Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].O>CO>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[N:21]1
Reactant: CCOC(=O)c1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.3 %

Procedure:
Compound 169 (73 mg, 0.19 mmol) was dissolved in methanol (1.0 mL) and 2 mol/L sodium hydroxide (1.0 mol) was added, followed by stirring at room temperature for 1.5 hours. Water was added to the mixture and the organic layer was extracted with ethyl acetate and the aqueous layer was neutralized using 6 mol/L hydrochloric acid. The precipitated solid was triturated in ethyl acetate to obtain Compound 170 (14 mg, 21%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:22]>>[NH2:22][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Product: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Temperature: 130 °C
Yield: 60 %

Procedure:
To a mixture of (5-bromopyridin-3-yl)(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 37, 4.3 g, 12.5 mmol) in aqueous 880 ammonia (65 mL) was added CuSO4.5H2O (936 mg, 3.75 mmol) and the reaction was heated at 130° C. in an autoclave for 18 hours. The reaction was extracted into DCM and the organic layer collected, filtered, dried over sodium sulphate and concentrated in vacuo. The residue was purified through alumina eluting with 1-3% MeOH in DCM to afford the title compound as a white solid (2.1 g, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([CH3:27])[CH:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1N=C(c2ccc(NC(=O)OCc3ccccc3)c(C)c2)OC1C
Agent: ClC(Cl)(Cl)CBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1nc(-c2ccc(NC(=O)OCc3ccccc3)c(C)c2)oc1C
Reaction time: 3 h
Yield: 40 %

Procedure:
A solution of methyl 2-(4-{[(benzyloxy)carbonyl]amino}-3-methylphenyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate obtained in Example (108c) (4.4 g, 11.5 mmol) in dichloromethane (50 mL) was cooled to 0° C., and bromotrichloroethane (3.20 g, 16.1 mmol) and DBU (2.45 g, 16.1 mmol) were added. The mixture was stirred at the same temperature for three hours, washed with a 1 N aqueous hydrochloric acid solution and brine, and dried over magnesium sulfate. Following concentration, the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 2/2, 2/1) to obtain 1.75 g of the title compound as a colorless solid (40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:54][N:55](C)C=O>[C-]#N.[Zn+2].[C-]#N.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].O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([C:54]#[N:55])[CH:3]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: C[C@H](Nc1nc(C#N)cc(Nc2cnccn2)n1)c1ccc(F)cc1

Procedure:
To 500 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl) pyrimidine-2,4-diamine (Example 9), 197 mg of zinc cyanide, 66 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 66 mg of tris(dibenzylideneacetone)dipalladium was added a mixed solution of dimethylformamide and water (99/1), and the solution was bubbled with argon gas for three minutes, and subjected to microwave irradiation at 150° C. for 15 minutes. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 323 mg of the objective compound as pale yellow powder.
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][NH2+:17][CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1.[N:22]([C:25]1[CH:26]=[C:27]([C:31]2[N:32]=[C:33]([CH3:36])[S:34][CH:35]=2)[CH:28]=[CH:29][CH:30]=1)=[C:23]=[O:24]>>[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][N:17]([C:23]([NH:22][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:32]=[C:33]([CH3:36])[S:34][CH:35]=5)[CH:26]=4)=[O:24])[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1
Reactant: Cc1nc(-c2cccc(N=C=O)c2)cs1
Reactant: Brc1n[nH]c2ncc3c(c12)CC[NH2+]C3
Agent: O=C([O-])C(F)(F)F
Product: Cc1nc(-c2cccc(NC(=O)N3CCc4c(cnc5[nH]nc(Br)c45)C3)c2)cs1

Procedure:
The compound 1-bromo-N-(3-(2-methylthiazol-4-yl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide was prepared using 1-bromo-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate and 4-(3-isocyanatophenyl)-2-methylthiazole as described in general procedure M and was obtained as a pale yellow solid (0.025 g, 15%). M.p.=258-261° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.96 (s, 1H), 8.87 (s, 1H), 8.42 (s, 1H), 8.05 (m, 1H), 7.82 (m, 1H), 7.56-7.48 (m, 2H), 7.32-7.26 (m, 1H), 4.79 (s, 2H), 3.85 (t, J=6 Hz, 2H), 3.39 (t, J=6 Hz, 2H), 2.71 (s, 3H); LCMS [M+H]: 468.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c2cc1OC
Yield: 73.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 3-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol) using the procedure in Example 182 to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (109 mg, 0.22 mmol, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 9.03 (s, 1H), 8.70 (s, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7.62-7.41 (m, 4H), 7.39-7.24 (m, 4H), 3.99 (s, 6H); LC-MS (ESI) m/z 501 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[S:26]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:14]=1)(=[O:28])=[O:27]
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cc(F)ccc1F

