Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>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].CO.C(OCC)(=O)C.COCCOC>[Cl:17][C:18]1[C:19]([C:2]2[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[N:4][CH:3]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: CN(CC1CCOCC1)c1cncc(Cl)n1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CC1CCOCC1)c1cncc(-c2cc(F)ncc2Cl)n1
Temperature: 112.5 °C
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To 6-chloro-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (450 mg, 1.862 mmol) was added 5-chloro-2-fluoropyridin-4-ylboronic acid (588 mg, 3.35 mmol), PdCl2(dppf).CH2Cl2 adduct (182 mg, 0.223 mmol), DME (8 ml) and 2M sodium carbonate (2.79 ml, 5.59 mmol). The resulting reaction mixture was stirred at 110-115° C. for 90 minutes, and the reaction progress was followed by LCMS. The reaction mixture was cooled, 20 ml of ethyl acetate and 10 ml of methanol were added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 24 g column eluting with 20-75% ethyl acetate in heptane. The desired fractions were concentrated to constant mass, giving 499 mg of titled compound as free base. LCMS (m/z): 337.1 (MH+), retention time=0.90 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:27]([O-])=O)=[C:11]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:12]=1.C(O)=O>C1COCC1.CO.[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:27])=[C:11]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=CO
Product: Nc1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 20 h
Yield: 84.4 %

Procedure:
A mixture of 1-[5-(4-chloro-butoxy)-2-nitro-phenyl-methanesulfonyl]-naphthalene (1.94 g, 4.5 mmoles) and 10% Pd/C in THF (20 mL), methanol (20 mL), and formic acid (5 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% EtOAc/CH2Cl2 to afford the title compound as an off-white solid (1.54 g, 3.8 mmoles).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[CH:5]=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[N:48]=[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:47])[C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:44])[CH3:43])[CH:37]=4)[CH:30]=[CH:31][C:32]=3[CH3:33])=[CH:25][N:20]2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CO.O1CCCC1.O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:17][C:18]2[N:48]=[C:21]3[CH:22]=[CH:23][C:24]([O:26][C:27]4[CH:28]=[C:29]([NH:34][C:35]([C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:43])[CH3:44])[CH:37]=5)=[O:47])[CH:30]=[CH:31][C:32]=4[CH3:33])=[CH:25][N:20]3[N:19]=2)=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cncc(Br)c3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 5-bromopyridine-3-carboxylic acid (375 mg, 1.87 mmol) in tetrahydrofuran (6 mL) were added oxalyl chloride (204 μL, 2.34 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (400 mg, 0.937 mmol) were dissolved in pyridine (7 mL), and the mixture was stirred at room temperature for 1 hr. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (3 mL) and saturated brine (2 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue in methanol-tetrahydrofuran mixed solution (2:1, 6 mL) was added potassium carbonate (130 mg, 0.937 mmol), and the mixture was stirred at room temperature for 14 hr. A saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=30/70→0/100), and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (490 mg, 86%) as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)N)(C)(C)C.[CH3:16][N:17]([CH:21]1[CH2:26][CH2:25][C:24]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:29][N:28]=2)=[CH:23][CH2:22]1)C(=O)O.[OH-].[Na+]>ClCCl>[CH3:42][C:41]1[N:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:52])[F:51])=[CH:45][N:44]=2)[N:39]=[CH:38][C:37]=1[C:35]([NH:34][C:30]1[CH:29]=[N:28][C:27]([C:24]2[CH2:25][CH2:26][CH:21]([NH:17][CH3:16])[CH2:22][CH:23]=2)=[C:32]([CH3:33])[CH:31]=1)=[O:36]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCC(N(C)C(=O)O)CC1
Agent: CC(C)(C)OC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CC=C(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Reaction time: 4 h
Yield: 105.9 %

Procedure:
Trifluoroacetic acid (5.0 ml) was added at room temperature to a solution of N-methyl-{4-[3-methyl-5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}-amino)pyridin-2-yl]cyclohex-3-en-1-yl}carbamoic acid carbamic acid tert-butyl ester (1.47 g) of Example D249 in dichloromethane (25 ml), and stirred at the same temperature for four hours. After completion of the reaction, 4N aqueous solution of sodium hydroxide (15 ml) was added and the solvent was evaporated. Ethanol (15 ml) and water were added to the resulting residue, stirred at room temperature for 30 minutes and the solid was filtered to give the titled compound (1.16 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1O[C:9]1([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:10](=O)[CH3:11].O.[NH2:21][NH2:22]>C(O)C>[CH3:11][C:10]1[NH:22][N:21]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: CC(=O)C1(c2ccncc2)OC1c1ccccc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1n[nH]c(C)c1-c1ccncc1

