN(C)C=O>[Cl:17][C:12]1[C:13]2[N:1]=[CH:2][NH:3][C:4]=2[C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: Oc1nc2ccccc2c2[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2cccnc2c2[nH]cnc12

Procedure:
To a mixture of 7.7 g (0.0416 mole) of 1H-imidazo[4,5-c]quinolin-4-ol and 50 mL of N,N-dimethylformamide was added in small portions 12 mL (0.13 mole) of phosphorus oxychloride. The mixture was heated on a steam bath for 1.5 hour, poured onto ice and basified with concentrated ammonium hydroxide. The solid precipitate was separated by filtration, washed with water and dried to provide 4-chloro-1H-imidazo[4,5-]quinoline as a tan powder corresponding to the product of Example 18.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:7][CH:6]=1.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>C1C=CC=CC=1>[N:27]1([CH2:26][CH2:25][O:12][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([S:4][CH3:3])=[CH:6][CH:7]=2)[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1ccc(C(O)c2cccc3ccccc23)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CSc1ccc(C(OCCN2CCCCC2)c2cccc3ccccc23)cc1

Procedure:
To a suspension of sodium hydride (0.09 g, 3.84 mmol) in dry benzene (15 ml), (4-methylthiophenyl)-naphth-1-yl-carbinol (0.3 g, 1.07 mmol) was added. The contents were refluxed for 10 minutes and then N-[2-chloroethyl]-piperidine hydrochloride (0.4 g, 2.17 mmol) was added. The reaction mixture was refluxed for 24 hours and neutralized by ethyl alcohol and concentrated. The concentrate was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate and concentrated to give oil, which was purified by column chromatography on basic alumina by using benzene-hexane as eluent to yield the desired product.