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 2,5-difluoro-benzenesulfonyl chloride (0.058 g) as a light yellow gum (0.075 g). MS (ESI−): 407.2 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:18]=[CH2:19])[CH:14]=2)[N:9]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]1=[O:26].[OH-:32].[Na+].OO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][CH2:19][OH:32])[CH:14]=2)[N:9]([CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:8]1=[O:26]
Reactant: C=Cc1ccc2c(c1)c(=O)n(Cc1ccc(OC)c(OC)c1)c(=O)n2C1CCOCC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(CCO)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.95 ml of a 1N solution of BH3-THF complex in THF is added, at 0° C., to a mixture of 0.1 g of 3-(3,4-dimethoxybenzyl)-6-ethenyl-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione in 2 ml of THF. The reaction medium is allowed to warm to room temperature and is stirred for 1 hour. 2 ml of 1N sodium hydroxide and then 2 ml of 30% aqueous hydrogen peroxide solution are added. The resulting mixture is refluxed for 1 hour and then extracted with DCM. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (80/20, v/v) to (40/60) to give 0.057 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25](OCC)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.[NH:34]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]1>>[CH3:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([N:34]2[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]2)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: O[C@H]1CCNC1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1C
Product: Cc1cnc(Nc2cccc(N3CCN(C)CC3)c2)nc1Nc1ccccc1C(=O)N1CC[C@H](O)C1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
Ethyl 2-[(5-methyl-2-{[3-(4-methyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)amino]benzoate (120 mg., 0.27 mmol) and (S)-(+)-3-pyrrolidinol (0.65 mL, used as solvent) were combined in a vessel, which was sealed and heated with stirring at 125° C. for 18 h. The reaction was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified using normal phase HPLC eluting with a gradient of dichloromethane/methanol/ammonium hydroxide (90:10:0-90:10:1) affording the title compound as an off-white solid; yield 98 mg. (75%). MS: M(C27H33N7O2)=487.60, (M+H)+=488.2.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(O)[CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1)C.Cl>CCO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:27][CH:26]=1
Reactant: CCOC(OCC)c1ccc(C(O)(c2ccc(OC)cc2)C(CC)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCC(=C(c1ccc(C=O)cc1)c1ccc(OC)cc1)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of compound 3 (163.09 g, 375 mmol) in EtOH (750 mL) was charged with concentrated aqueous HCl (150 mL) and the resulting solution heated at 80° C. for 90 min. The solution was allowed to cool to RT and then was concentrated to the aqueous layer. H2O (500 mL) was added and the mixture extracted with CH2Cl2 (3×150 mL). The combined organic layers were dried (MgSO4) and concentrated to provide 4 (119.78 g, 93% over 2 steps) as a brown oil (3:1 mixture of Z:E isomers). The mixture was carried on without further purification. Z-isomer: 1H NMR (400 MHz, CDCl3): δ 0.94 (t, J=7.5 Hz, 3H), 2.45 (q, J=7.5 Hz, 2H), 3.68 (s, 3H), 6.56 (d, J=8.6 Hz, 2H), 6.75 (d, J=8.6 Hz, 2H), 7.08-7.21 (m, 5H), 7.41 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.1 Hz, 2H), 10.02 (s, 1H). E-isomer: 1H NMR (CDCl3): δ 0.97 (t, J=7.4 Hz, 3H), 2.52 (q, 7.4 Hz, 2H), 3.83 (s, 3H), 6.90 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.0-8-7.21 (m, 7H), 7.51 (d, J=8.1 Hz, 2H), 9.83 (s, 1H).
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClC(Cl)C>[CH:1]1[C:9]([NH:10][C:25](=[O:26])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Solvent: CC(Cl)Cl
Product: O=C(Cc1ccccc1)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 6.6 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), phenylacetyl chloride (0.058 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-yl-2-phenylacetamide (10 mg). MS (ESI) m/z 345; HPLC purity 100% at 210-370 nm, 10.6 min.; 100% at 252 nm, 10.6 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H24N2O+H+, 345.19614; found (ESI, [M+H]+), 345.1959.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:20])=[O:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A mixture of 16.2 g (64.5 mmol) of 4-(tert-butoxycarbonylaminomethyl)benzoic acid, 13.6 g (70.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.00 g of 4-dimethylaminopyridine and 200 ml of methanol was stirred at room temperature for 4 hours. Methanol was distilled off under reduced pressure and ice water was poured to the residue thus obtained. The mixture was extracted twice with ethyl acetate and the extract was washed with 10% citric acid aqueous solution and then with saturated sodium hydrogencarbonate aqueous solution and finally with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 14.3 g (83.6%) of methyl 4-(tert-butoxycarbonylaminomethyl)-benzoate.
Reaction SMILES: Br[C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH3:15])=[N:13][N:14]=[C:6]3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.[Pd].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.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>[CH3:15][C:12]1[N:7]2[C:8](=[O:11])[C:9]3[NH:10][C:2]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:3][C:4]=3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]2=[N:14][N:13]=1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C)nnc12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCCn1c2nc(-c3ccccc3)[nH]c2c(=O)n2c(C)nnc12
Yield: 15.9 %

