Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:15]=[C:14]2[CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[C:40]([C:41]#[N:42])=[C:39]([NH2:43])[N:38]=[CH:37][N:36]=3)[CH2:31][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:44]O>CS(C)=O>[NH2:43][C:39]1[N:38]=[CH:37][N:36]=[C:35]([N:32]2[CH2:31][CH2:30][CH:29]([C:14]3[N:13]([CH:10]4[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=4)[N:15]=3)[CH2:34][CH2:33]2)[C:40]=1[C:41](=[O:44])[NH2:42]
Reactant: OO
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C#N)CC2)C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C(N)=O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A reaction mixture of 3-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100.00 mg; 0.17 mmol; 1.00 eq.) and 2.0N NaOHaq (0.83 ml; 1.66 mmol; 10.00 eq.), in DMSO 8 ml was stirred at RT for 5 mins, added H2O2 (0.16 ml; 1.66 mmol; 10.00 eq.) stirred at RT for 2 hr. Purified the product by HPLC (basic), collected title compound 45 mg, yield 43%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[C:18]([CH2:19][N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)[CH:21]=[CH:22][CH:23]=1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (100 mg, 0.5 mmol) in CH2Cl2 (5 mL) was mixed with 3-bromo benzaldehyde (0.06 mL, 0.5 mmol) and NaB(OAc)3H (0.16 g, 0.75 mmol). The resulting mixture was stirred for 12 hours, diluted with dichloromethane (30 mL) and washed with brine (50 mL). The organic layer was collected, dried over Na2SO4 and concentrated. Separation via a combiflash system then afforded the title compound (150 mg, 81%): LC/MS: m/z, 369 (M+H); 1HNMR (MeOD) δ 1.26 (3H, d), 1.47 (9H, s), 2.0 (1H, m), 2.1 (1H, m), 2.6 (1H, m), 2.8 (1H, m), 3.1 (1H, m), 3.3 (2H, s), 3.4 (1H, m), 3.5 (1H, m), 3.8 (1H, m), 4.2 (1H, m), 4.88 (1H, s), 7.25 (1H, m), 7.3 (1H, m), 7.4 (1H, m), 7.55 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([CH3:28])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[OH:27])[C:9](=[O:10])[C:4]=2[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:35][CH2:36][F:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([CH3:28])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[O:27][CH2:35][CH2:36][F:37])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1OCCF
Temperature: 80 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
6-chloro-3-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]-pyrimidin-4(3H)-one (10 mg), 2-fluoroethyl tosylate (7.6 mg) and potassium carbonate (16 mg) were mixed in dimethylformamide (2 mL) and stirred at 80° C. for 10 hours. Distilled water was added, the mixture extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The product was purified by silica gel thin layer chromatography (chloroform/methanol=10/1), and the title compound (8.5 mg, 77%) was obtained as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29])CCC.[Cl-].[Li+]>CN(C)C(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1C#N
Reactant: FC(F)(F)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1nccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
