Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
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: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1ccccc1Cl
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 38.4 mg, 0.123 mmol), (2-chlorophenyl)boronic acid (Aldrich; 28.8 mg, 0.184 mmol), Na2CO3 (39.0 mg, 0.368 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 7.09 mg, 6.14 μmol) in a mixture of 1,4-dioxane (1.5 mL) and water (0.500 mL) was stirred under argon at 100° C. for 20 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(2-chlorophenyl)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (40.3 mg, 0.104 mmol, 84% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.00 (1H, br. s.), 8.11 (1H, dd, J=7.6, 1.2 Hz), 7.92 (1H, dd, J=8.4, 1.2 Hz), 7.79 (1H, t, J=8.0 Hz), 7.59-7.64 (1H, m), 7.46-7.55 (3H, m), 7.24 (1H, d, J=2.2 Hz), 5.65 (1H, br. s.), 3.61 (2H, t, J=6.7 Hz), 2.89 (2H, td, J=6.7, 1.4 Hz), 2.67 (3H, s). m/z (ESI, +ve) 388.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(N)cc1F
Reaction time: 0.5 h

Procedure:
To an amount of 4-amino-2-fluoro-5-methoxybenzoic acid (4 g, 21.62 mmole) that was dissolved in DCM (40 ml) and MeOH (11 mL), was added TMS-diazomethane (16.2 mL, 32.43 mmole) slowly. The mixture was stirred at r.t for 30 mins. After the removal of solvent, the resulting tan solid (4.0 g, 93%) carried onto the next reaction without any purification. [M+H] calc'd for C9H10FNO3, 200; found 200.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)=[O:3].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CC([O-])(C)C.[Na+].C(Cl)(Cl)Cl>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(N2CCOCC2)cc1
Yield: 74.1 %

Procedure:
According to General Procedure B, a mixture of 4-chloroacetophenone (65 μL, 0.50 mmol), morpholine (52 μL, 0.60 mmol), NaOt-Bu (67 mg, 0.70 mmol), Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol) and 12f (8 mg, 0.02 mmol) in PhMe (2.5 mL) was heated, cooled and filtered. Evaporation of the solvent under reduced pressure and column chromatography of the pre-adsorbed crude material (83:2:15 to 78:2:20 hexane/Et3N/EtOAc, silica gel) gave 52b (76 mg, 74%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.90 (d, 2H, J=9.0 Hz), 6.87 (d, 2H, J=9.0 Hz), 3.86 (t, 4H, J=4.8 Hz), 3.31 (t, 4H, J=5.1 Hz), 2.53 (s, 3H); 13C NMR (75.5 MHz, CDCl3) 196.4, 154.2, 130.3, 128.1, 113.2, 66.5, 47.5, 26.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.[Cl:26][C:27]1[CH:32]=[C:31](I)[C:30]([F:34])=[CH:29][N:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:31]3[C:30]([F:34])=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: Fc1cnc(Cl)cc1I
Product: Cc1cc(-c2cc(Cl)ncc2F)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 2-Chloro-5-fluoro-4-iodopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a off-white solid, MS (ISP): m/e=363.2, 365.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:15]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[C:13]([Br:15])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cnc2cc(N)ccc21
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Cn1cnc2c(Br)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isobutyl-5-aminobenzimidazole (2.4 g, 13 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.2 g (4.5 mmol, 35%) of the product.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.S(Cl)([Cl:12])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH:1]1([C:7]([Cl:12])=[O:9])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CC=CCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CC=CCC1
Yield: 84.4 %

Procedure:
An acid chloride was prepared as follows: anhydrous 3-cyclohexenecarboxylic acid (50 g, 0.4 mol) was placed in a 500 mL round-bottom flask and a few drops of N,N-dimethylformamide was added as a catalyst. To this was added dropwise thionyl chloride (58.4 mL, 0.8 mol), diluted with anhydrous toluene (50 mL), at room temperature and the reaction mixture was refluxed for 4 hours. The final product was fractionally distilled to yield 48.8 grams of 3-cyclohexenecarboxylic acid chloride at a yield of 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([C:34]([F:36])([F:35])[F:37])([C:38]([F:41])([F:40])[F:39])[OH:33])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 200.4 %

