Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.Br[CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:27][CH2:28][OH:29])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: OCCBr
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(O)ccc3n2)Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(OCCO)ccc3n2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol (250 mg, 0.67 mmol, prepared in analogy to the one in Example 29), 2-bromo-ethanol (166.7 mg, 1.33 mmol), and potassium carbonate (277 mg, 2.01 mmol) in acetone (30 mL) was stirred at room temperature overnight and then refluxed for 12 hours. The reacting mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC to afford 230 mg of the desired product (yield was 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:11][CH3:12])[CH:3]=[CH:2]1.Cl.Cl.[CH3:15][N:16]1[CH2:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18](=[O:32])[CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:11]([CH3:12])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]2[CH:25]=[N:26][C:20]3[NH:19][C:18](=[O:32])[CH2:17][N:16]([CH3:15])[CH2:22][C:21]=3[CH:23]=2)[CH:3]=[CH:2]1
Reactant: CNCc1cccc2cc[nH]c12
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3cccc4cc[nH]c34)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of (1H-indol-7-ylmethyl)methylamine (103 mg, 0.6 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (160 mg, 0.5 mmol), HOBt (81 mg, 0.5 mmol) and diisopropylethylamine (0.41 mL, 2 mmol) in DMF (12 mL) was added EDC hydrochloride (114 mg, 0.6 mmol). The mixture was stirred overnight at room temperature. Water (75 mL) was added and the solution stirred for 1 hr. The precipitate was collected by filtration and triturated with hexanes to afford (E)-N-(1H-indol-7-ylmethyl)-N-methyl-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (155 mg, 79%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.78-11.23 (m, 1H), 10.34-10.30 (m, 1H), 8.54-8.45 (m, 1H), 8.14-8.00 (m, 1H), 7.64-7.27 (m, 4H), 6.99-6.75 (m, 2H), 6.47-6.45 (m, 1H), 5.10-4.82 (2×s, 2H), 3.79-3.71 (2×s, 2H), 3.42-3.38 (m, 2H), 3.15-2.95 (2×s, 3H), 2.36-2.31 (2×s, 3H); ESI MS m/z 390 [C22H23N5O2+H]+
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:4]2[CH:25]=[CH:26][S:27][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1.C1(C)C=CC=CC=1>[S:37]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:4]2[CH:25]=[CH:26][S:27][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccsc2c1=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccsc2c1=S
Temperature: 25 °C

Procedure:
Ethyl 4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4-dihydrothieno[3,2-c]pyridazine-3-carboxylate (37 mg, 0.097 mmol) suspended in dioxane (5 mL) and toluene (5 mL), placed into an oil bath preheated at 110° C. and treated with Lawesson's Reagent (39 mg, 0.097 mmol, 1 equiv) portionwise over 10 minutes. The mixture was heated for an additional 30 minutes, cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 25:75; hexanes:ethyl acetate), providing the titled compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=3)[CH:5]([C:16](O)=[O:17])[C:4]=2[CH:3]=1>C1COCC1>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=3)[CH:5]([CH2:16][OH:17])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(CO)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A solution of 2,7-dimethyl-9-fluorenecarboxylic acid (4.3 g, 18.0 mmol) in THF (100 mL) was charged with 1M THF solution of BH3 -THF complex (36.0 mL, 36.0 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature then quenched with water (100 mL) and HCl (3 mL). After addition of ethyl acetate (50 mL) the organic layer was separated and washed with 10% potassium carbonate solution, water, brine, dried over magnesium sulfate and evaporated to afford 2,7-dimethyl-9-fluorenemethanol (3.0 g, 74.4%).
Reaction SMILES: [C:1]([O:6]O)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:8]([O:14]CC)([CH2:11][CH2:12][CH3:13])([CH3:10])[CH3:9]>>[C:8]([O:14][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])([CH2:11][CH2:12][CH3:13])([CH3:9])[CH3:10]
Reactant: CCC(C)(C)OO
Reactant: CCCC(C)(C)OCC
Product: CCCC(C)(C)OOC(C)(C)CC