Procedure:
To a mixture of 7-bromo-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.30 mmol), phenylboronic acid (39.5 mg, 0.32 mmol), sodium carbonate (100 mg, 0.94 mmol) in water (2 ml) and 1,2-dimethoxyethane (20 ml) was added tetrakis(triphenylphosphine)-palladium(0) (200 mg, 0.10 mmol) The mixture was heated to reflux overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative LCMS to yield the desired product (16 mg, 16%). 1HNMR (400 MHz, CD3OD): δ 8.06 (m, 2H), 7.49 (m, 3H), 4.38 (t, J=8.0 Hz, 2H), 2.83 (s, 3H), 1.95 (m, 2H), 1.42 (m, 4H), 0.92 (m, 3H). LCMS calculated for C18H21N6O (M+H): 337.2. Found 337.2.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][N:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[CH3:9][C:6]1[C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([C:17]3[CH:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)=[CH:3][C:4]=2[O:8][N:7]=1
Reactant: Cc1cc2c(C)noc2cc1Br
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2c(C)noc2cc1-c1ccc(N)nc1
Temperature: 85 °C
Yield: 91.9 %

Procedure:
A mixture of 6-bromo-3,5-dimethylbenz[d]isoxazole (104) (46 mg, 0.2 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (66 mg, 0.3 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (21 mg, 10% mol) and K3PO4 (64 mg, 0.3 mmol) in 0.5 ml ACN, 0.5 ml dioxane, 0.25 ml H2O was bubbled with argon before heated at 85° C. for 2.5 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to silica gel flash column chromatography (0-100% B, A: hexane; B: EA) to give 5-(3,5-dimethylbenzo[d]isoxazol-6-yl)-2-pyridylamine (105) (44 mg, yield: 91.9%, purity>90%) as yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH:22]=O)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12.[CH:24]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])=[CH2:25].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>ClCCCl>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH2:22][NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[C:26]([CH:24]=[CH2:25])[CH:27]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12
Reactant: C=Cc1cccc(N)c1
Reactant: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3ncnn3c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=Cc1cccc(NCc2nc(-c3ccc4ncnn4c3)c(-c3cccc(C)n3)[nH]2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a stirred solution of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazole-2-carbaldehyde (4.00 g, 13.14 mmol) in 1,2-dichloroethane (240 mL) were added 3-vinylaniline (2.36 g, 19.71 mmol) and AcOH (0.79 g, 13.14 mmol), and the mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to 0° C. and, to it, was added NaBH(OAc)3 (5.56 g, 26.20 mmol). The mixture was stirred at 40° C. overnight, and then the pH of the reaction mixture was adjusted to 7-8 at 0° C. with 10% K2CO3 solution. The reaction mixture was extracted with 5% MeOH in CHCl3 (2×200 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19 (v/v)) as eluent to give the titled compound (2.89 g, 63%) as a solid. 1H NMR (400 MHz, CDCl3) δ 10.59 (br s, 1H), 8.94 (s, 1H), 8.37 (s, 1H), 7.81 (d, 1H, J=9.2 Hz), 7.77 (d, 1H, J=9.2 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.20 (br d, 1H, overlapped, J=7.6 Hz), 7.15 (t, 1H, overlapped, J=7.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.86 (d, 1H, J=7.6 Hz), 6.75 (t, 1H, J=2.0 Hz), 6.63 (dd, 1H, overlapped, J=17.6, 10.8 Hz), 6.61 (dd, 1H, overlapped, J=8.0, 2.0 Hz), 5.69 (dd, 1H, J=17.6, 0.8 Hz), 5.21 (dd, 1H, J=10.8, 0.8 Hz), 4.55 (s, 2H), 4.39 (br s, 1H), 2.51 (s, 3H); MS (ESI) m/z 408.21 (MH+).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][N:5]=1.CN(C)C(=O)C.[SH:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>CC(C)=O>[ClH:2].[CH3:10][C:9]1[C:4]([CH2:3][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CCl
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
12.71 g (0.0459 mole) of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride were suspended in 322 ml of acetone in the presence of 2.52 ml N,N-dimethylacetamide. Then 7.24 g (0.0597 mole) of 2-mercaptobenzimidazole were added. The mixture was heated to reflux and stirred for 5 hours. After cooling to room temperature, the resulting suspension was filtered to obtain the wet product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1>CO.C(Cl)Cl>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:30]3[CH:29]=[N:28][C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:32][CH:31]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Oc3cccc(Cl)c3)CCN4)cn2)CC1
Yield: 55 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (25.0 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent gave the title compound as an orange foam (55% yield). LCMS: m/z=436.12 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, 1H), 2.21-2.32 (m, 1H), 2.36 (s, 3H), 2.54 (t, J=5.0 Hz, 4H), 3.39-3.49 (m, 1H), 3.53-3.68 (m, 1H), 3.59 (t, J=5.0 Hz, 4H), 5.10 (s, 1H), 5.37 (t, J=3.5 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.90 (dd, J=2.3 and 8.3 Hz, 1H), 6.98-7.07 (m, 2H), 7.20-7.27 (m, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.56 (dd, J=2.5 and 8.8 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H).