Procedure:
1-(2-Chloro-phenyl)-5-[6-(4-BOC-piperazin-1-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (65.0 mg, 0.11 mmol) prepared in Example 355 was added to a saturated solution of hydrochloric acid in ethyl acetate (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 60.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2ncc3c(n2)C(OS(C)(=O)=O)CCC3)ccc1-n1cnc(C)c1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(n2)C(N2CCCCC2)CCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
To a suspension of methanesulfonic acid 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-5,6,7,8-tetrahydro-quinazolin-8-yl ester (76 mg, 0.18 mmol) in dimethylformamide (2 mL) was added under nitrogen at 0° C. piperidine (30 mg, 0.35 mmol) and triethyl amine (36 mg, 0.35 mmol). The reaction was stirred at room temperature over night. Piperidine (30 mg, 0.35 mmol) was added and the reaction stirred at room temperature for 3 hours. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane/methanol/concentrated aqueous ammonia (19:1:0.2 v/v/v) as eluent to yield the title compound (13 mg, 18%) as an orange solid. MS ISP (m/e): 334.3 (27), 419.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.60 (s, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.60 (d, 1H), 7.19 (d, 1H), 7.03 (s, 1H), 3.80 (s, 3H), 3.63 (m, 1H), 3.05 (m, 1H), 2.55-2.80 (m, 2H), 2.25 (m, 2H), 2.14 (s, 3H), 1.89 (m, 2H), 1.38-1.68 (m, 8H).
Reaction SMILES: [Pb].[N].[C:3]([O-:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[Na+].C(C(Cl)C([O-])=O)=C.[C:21]([O:40][CH:41]=[CH2:42])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CN(C)C=O>[C:3]([O:12][CH2:22][C:21]([O:40][CH:41]=[CH2:42])=[O:39])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[C:21]([O:40][CH:41]=[CH2:42])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: O=C([O-])c1ccccc1O
Agent: C=CC(Cl)C(=O)[O-]
Agent: C=COC(=O)CCCCCCCCCCCCCCCCC
Agent: [N]
Solvent: CN(C)C=O
Product: C=COC(=O)COC(=O)c1ccccc1O

Procedure:
Into a 50 ml flask provided with a condenser, a nitrogen lead in tube and an agitator, there are introduced 1.6 g of sodium salicylate, 4 g of a copolymer composed of 30% vinylchloroacetate and 70% of vinyl stearate (MW = 40,000) and 20 g of dimethylformamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C@H:5]([CH3:33])[CH2:6][C@H:7]([NH:21][C:22](=[O:32])[CH2:23][CH2:24][C:25](=O)[NH:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:72]=[N+:73]=[N-:74])(C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:34])[C@H:5]([CH3:33])[CH2:6][C@H:7]([NH:21][C:22](=[O:32])[CH2:23][CH2:24][C:25]1[N:26]([CH2:27][CH2:28][C:29]#[N:30])[N:74]=[N:73][N:72]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)NCCC#N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Reaction time: 0.17 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester (150 mg, 0.324 mmol) in THF (2 mL) is added triphenylphosphine (85 mg, 0.324 mmol). After stirring for 10 minutes, diisopropyl azodicarboxylate (0.063 mL, 0.324 mmol) and trimethylsilyl azide (0.043 mL, 0.324 mmol) are added. The mixture is stirred for 8 hours and additional triphenylphosphine, diisopropyl azocarboxylate, and trimethylsilyl azide (each 0.324 mmol) are added. After stirring overnight, the mixture is concentrated and purified by silica gel column chromatography to give (2R,4S)-5-biphenyl-4-yl-4-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-2-methyl-pentanoic acid ethyl ester. HPLC Retention time 1.42 minutes (condition B); MS 489 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 1.11 (d, J=7.07 Hz, 3H), 1.23 (t, J=7.07 Hz, 3H), 1.47 (ddd, J=4.29, 10.10, 14.39 Hz, 1H), 1.91 (ddd, J=4.04, 9.60, 13.64 Hz, 1H), 2.31-2.41 (m, 1H), 2.67-2.81 (m, 4H), 3.00 (t, J=6.82 Hz, 2H), 3.05-3.17 (m, 2H), 4.03-4.22 (m, 3H), 4.50-4.68 (m, 2H), 5.69 (d, J=9.09 Hz, 1H), 7.14 (d, J=8.08 Hz, 2H), 7.34 (t, J=7.33 Hz, 1H), 7.44 (t, J=7.83 Hz, 2H), 7.50 (d, J=8.34 Hz, 2H), 7.59 (d, J=7.07 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:27])[N:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[N:15]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:17]=3[OH:18])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[OH:18][C:17]1[C:16]([CH:19]([CH3:21])[CH3:20])=[N:15][N:14]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C:13](=[O:27])[C:12]=1[C:7]1[NH:6][C:5]2[CH:28]=[CH:29][C:2]([NH:1][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:3][C:4]=2[S:9](=[O:10])(=[O:11])[N:8]=1
Reactant: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc(NC(=O)c4ccccc4)ccc3N2)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
To a solution of 5j (0.048 g, 0.11 mmol) and 4-dimethylaminopyridine (0.0014 g, 0.011 mmol) in DMF was added triethylamine (18 μL, 0.125 mmol) followed by benzoyl chloride (16 μL, 0.137 mmol). The reaction mixture was stirred 4 h at 80° C. and cooled to room temperature. The reaction mixture was treated with sat NaHCO3 (1 mL) and extracted two times with EtOAc (3 mL). The combined organic layer was washed with brine (1 mL), dried over MgSO4, and concentrated in vacuo. The crude mixture was purified by flash column chromatography using silica gel (0-40% EtOAc/hexanes) to give 5k (0.030 g, 50%) as a yellow solid. 1H NMR (400 MHz, D6-DMSO) δ 10.63 (br s), 8.45 (d, J=2.4 Hz, 1H), 8.09 (dd, J=8.8, 2 Hz, 1 H), 8.97 (d, J=7.2 Hz, 2 H), 7.67 (d, J=9.2 Hz, 1 H), 7.60 (d, J=7.2 Hz, 1 H), 7.54 (t, J=7.2 Hz, 2 H), 4.13 (d, J=6.8 Hz, 2 H), 3.25 (m, 1 H), 1.63 (m, 3 H), 1.22 (d, J=6.8 Hz, 6 H), 0.93 (d, J=6.4 Hz, 6 H). LC-MS(ESI+) m/e 524 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]3[C:26]([NH:38][CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[C:27]4[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]4=[N:29][C:30]=3[CH2:31][CH3:32])=[O:22])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:45]([C:47]1[CH:48]=[C:49](B(O)O)[CH:50]=[CH:51][CH:52]=1)=[O:46].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:36]([N:33]1[C:28]2=[N:29][C:30]([CH2:31][CH3:32])=[C:25]([CH2:24][NH:23][C:21]([C:16]3[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:51]5[CH:50]=[CH:49][CH:48]=[C:47]([CH:45]=[O:46])[CH:52]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[CH:15]=3)=[O:22])[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]2[CH:35]=[N:34]1)[CH3:37]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(Br)c2)c1
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: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)c1
Yield: 64.4 %