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([CH3:27])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: CC(C)(N)c1nccs1
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Product: COc1ccc(C(=O)NC(C)(C)c2nccs2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid and (Example 81 c) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=388.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@H:8]([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[O:17][CH3:18].CON(C)[C:22](=[O:25])[CH2:23][Cl:24]>C1COCC1>[Cl:24][CH2:23][C:22]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C@@H:8]([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[O:17][CH3:18])=[O:25]
Reactant: CCCCCC[C@H](OC)c1cccc(Br)c1OC
Reactant: CON(C)C(=O)CCl
Solvent: C1CCOC1
Product: CCCCCC[C@H](OC)c1cccc(C(=O)CCl)c1OC
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a THF solution of (5)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (9, 12.5 g) obtained in the second step was added dropwise a 2M isopropyl magnesium chloride THF solution (44 mL) under ice-cooling. After the reaction solution was stirred at 45° C. for 3 hours, N-methyloxy-N-methyl-2-chloroacetamide (10, 3.5 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and purified by silica gel chromatography to obtain (S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:17]SC1C(C2C=NC=CC=2)=NNC=1>>[CH2:1]([O:5][C:6]1[C:7]([C:11]2[CH2:12][N:13]([CH3:17])[CH2:14][CH2:15][CH:16]=2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c[nH]nc1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CCCCOc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 32C was converted to the title compound (33C), using the methodology described for the conversion of 21A to 22A (see Scheme 3).
Reaction SMILES: [C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])[CH2:13][CH:12]([NH:30]C(OC(C)(C)C)=O)[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])[CH2:13][CH:12]([NH2:30])[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)c1ccccn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, the solution was washed with diethyl ether, alkaline with saturated aqueous sodium bicarbonate,and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 886 mg of the titled compound (Yield: 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].I[CH3:14]>>[CH3:14][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CI
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Product: COC(=O)c1cc([N+](=O)[O-])cn1C
Yield: 89 %

Procedure:
Following the basic procedure of Example 25(d), by reacting 2.9 g (17 mmol) of methyl 4-nitro-2-pyrrolecarboxylate with 1.1 ml of iodomethane, 2.8 g (89%) of the expected compound of melting point 122°-124° C. were obtained.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[CH:8][C:7]([CH:18]=[O:19])=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[C:9]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[CH:8][C:7]([CH2:18][OH:19])=[CH:6][CH:5]=1
Reactant: Cc1cccc(C)c1-c1cc(C=O)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C)c1-c1cc(CO)ccc1F
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, tetrakistriphenylphosphine palladium was added to a mixture of 2-bromo-1,3-dimethylbenzene, 2-fluoro-5-formylphenyl boronic acid, a 1 M sodium carbonate aqueous solution, ethanol and toluene, followed by stirring at 80° C. for 8 hours to obtain 6-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde. Under cooling on an ice-methanol bath, sodium borohydride was added in small portions to an ethanol solution of the resulting 6-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde, and the reaction mixture was stirred at the same temperature for 1 hour to obtain (6-fluoro-2′,6′-dimethylbiphenyl-3-yl)methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2.[C-:21]#[N:22].[Na+].CCCCCC.CCOC(C)=O>C(#N)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>[CH3:11][C:9]1[CH:10]=[C:2]([C:21]#[N:22])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: [C-]#N
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 531.2 %

Procedure:
A mixture of 5-bromo-7-methyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.205 g, 0.59 mmol), Pd(PPh3)4 (0.070 g, 0.06 mmol), sodium cyanide (0.038 g, 0.8 mmol), and CuI (0.013 g, 0.07 mmol) in acetonitrile (3 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 7-methyl-1-oxo-2-(4-chloro-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (0.93 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.78 (s, 3H), 4.26 (s, 2H), 4.65 (s, 2H), 7.24 (d, 2H), 7.33 (d, 2H), 7.52 (d, 2H). GC-MS: m/z 296 (M)+, 261 (M−35)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]([C:14]#[C:15][C:16](OC)=[O:17])=[O:13]>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]2[C:3]=1[C:16](=[O:17])[CH:15]=[C:14]([C:12]([O:11][CH3:10])=[O:13])[NH:5]2
Reactant: Cc1cc(C)cc(N)c1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1cc(=O)c2c(C)cc(C)cc2[nH]1
Yield: 3.3 %