Procedure:
A solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g, 0.868 mmol) in ethyl alcohol (50 ml) was heated at reflux for 20 hours. The solvent was removed and the resulting residue was purified by chromatography to give 4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1>>[CH3:29][O:28][C:25]1[N:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cn1
Yield: 37.3 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (210 mg, 0.765 mmol) synthesized in Reference example 61 and 5-bromo-2-methoxypyridine (216 mg, 1.15 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 109 mg (yield 37%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:35]([N:19]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[C:40]([NH:42][S:2]([CH3:1])(=[O:4])=[O:3])[CH:39]=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Add methanesulfonyl chloride (13 μl, 0.170 mmol) dropwise to a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.082 g, 0.154 mmol) and pyridine (15 μl, 0.185 mmol) in dichloromethane (2 mL) at 0° C. under nitrogen. Stir the orange suspension for 0.5 h, then remove the cooling bath and warm the mixture to room temperature and stir overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N HCl, water and brine (10 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with ethyl acetate/hexanes (70:30), to provide the title compound as a white solid (0.055 g, 58%): ESI MS 610 (M+H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:49])[CH2:6][C:7]1[C:44]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:42]=[CH:41][C:8]=1[CH2:9][CH2:10][C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[N:12]=1>C1COCC1.CO.O>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:8]4[CH:41]=[CH:42][CH:43]=[C:44]([C:45]([F:46])([F:48])[F:47])[C:7]=4[CH2:6][C:5]([OH:49])=[O:4])[C:16]([C:17]([F:18])([F:20])[F:19])=[CH:15][N:14]=3)=[CH:27][CH:26]=2)[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)Cc1c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(F)(F)F)c4CC(=O)O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
LiOH (31 mg, 1.3 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A95) (0.106 g, 0.159 mmol) in THF (2.0 mL), MeOH (1.0 mL) and water (1.0 mL) and the resulting mixture was stirred at room temperature for 16 hours. Water (20 mL) was added and the mixture extracted with EtOAc (2×20 mL). The combined organic extracts were concentrated under reduced pressure and the residue taken up in THF (2.0 mL), MeOH (1.0 mL) and water (1.0 mL). LiOH (0.103 g, 4.30 mmol) was added and the resulting mixture stirred for 136 hours at room temperature. The mixture was diluted with water (30 mL) then extracted with EtOAc (3×30 mL). The combined organic extracts were passed through a phase separation cartridge then concentrated under reduced pressure to give the title compound A96 (0.104 g, 99%); 1H NMR (400 MHz, d6-DMSO) δ 10.27 (bs, 1H), 8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.45 (d, J=7.7 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 4.06 (m, 2H), 3.48 (s, 2H), 3.14 (m, 2H), 3.05 (m, 2H), 2.80 (m, 2H), 2.61 (m, 1H), 1.74 (m, 2H), 1.48 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.78 min; m/z 653.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
(2.15 ml, 16.8 mmol) Dibenzylamine was dissolved in acetonitrile (30 ml). Potassium carbonate (2.3 g, 16.8 mmol, 1.5 equiv.) and 1-bromo-3,3-dimethylbutan-2-one (1.5 ml, 11.2 mmol, 1.0 equiv.) were added and the mixture was stirred for 16 hours at 90° C. The reaction mixture was extracted with sat. NaHCO3-solution and two times EtOAc. The organic layers were extracted with water, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (70 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(dibenzylamino)-3,3-dimethylbutan-2-one (1.6 g, 48.5% yield) was obtained as a yellow oil, MS: m/e=296.3 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:6]=1[CH2:18][N:19](CC1C=CC(OC)=CC=1OC)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])C.CCC([O-])(C)C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:24]([O:23][C:21]([C:20]1[N:19]=[CH:18][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2cccnc2)ccc1C(=O)OCC
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ncc2cc(Oc3cccnc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To an ice-water bath cooled solution of 2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-4-(pyridin-3-yloxy)-benzoic acid ethyl ester (1.71 g) in THF (30 mL) was added a solution of potassium tert-pentoxide (3.36 mL, 1.7 M in toluene); the mixture was stirred for 60 min at rt after addition; then the mixture was quenched with 2 M HCl, diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (30 mL) and treated with thionyl chloride (0.47 mL) overnight. Then concentrated, the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (673 mg). LC MS ESI: 311 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([Sn](C)(C)C)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19].Br[C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[N:31]=[CH:30][N:29](C3CCCCO3)[N:28]=2)=[CH:25][CH:26]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([C:21]3[C:22]([CH3:38])=[N:23][C:24]([C:27]4[NH:31][CH:30]=[N:29][N:28]=4)=[CH:25][CH:26]=3)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19]
Reactant: COCCN1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Reactant: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCN1C(=O)CNc2ncc(-c3ccc(-c4nnc[nH]4)nc3C)nc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
1-(2-Methoxyethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.5 g, 1.348 mmol), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.436 g, 1.348 mmol), tris(dibenzylidineacetone)dipalladium(0) (0.123 g, 0.135 mmol), tri-o-tolylphosphine (0.082 g, 0.270 mmol), triethylamine (0.584 mL, 4.04 mmol) and N,N-dimethylformamide (10 mL) were combined in a 75 mL sealable flask, the atmosphere in the flask was removed and replaced with nitrogen. The mixture was stirred at 130° C. for 3 h. The resulting mixture was cooled to room temperature and filtered. The organic layer was concentrated under reduced pressure. The resulting residue was diluted with methanol and dimethylsulfoxide, filtered and purified using reverse-phase preparatory HPLC (10-30% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X-C solid phase extraction column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol eluent and was concentrated under reduced pressure. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.05 g, 0.136 mmol, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.10 (br. s., 1H), 7.98 (br. s., 1H), 7.94 (s, 1H), 7.73 (br. s., 1H), 4.13-4.28 (m, 4H), 3.55 (t, J=6.25 Hz, 2H), 3.24 (s, 3H), 2.70 (br. s., 3H); MS (ESI) m/z 367.2[M+1]+.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[C:15]([C:21]#[N:22])=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:13]=2)OC1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:20][C:17]1[CH:16]=[C:15]([C:21]#[N:22])[C:14]([C:12]2[CH:13]=[C:8]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=[CH:10][C:11]=2[F:23])=[CH:19][CH:18]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2n1
Yield: 54 %