Procedure:
N-{[3-Bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (900 mg, 1.356 mmol), (3-formylphenyl)boronic acid (203 mg, 1.356 mmol), potassium carbonate (562 mg, 4.07 mmol), and Pd(Ph3P)4 (78 mg, 0.068 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. It was taken up in DCM and absorbed on Isolute® Sorbent and purified by CombiFlash using an 80 g silica column eluted with 0-10% MeOH/DCM. The product fractions were combined and concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide (632 mg, 0.873 mmol, 64.3% yield) as a white solid. LC-MS m/z 689.8 (M+H)+, 0.95 min (ret time); mp 117-119° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:34]=[C:33]3[C:29]([N:30]=[CH:31][N:32]3[C@@H:35]3[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[C@@H:37]([OH:45])[C@H:36]3[OH:46])=[C:28]([NH:47][CH2:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:34]=[C:33]3[C:29]([N:30]=[CH:31][N:32]3[C@@H:35]3[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[CH:37]([OH:45])[CH:36]3[OH:46])=[C:28]([NH:47][CH2:48][CH:49]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:27]=2)=[O:25])[CH2:15][CH2:16]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)OCc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCNCC4)nc32)C(O)C1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-[3-(2-{[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carbonyl]-amino}-ethyl)-ureido]-piperidine-1-carboxylic acid benzyl ester (0.145 g, 0.174 mmol) in methanol (1 ml) under an atmosphere of Argon is treated with palladium hydroxide on carbon (0.054 g, 20% w/w carbon). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 72 hours and then filtered. The filtrate is concentrated in vacuo to yield the titled compound as a green oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](C(OC(C)(C)C)=O)[C:11]1[CH:40]=[CH:39][C:14]([O:15][C:16]2[C:17]([C:22]3([C:35](OC)=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:13][CH:12]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[C:17]([C:22]3([CH2:35][OH:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:39][CH:40]=1
Reactant: COC(=O)C1(c2nccnc2Oc2ccc(N(C(=O)OC(C)(C)C)c3nc4ccccc4s3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice cooled solution of 1-tert-butyl 4-methyl 4-(3-(4-(benzo[d]thiazol-2-yl(tert-butoxycarbonyl)amino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate (122 mg, 0.184 mmol) in dry THF (5 mL) was added LAH, 2M in THF (0.08 mL, 0.160 mmol). After stirring for 16 hours, LC-MS indicates a mixture of product, starting material, desBoc starting material and desBoc product. The reaction was treated with more LAH, 2M in THF (0.09 mL). After 4 hours, LC-MS shows one main peak that is consistent with desired product minus Boc (m/z 534 MH+). The reaction was quenched with sat'd rochelle's salt and diluted with EtOAc (10 mL). The aqeuous layer was extracted with EtOAc (10 mL) and the combined EtOAc layers were concentrated in vacuo. The brown residue was purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (5 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with an linear gradient of 10% to 80% MeCN (0.1% TFA) in water (0.1% TFA) over 20 minutes to give tert-butyl 4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (8.2 mg) as a TFA salt and white solid after lypholization. MS (ESI, pos. ion) m/z: 534.0 (M+1). IC50 (uM) ++++.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:29]6[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=6)=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Reactant: OB(O)c1cccnc1
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: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(-c6cccnc6)n5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 80 mg, 0.196 mmol) was dissolved in DME (0.653 mL) with pyridin-3-ylboronic acid (24.1 mg, 0.196 mmol), 2 M Na2CO3 solution (0.353 mL, 0.705 mmol) and tetrakis(triphenylphosphine)palladium (11.3 mg, 0.010 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. Then it was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and passed through an SPE cartridge of PL-Thiol MP to remove the palladium. Then the filtrate was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 0.6 min (conditions 2), MH+=407).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CC(C)c1ccc(N)c(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
2-bromo-4-isopropylaniline and 3-nitrobenzene boronic acid were combined to form 2-(3-nitrophenyl)-4-isopropylaniline,