Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6](O)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[CH:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: OC1CCOc2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)OCC=C2
Yield: 13.3 %

Procedure:
A reaction vessel charged with 0.5 gram (0.03 mole) of 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran and 0.02 gram (catalyst) of p-toluenesulfonic acid in 50 mL of toluene was fitted with a Soxhlet extractor containing molecular sieves (3-4 angstrom). The stirred contents of the reaction vessel was heated at reflux for 90 minutes, during which time the water by-product was collected on the molecular sieves. The reaction mixture was combined with the reaction mixture of another preparation of this compound and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:9 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.6 gram of 7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[C:7]([CH2:9][C:10]1([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)[CH2:13][NH:12][CH2:11]1)#[N:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([CH2:3][C:4]([N:12]1[CH2:13][C:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)([CH2:9][C:7]#[N:8])[CH2:11]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanoacetic acid (3.1 mg, 0.036 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (11.9 mg, 0.0241 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16 mg, 0.036 mmol) in N,N-dimethylformamide (0.6 mL), followed by triethylamine (10. μL, 0.072 mmol). The reaction mixture was stirred at r.t. for 1 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=563.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.BrN1C(=[O:21])CCC1=O.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C)cc2)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 120 °C
Yield: 24 %

Procedure:
Into CCl4 solvent, 2.4 g(13.3 mmol) of the compound produced in Example 1 (Compound 1) and 0.536 g(3.0 mmol) of N-bromosuccinimide were added and refluxed for 24 hours. After cooled down, the reactant was suction-filtrated and the resultant solution was washed with distilled water and then was dried with anhydrous magnesium sulfate. The dried product was dissolved again in chloroform together with 5.34 g(51.2 mmol) of hexamethylenetetraamine and refluxed for 5 hours. After the reactant was cooled down, the solvent was distilled off under reduced pressure and the residue was refluxed severely in acetic acid/H2O(17 mL/17 mL) at 120° C. for 2 hours. Finally, 7 mL of HCl was added to be refluxed. After cooled down, the reactant was extracted with methylene chloride. The solution was distilled off under reduced pressure and the residue was purified through the column chromatography (silica gel, ethyl acetate/n-hexane=1:3) to be dried. Yield; 24%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C@H:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:25]1=[O:26]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1F)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2F)C1=O)C(C)(C)C
Yield: 101.1 %

Procedure:
A solution of Example 135A (183 mg, 0.54 mmol) and disuccinimidyl carbonate (0.165 g, 0.645 mmol) in dichloromethane (3 mL) was treated with triethylamine (90 uL, 0.645 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to give the crude title compound (199 mg, crude yield).
Reaction SMILES: Br[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12].[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16].C1(NC2CCCCC2)CCCCC1>C(#N)C.[Cu]I.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>[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[C:16][C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12]
Reactant: CCOC(=O)c1noc(Br)c1C
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Product: CCOC(=O)c1noc(C#CC(C)(C)C)c1C
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (100 mg, 0.427 mmol) and 3,3-dimethylbut-1-yne (0.058 mL, 0.470 mmol) in acetonitrile (3 mL) were degassed thoroughly refilling with nitrogen. Dicyclohexylamine (0.085 mL, 0.427 mmol), CuI (2.85 mg, 0.015 mmol) and PdCl2(PPh3)2 (7.50 mg, 10.68 mmol) were added. The mixture was stirred in the microwave at 100° C. for 45 mins. The resulting mixture was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]Cl)=[CH:4][C:3]=1[Cl:19].[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[Cl:19][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:11][N:34]1[CH2:35][CH2:36][CH:31]([C:27]2[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=2)[CH2:32][CH2:33]1
Reactant: ClCC[C@H](Oc1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Cl)c(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A using 1,2-dichloro-4-{[(1S)-3-chloro-1-phenylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 525.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(=O)O
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (70 mg, 0.261 mmol), 3-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (131 mg). The crude (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (131 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (30 mg). MS 394.4 (M+H); UV 201.1, 247.4, 297.8, 352.3 nm; t 0.476 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=1)=[O:10])(C)(C)C.CCOC(C)=O.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:7][CH2:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cc2ccccc2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCC(=O)c1cc2ccccc2s1
Reaction time: 8 h
Yield: 94.7 %