Procedure:
Using the method described in Example 18a with 3,5-dimethylaniline (20 g) and dimethylacetylene dicarboxylate (23.4 g) as reagents gave methyl 5,7-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.25 g), m.p. 227°-229° C. δ (360 MHz, DMSO-d6) 2.34 (3H, s, 7-Me), 2.74 (3H, s, 5-Me), 3.94 (3H, s, CH3O), 6.49 (1H, s, 3-H), 6.89 (1H, s, 6-H) and 7.54 (1H, s, 8-H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](N(OC)C)=[O:12])=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1nn(C2CCCCO2)c2ncc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (X) (0.290 g, 0.78) in dry THF (5 mL) stirred at 0° C. under nitrogen was added lithium aluminum hydride (36 mg, 0.94 mmol). The solution was further stirred at 0° C. for 30 min. The reaction was quenched with a 0.4 N NaHSO4 solution (10 mL). The solution was extracted with DCM (3×15 mL). The combined organic layer was washed subsequently with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) as a viscous liquid (218 mg, 0.70 mmol, 91% yield). 1H NMR (CDCl3) δ ppm 1.52-1.74 (m, 2H), 1.95-2.18 (m, 2H), 2.37-2.49 (m, 2H) 3.87-3.98 (m, 1H), 3.99 (m, 1H), 6.18 (dd, J=10.20, 2.39 Hz, 1H), 8.73 (d, J=3.01 Hz, 1H), 8.85 (d, J=3.01 Hz, 1H), 10.16 (s, 1H); ESIMS found for C12H12BrN3O2 m/z 310.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(Cc1ccc(O)cc1)NC(=O)CCCCCCc1ccccc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(Cc1ccc(OCc2ccccn2)cc1)NC(=O)CCCCCCc1ccccc1
Yield: 68.8 %

Procedure:
(RS)-5-(4-Hydroxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester 92 (889 mg, 2.16 mmol), 2-picolylchloride hydrochloride (570 mg, 3.47 mmol) and finely powdered anhydrous K2CO3 (1.45 g, 10.5 mmol) was stirred in dry DMF (7 mL) for 48 hr. The mixture was poured onto water (40 mL) and extracted into EtOAc. The extract was successively washed with HCl solution (1 M, 30 mL), saturated NaHCO3 solution, brine, and then dried with MgSO4. Concentration of the solvent in vacuo afforded 93 (747 mg, 69 %): 1H NMR (CDCl3) δ 1.15-1.40 (m, 4H); 1.40-1.70 (m, 5H); 1.73-1.85 (m, 1H); 2.08 (t, J=7.6 Hz, 2H); 2.34 (m, 2H); 2.58 (t, J=7.6 Hz, 2H); 2.69 (dd, J=15, 6.9 Hz, 1H); 2.77 (dd, J=15, 6.2 Hz, 1H); 3.64 (s, 3H); 4.06-4.21 (m, 1H); 5.17 (s, 2H); 5.37 (d, J=9.3 Hz, 1H); 6.91 (d, J=8.4 Hz, 2H); 7.10 (d, J=8.4 Hz, 2H); 7.12-7.31 (m, 6H); 7.51 (d, J=7.5 Hz, 1H); 7.71 (dt, J=7.5, 1.6 Hz, 1H); 8.60 (m, J=6.0 Hz, 1H). 13C NMR (CDCl3) δ 174.4, 173.0, 157.5, 157.3, 149.4, 142.8, 137.0, 130.3, 125.8, 122.8, 121.5, 130.6, 128.5, 128.4, 115.0, 70.8, 51.9, 50.2, 40.6, 37.0, 36.0, 31.4, 31.1, 29.2, 29.1, 29.0, 25.8. ESMS 503 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(O)c12