Procedure:
5′-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile (see Example 1) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 54% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 215° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.27 (1H, br s), 7.35-7.59 (4H, m), 8.09-8.15 (2H, m), 8.26 (1H, s), 8.78 (1H, s); MS (ES+) m/z 392 [M+H]+. Anal. Found: C, 64.38; H, 3.88; N, 17.66%. Required for C21H15F2N5O: C, 64.45; H, 3.86; N, 17.89%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:16]2[CH2:17][CH2:18][C:19]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:11][CH:12]=[CH:13][C:14]=3[CH2:15]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2nccc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Nc2nccc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 150 °C
Yield: 27.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (200 mg, 0.68 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added 2,3-dichloropyridine (200 mg, 1.36 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.36 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (76 mg, 27%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=O)[CH2:5][CH2:4]1.Cl.[NH2:20][OH:21]>C(O)C>[CH3:1][N:2]([CH3:18])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=[N:20][OH:21])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CN(C)C1(c2ccccc2)CCC(C)(C=O)CC1
Agent: Cl
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(C)(C=NO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the title compound of step 2 (5.90 g, 24.0 mmol) and hydroxylamine hydrochloride (2.50 mg, 36.0 mmol) in abs. ethanol (100 mL) were mixed with Amberlyst A 21 (17.0 g) and stirred for 20 h at RT. The ion exchanger was filtered off, the solution concentrated to low volume and the residue made alkaline with 1N NaOH. The aqueous phase was extracted with ethyl acetate, dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([O:14][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=1)[CH2:16][NH2:17])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([O:14][CH:11]([CH3:13])[CH3:12])[C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=1)=[O:6]
Reactant: Cc1ncc(C(CN)OC(C)C)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)OC(C)C)cn1

Procedure:
From 2-chlorobenzoic acid and 2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=334.0, tR (minutes, Method E)=0.52
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].[C:12](Cl)([Cl:14])=[O:13].C1(C)C=CC=CC=1>C1COCC1>[C:12]([Cl:14])(=[O:13])[O:11][CH2:10][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=1
Reactant: N#Cc1cc(Cl)cc(CO)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(COC(=O)Cl)c1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
3-Chloro-5-(hydroxymethyl)benzonitrile (25 g, 145 mmol) was dissolved in THF (200 mL). The resulting yellow solution was cooled to 10° C. in an ice bath and treated dropwise with phosgene in toluene (152 mL, 289 mmol). The reaction mixture was stirred at ambient temperature for 16 hrs. The mixture was concentrated under reduced pressure and the crude material was diluted with toluene (200 ml) and re-concentrated under reduced pressure. The residue was purified by chromatography on silica (Redisep 340 g column on a Biotage system), eluting with EtOAc/iso-hexane to give 3-chloro-5-cyanobenzyl carbonochloridate as an oil.