To a degassed solution of the product of Example 5 (70 mg, 0.23 mmol) in N,N-dimethylacetamide (2 ml) was added 2-tributylstannylbenzonitrile (183 mg, 0.46 mmol), lithium chloride (27.5 mg, 0.58 mmol), copper(I) iodide (5 mg) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (9 mg) and the mixture heated at 90° C. for 4 h. After cooling to ambient temperature the reaction was poured onto a strong cation exchange cartridge and eluted with methanol. The product was then eluted with a 2.0M solution of ammonia in methanol and evaporated in vacuo. The residue was dissolved in 5% methanol in dichloromethane and applied to two preparative TLC plates (silica gel) and eluted with 1:1 ethyl acetate in isohexane. The appropriate band was collected and processed to give a solid which was recrystallised from dichloromethane/ethyl acetate/isohexane to give 2-[4-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyrimidin-2-yl]benzonitrile (10 mg) as a white solid: δH (400 MHz, CDCl3) 7.50 (1H, d, J 7.4), 7.65-7.69 (1H, m), 7.78-7.82 (2H, m), 7.94 (1H, dd, J 7.8 and 1.2), 8.34 (1H, dd, J 8.0 and 1.0), 8.74 (1H, s), 8.97 (1H, d, J 5.5), 10.74 (1H, d, J 7.4); m/z (ES+) 366 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Mg+].[Br-].OS(O)(=O)=O.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH2:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Compound 1 (4.0 g, 13.1 mmol) was dissolved in dry THF (40 mL) and the solution was cooled to 0° C. CH3MgBr (15 mL, 19.5 mmol, 1.3 M) was added drop-wise. The resulting mixture was stirred at room temperature overnight. The solution was cooled to 0° C. and H2SO4 (2 mL, 98%) was added. A precipitate was formed and the inhomogeneous mixture was stirred at room temperature for 1 h. H2O (20 mL) was added and the mixture was extracted with diethyl ether (2×100 mL). The organic phase was washed with NaHCO3 (2×50 mL, saturated aqueous solution) and brine (50 mL) and dried over Na2SO4. Filtration and evaporation of the solvent under reduced pressure gave a crude material which was purified by column chromatography (heptane:ethyl acetate 6:1). Yield 2.58 g, 65% as an off-white solid. 1H-NMR (CDCl3) δ; 7.46-7.36 (m, 4H), 7.36 (m, 5H), 7.18-7.03 (m, 2H), 6.93 (d, 2H, J=8.6 Hz), 5.68 (d, 1H, J=1.0 Hz), 5.32 (s, 1H), 5.07 (s, 2H); 13C-NMR (CDCl3) δ 160.1 (d, J=248 Hz), 158.6, 143.5, 137.0, 133.4, 131.5 (d, J=3.5 Hz), 129.2 (d, J=8.1 Hz), 128.6 (2C), 128.0 (4C), 127.5 (2C), 123.9 (d, J=3.8 Hz), 115.7 (d, J=22.3 Hz), 115.3 (d, J=1.9 Hz), 114.6 (2C), 70.0.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[C:20]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].Br[CH2:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37].Cl>C1COCC1.O>[C:20]([O:24][C:25]([C:27]1([CH2:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)C1CCCCC1
Reactant: CCC(CC)CBr
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)CC1(C(=O)OC(C)(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 52.1 %

Procedure:
To a solution of dicyclohexylamine (13.19 g, 72.72 mmol) in THF (90 mL) 1.6 M n-BuLi in hexane (40.7 mL, 65.12 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid t-butyl ester (10.0 g, 54.3 mmol) in THF (30 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C., then 1-bromo-2-ethylbutane (12.54 g, 76.0 mmol) in THF (37.5 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and toluene. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with toluene. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (12.9 g) was distilled at 60° C. (0.05 mbar) to give 7.6 g (52%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid t-butyl ester as a colorless oil, purity 96% (GC area). 1H-NMR (CDCl3, 400 MHz): ppm 0.81 (t, 6H), 1.12-1.60 (m, 15H), 1.48 (s, 9H), 1.95-2.05 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>C(O)C>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Clc1ccccc1C=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.3 mg, 0.0563 mM), then 2-chloro-benzaldehyde (6.3 μL, 0.056 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (4.3 mg, yield: 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]#[C:39][NH2:40]>>[C:39]([NH:40][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1)#[N:38]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: N#CN