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (Example 156, Step 2) was dissolved in a 40% TFA/methylene chloride solution at room temperature for 4 hours. 4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid was isolated as a white powder by evaporation of the solvent.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([CH2:21][C:22](=[O:24])[NH2:23])[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27](=O)[C:28]([C:30]1[C:40]2=[C:41]3[C:36](=[CH:37][C:38]([F:42])=[CH:39]2)[C:35]([CH3:44])([CH3:43])[CH2:34][CH2:33][N:32]3[CH:31]=1)=O>>[C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([C:21]4[C:22](=[O:24])[NH:23][C:27](=[O:26])[C:28]=4[C:30]4[C:40]5=[C:41]6[C:36](=[CH:37][C:38]([F:42])=[CH:39]5)[C:35]([CH3:43])([CH3:44])[CH2:34][CH2:33][N:32]6[CH:31]=4)[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(CC(N)=O)ccc(c32)CN1
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Product: CC(C)(C)OC(=O)C1Cn2ccc3c(C4=C(c5cn6c7c(cc(F)cc57)C(C)(C)CC6)C(=O)NC4=O)ccc(c32)CN1

Procedure:
Beginning with 7-Carbamoylmethyl-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester and (8-Fluoro-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester, the title compound was prepared essentially as Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[O:25][CH3:26])=[O:9])=[CH:4][CH:3]=1>C(OCC)C.CCCCCC.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[O:25][CH3:26])=[O:9])=[CH:27][CH:28]=1
Reactant: COc1cc(C#CCO)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Agent: [Pd]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(CCCO)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Yield: 62.6 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolinecarboxamide (397 mg) from Example No. 118 is dissolved in methanol/dichloromethane (1/1, 80 mL) and palladium on carbon (5%, 80 mg) are --added. The mixture is placed under a hydrogen atmosphere (23 psi) for 1 h, filtered through celite, and concentrated. The crude product is purified by column chromatography (dichloromethane/methanol, 50/1 to 20/1) to afford 251 mg (63%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=3)=[N:9][C:5]=2[CH:4]=1.C(OCC)(=[O:29])C>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[NH:7][C:8]([S:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=3)=[O:29])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccnc(-c2ccccc2Sc2nc3cc(OC)ccc3[nH]2)c1
Reactant: CCOC(C)=O
Product: COc1ccnc(-c2ccccc2S(=O)c2nc3cc(OC)ccc3[nH]2)c1

Procedure:
The product of step (c) above (103 mg) was dissolved in ethyl acetate (7.5 ml) and stirred at -10° . A solution of m-chloroperbenoic acid (58 mg of 85%) in ethyl acetate (0.5 ml) was added and the mixture stirred for 50 minutes. The solution was washed with sodium bicarbonate solution, sodium bisulphite solution, water and brine then dried and evaporated. After trituration with ether the solid was dried to afford the title compound. MS (FAB) M+1 at 380.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](O)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16]2)[CH2:12]1)=[O:21]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4c(F)cccc4F)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 23 and 2,6-difluorobenzoic acid. MS (ESI): mass calculated for C19H20F2N4O, 358.16; m/z found 359.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.34 (tt, J=8.4, 6.4, 1H), 6.93 (s, 2H), 6.30 (s, 1H), 4.12-3.76 (m, 3H), 3.75-3.45 (m, 4H), 3.36-2.88 (m, 3H), 2.30 (s, 6H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:32]=[CH:31][C:30]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]=4[CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>II.C1COCC1>[Br:33][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:32]=[CH:31][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[CH:16]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: c1ccc2c(-c3ccc4c5ccccc5c5ccccc5c4c3)c3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2ccc3c4ccccc4c4ccccc4c3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
Under the nitrogen atmosphere, 2-(anthracen-9-yl)triphenylene (3.3 g) as the eleventh intermediate compound, N-bromosuccinimide (NBS) (1.7 g), iodine (0.1 g) and THF (25 ml) were added to a flask, and stirred at room temperature for 5 hours. An aqueous solution of sodium thiosulfate was added and the reaction was terminated. The precipitates were collected by suction filtration. The obtained solid was washed with methanol and subsequently with heptane and purified by silica gel column chromatography (solvent: toluene) to give 2-(10-bromoanthracen-9-yl)triphenylene (3.5 g) as a twelfth intermediate compound. The scheme is shown in the following “Reaction 22”.