Procedure:
(2-Benzo[b]thiophen-2-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester (544 mg, 1.867 mmol) was dissolved into 3 mL of EtOAc and 10 mL of 4.0 M HCl in dioxane was added. The mixture was allowed to stir overnight with a white precipitate forming. The precipitate was triturated with 3×10 mL of EtOAc and dried under vacuum to give 400 mg, 94.7% of crude 2-amino-1-benzo[b]thiophen-2-yl-ethanone HCl salt. The material was carried on without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[CH2:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[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>[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: OCc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(-c2ccc(CO)s2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of 60.2 (0.300 g, 1.55 mmol), 4-n-butylbenzeneboronic acid 60.3 (0.553 g, 3.11 mmol), K2CO3 (0.644 g, 4.66 mmol), and Pd(PPh3)4 (0.180 g, 0.16 mmol) in toluene (5 mL) was stirred overnight at 95° C. The mixture was cooled to room temperature, filtered through a pad of silica gel (EtOAc), and concentrated. The crude product was chromatographed on silica gel (0-40% EtOAc/hexane) to afford 60.4 (0.072 g, 19%). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H), 7.18 (d, 2H), 7.13 (d, 1H), 6.97 (d, H), 4.82 (s, 2H), 2.62 (t, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[CH2:32]([O:34][CH2:35][CH2:36][NH2:37])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:32]([O:34][CH2:35][CH2:36][NH:37][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:15])[CH3:33]
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCOC
Yield: 42.3 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (49.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 525; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (1H, br. s), 8.06 (1H, br. s), 7.91 (1H, br. s), 7.71 (1H, br. m), 7.49-7.47 (1H, m), 7.35-7.34 (1H, m), 4.34 (2H, br. s), 3.72-3.69 (2H, br. t), 3.52-3.40 (6H, m), 3.22 (3H, s), 1.13-1.09 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>ClCCl>[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH:53][C:8]([C:4]2[S:3][C:2]([Br:1])=[N:6][C:5]=2[CH3:7])=[O:10])=[CH:50][CH:49]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.4 %

Procedure:
Part A. To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (10 g, 45.0 mmol, 1.0 equiv) and diisopropylethylamine (15.6 mL, 90.0 mmol, 2.0 equiv) in anhydrous dichloromethane (400 mL) was added benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 22 g, 49.5 mmol, 1.1 equiv) and 4-fluorobenzylamine (5.7 mL, 49.5 mmol, 1.1 equiv). The resulting mixture was stirred at ambient temperature for 12 hr. The reaction mixture was diluted with dichloromethane, washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography [SiO2, ethyl acetate/hexanes, 10:90 to 40:60, v/v], followed by stirring in pentane and filtering the solid to afford 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (8.5 g, 57% yield). MS (M+H)+=330.1, Rt=1.36 min.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:17]([C:19]1[N:29]([CH2:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[CH:34]=[O:35])[C:22]2=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]2[N:20]=1)[CH3:18].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([CH:34]([C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([CH2:30][N:29]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:17][CH3:18])[CH:32]=2)[OH:35])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
4-Bromobenzyloxy-tert-butyldimethylsilane (1.23 g, 4.08 mmol) obtained in Step 1 was dissolved in THF (30 mL) and the flask was filled with argon. The reaction mixture was cooled to −78° C., and a 1.57 mol/L n-butyl lithium-hexane solution (2.60 mL, 4.09 mmol) was added thereto, followed by stirring at same temperature for 5 minutes. A solution of 3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)benzaldehyde (0.800 g, 2.72 mmol) obtained in Step 2 in THF (5 mL) was dropped into the mixture for 15 minutes, followed by stirring at −78° C. for 1 hour. The reaction mixture was added with a saturated aqueous ammonium chloride solution to terminate the reaction, and diluted with ethyl acetate. The organic layer was separated from the aqueous layer, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:2) to obtain [4-(tert-butyldimethylsilyloxymethyl)phenyl][3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]methanol (0.923 g, yield 66%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH:31]3[CH2:33][CH2:32]3)[CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([OH:19])=[N:14][CH:13]=[CH:12]2.COC(OC)N(C)C.[Br:42]N1C(=O)CCC1=O>CN(C=O)C>[ClH:1].[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([N:29]([CH:31]3[CH2:32][CH2:33]3)[CH3:30])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([OH:19])=[N:14][CH:13]=[C:12]2[Br:42]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(O)nccc4c3)n2)cc1
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(O)ncc(Br)c4c3)n2)cc1
Yield: 41.3 %