Product: N#CNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyanamide according to conditions described in general procedure C. 1H NMR (400 MHz, CDCl3) δ 3.21 (t, J=4.8 Hz, 4 H), 3.81 (t, J=5.2 Hz, 4 H), 6.34 (d, J=6.0 Hz, 1 H), 6.70 (d, J=12.0 Hz, 1H), 7.16-7.20 (m, 2 H), 7.32-7.46 (m, 4 H), 7.76-7.78 (s, 1 H), 7.86-7.89 (m 1 H), 8.05 (d, J=6.4 Hz, 1 H), 9.61 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17].[H-].[Na+]>CN(C=O)C>[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](=[O:17])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: COC(=O)c1cccc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CC(=O)c2cccc(OC)c2OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
To a solution of 4-methoxyacetophenone (2.0 g, 13.3 mmol) and methyl 2,3-dimethoxybenzoate (3.135 g, 15.98 mmol) in DMF (100 mL), was added a NaH (1.065 g, 26.63 mmol) and the reaction mixture was stirred for 24 h at rt under N2. The reaction mixture was poured into ice water and products were extracted with EtOAc. The organic layer was separated, washed with water, dried and concentrated to afford 1-(2,3-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (3.1 g, 74%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2]>[Pd].Cl.CO>[NH2:29][CH2:28][C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:30])=[N:15][C:16]=2[CH:27]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CN)ccc21
Reaction time: 6 h
Yield: 64 %

Procedure:
A mixture of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (230 mg, 0.57 mmol) and 10% palladium on carbon (50 mg) in 5% HCl-MeOH (10 mL) was placed in a Parr shaker under hydrogen (40 psi) for 6 h. The reaction mixture was filtered through celite and the solvent evaporated. The residue was purified by prep-HPLC (gradient 10% -100% B) to give 148 mg (64%) of 1-[5-aminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one as a hygroscopic white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:29][CH2:28]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>O.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>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=2)[CH2:29][CH2:28]3)=[CH:3]1
Reactant: CC(C)CCn1cc(Br)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)c2c(N)ncnc21
Temperature: 100 °C
Yield: 49.8 %

Procedure:
To 5-bromo-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (75 mg, 0.265 mmol) and 5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (160 mg, 0.371 mmol) were added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes then Pd(Ph3P)4 (30.6 mg, 0.026 mmol) was added and the vessel was capped. The reaction was then heated at 100° C. overnight. The reaction was then diluted with water (2 ml) then extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude was dissolved in 3 mL of DMSO and the product purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 40% ACN/H2O, 0.1% TFA to 65% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was transferred to a 40 mL vial with MeCN then water was added and the solution was freeze-dried. to afford 7-(3-methylbutyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (67 mg, 0.132 mmol, 49.8% yield) as a white solid. LC-MS (ES) m/z=508.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.11 (d, J=8.34 Hz, 1H), 7.69 (s, 1H), 7.56-7.66 (m, 3H), 7.33 (s, 2H), 7.24 (d, J=8.34 Hz, 1H), 6.10 (br. s., 2H), 4.27 (t, J=8.46 Hz, 2H), 4.18 (t, J=7.33 Hz, 2H), 4.03 (s, 2H), 3.26 (t, J=8.34 Hz, 2H), 1.69 (q, J=6.99 Hz, 2H), 1.50 (dt, J=6.69, 13.39 Hz, 1H), 0.93 (d, J=6.57 Hz, 6H).