Procedure:
To a room temperature slurry of 4-(5-amino-6-(1-hydroxyisoquinolin-6-yl)pyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide hydrochloride (1.00 g, 2.07 mmoL, prepared by general method C) in DMF (10 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (1 mL). Within minutes, the slurry discharged to a solution. Then, N-bromosuccinimide (386 mg, 2.17 mmol) was added in one portion. After 1 h the reaction was concentrated and flashed over silica gel (4-8% MeOH/DCM eluent) to provide 4-(5-amino-6-(4-bromo-1-hydroxyisoquinolin-6-yl)pyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide hydrochloride (480 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59-11.67 (br. s, 1H), 8.77 (s, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.24-8.30 (m, 2H), 8.17 (d, J=1.5 Hz, 1H), 7.99 (dd, J=8.3, 1.5 Hz, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.62 (d, J=6.0 Hz, 1H), 6.76 (br. s, 2H), 2.69 (s, 3H), 1.80-1.90 (m, 1H), 0.76 (s, 2H), 0.65-0.73 (m, 2H); MS (EI) m/z=527.4 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:29]=[CH:28][C:13]3/[C:14](=[CH:23]/[C:24]([NH:26][NH2:27])=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:30]=[CH:31][CH:32]=[CH:33][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:34](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:29]=[CH:28][C:13]3/[C:14](=[CH:23]/[C:24]4[O:25][CH:34]=[N:27][N:26]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:30]=[CH:31][CH:32]=[CH:33][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NN
Reactant: CCOC(OCC)OCC
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1nnco1
Temperature: 120 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To (E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetohydrazide (27 mg, 0.062 mmol) obtained in Example 7, step 1 was added triethyl orthoformate (0.5 mL), and the mixture was stirred at 120° C. for 20 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 0/100) to give the title compound (compound 11) (26 mg, 93%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.C(N(CC)CC)C.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)C>[CH2:16]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:3]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NC1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCOCC1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
Intermediate 1 (0.20 g) and triethylamine (0.55 ml) were suspended in ethanol (8 ml) and 4-aminotetrahydropyran (Intermediate 21, 0.088 g) was added. The mixture was stirred under nitrogen, heated at 80° C. for 16 h, then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was loaded directly onto an SPE cartridge (silica, 5 g) which was eluted sequentially witI; (i) DCM, (ii) DCM:Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O and (v) EtOAc. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 16 (0.21 g). LCMS showed MH+=319; TRET=2.93 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S([Cl:35])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:35][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1
Reactant: OCCN(Cc1ccccc1)Cc1ccoc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCN(Cc1ccccc1)Cc1ccoc1
Yield: 77.2 %

Procedure:
2-(Benzyl-(3-furylmethyl)amino)ethanol (6.5 g, 28 mmol), triethylamine (5.9 ml, 42 mmol), 4-dimethylaminopyridine (250 mg, 2.1 mmol) and tosyl chloride (6.4 g, 34 mmol) were stirred at room temperature for 17 hours in dichloromethane (260 ml). The reaction solution was mixed with dichloromethane, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 5.4 g of crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane. The crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane (1.8 g) was dissolved in anhydrous tetrahydrofuran (35 ml) and cooled to 0° C. In an atmosphere of argon, n-butyl lithium hexane solution (14 mmol) was added thereto to carry out 2 hours of the reaction at room temperature. The reaction solution was mixed with 1 N sodium hydroxide aqueous solution, the reaction product was extracted with dichloromethane, and then the organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 1.1 g (5.1 mmol, 73% in yield) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15]C)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc2c(c(C(=O)O)c1)CCCC2
Yield: 98.1 %

Procedure:
A solution of methyl 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (0.96 g, 4.46 mmol) in THF (54 mL), water (21 mL) and 1N NaOH (9.4 mL, 9.4 mmol) was stirred overnight at room temperature. The THF was removed in vacuo and the mixture acidified to pH 1with 1N HCl. The resulting precipitate was extracted with EtOAc, dried (MgSO4), filtered and concentrated to give the title compound as a white solid (0.88 g, 98%). 1H NMR (DMSO) δ 13.33 (s, 1H), 7.96 (d, 1H), 7.29 (d, 1H), 3.99 (d, 2H), 2.81 (d, 2H), 1.72 (m, 4H); MS m/z 200.1 (M−H).