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]([OH:25])=[C:8]([C:26]([O:28][CH3:29])=[O:27])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:25][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH:11]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1nc(COC(C)=O)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A glass lined Parr pressure reactor vessel equipped with a 4-blade impeller can be charged with 6c, Pd/C (about 0.4 to 0.5 molar equivalents), anhydrous Na2CO3 (about 0.5 molar equivalents), and ethyl acetate. The flask can then be vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask can then be pressurized with hydrogen to set point 60 psi and stirred at 60° C. for 6-8 hrs until completion of reaction (6c <0.5%). The flask can then be cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and filtered through glass microfiber filter paper. The filtrate can be concentrated and precipitated from cold methanol and dried under vacuum at 50±5° C.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:17]1.C[O:30][C:31](=O)[C:32]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[N:41]([CH3:43])[CH:40]=[CH:39]2)=O.Cl>CN(C=O)C.CCOC(C)=O>[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[C:26](=[O:27])[NH:28][C:31](=[O:30])[C:32]=2[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:42]=2[N:41]([CH3:43])[CH:40]=[CH:39]3)=[CH:17]1
Reactant: NC(=O)Cc1cn(CCCO)c2ccccc12
Reactant: COC(=O)C(=O)c1cccc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4cn(CCCO)c5ccccc45)C(=O)NC3=O)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.1 %

Procedure:
A 1.0 M solution of KOtBu in THF (9.2 mL, 9.2 mmol) was added to a solution of 2-[1-(3-hydroxypropyl)-1H-indol-3-yl]-acetamide (616 mg, 2.65 mmol) and (1-methyl-1H-indol-7-yl) -oxo-acetic acid methyl ester (566 mg, 2.61 mmol) in DMF (40 mL). The initially light yellow solution turned red-orange and was stirred 14 h at rt. 1N HCl was added and the mixture poured into EtOAc. The EtOAc layer was separated and washed with water (3×), saturated aq NaHCO3 (2×) and brine (3×), dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:CH2Cl2) afforded a red solid that was dried at 70° C. for 72 h giving the title compound (689 mg, 66%) as a bright red solid. 1H NMR (400 MHz, DMSO-d6) 11.12 (s, 1H), 8.05 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 6.92–7.04 (m, 2H), 6.87 (d, J=8 Hz, 1H), 6.44–6.50 (m, 2H), 6.21 (d, J=8 Hz, 1H), 4.64 (m, 1H), 4.27 (t, J=7 Hz, 2H), 3.68 (s, 3H), 3.30–3.40 (m, 2H), 1.80–1.90 (m, 2H). 13C NMR (75.5 MHz, DMSO-d6) 173.43, 172.37, 136.15, 134.62, 134.26, 131.54, 129.58, 129.19, 128.57, 125.20, 124.11, 122.07, 121.53, 121.03, 120.12, 118.56, 115.18, 110.34, 104.28, 100.73, 57.54, 42.94, 34.68, 32.54. IR (CHCl3, cm−1) 3436, 1721. MS (electrospray, m/z) 400 (M++1), 398 (M−−1). Anal. Calcd. for C24H21N3O3: C, 72.17; H, 5.30; N, 10.52. Found: C, 71.87; H, 5.29; N, 10.45.
Reaction SMILES: [N:1]1([C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:29]1[C:33](B(O)O)=[CH:32][C:31]2[CH:37]=[CH:38][CH:39]=[CH:40][C:30]1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[S:29]1[C:33]([C:8]2[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[N:9]=2)=[CH:32][C:31]2[CH:37]=[CH:38][CH:39]=[CH:40][C:30]1=2
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3)nc2c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(piperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (280 mg, crude) in dioxane (5 mL) was added benzo[b]thiophen-2-ylboronic acid (357 mg, 2.0 mmol), K3PO4 (425 mg, 2.0 mmol), Pd(PPh3)4 (39 mg, 0.033 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 3.3% ethyl acetate in petroleum ether to afford methyl 2-(benzo[b]thiophen-2-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (100.0 mg, 37% 2 steps).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]([C:33]([O:35]C)=[O:34])[CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1>[OH-].[K+].CO>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH2:21][CH:22]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)C1CN(Cc2cccc3c2ccn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1C(=O)O

Procedure:
1-tert-Butyl 2-methyl 4-{[1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1,2-dicarboxylate (all of Intermediate 50) was dissolved in 1M KOH (3 mL) in MeOH (3 mL) and THF (3 mL) and stirred overnight. The mixture was evaporated and diluted with dichloromethane and water. pH was adjusted to 4 with 1N HCl (2.5 mL) and saturated solution of dihydrogenphosphate. The organic phase was evaporated and purified by flash chromatography using 2.5% MeOH to 5% MeOH in dichloromethane. Yield: 85 mg (30%, calculated from 1-(phenylsulfonyl)-1H-indole-4-carbaldehyde). White solid. MS (electronspray; [M+H]+) m/z 500.4.