Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)[CH3:2].[OH-].[Na+].CC1C=CC(S(O[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=2)(=O)=O)=CC=1>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])=[CH:45][CH:46]=3)=[C:19]([O:24][CH3:25])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(C(F)(F)C(F)(F)F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
To a stirred solution of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-36-1) (0.24 g, 0.52 mmol) in tetrahydrofuran (20 mL) was added 5M aqueous sodium hydroxide solution (0.2 mLs, 1.00 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, and the residue was dissolved in N,N-dimethylformamide (10 mL). The mixture was treated with 4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate (0.40 g, 1.04 mmol), and the mixture was warmed to 80° C. After 3 h, the mixture was allowed to cool to room temperature and was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to provide 0.090 g of ethyl(6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]I.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])[CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Temperature: 25 °C

Procedure:
[II; R=5-CH3O, R'=CH3, R"=H, OR°=4-OCH2C6H5, Alk=CH3 ] is obtainable by N-alkylation of 1-[2-(4-benzyloxyphenylamino)-5-methoxyphenyl]ethanone (Example 1b) with methyl iodide in the presence of sodium hydride. A preferred procedure is to add slowly methyl iodide in excess to a cooled (0° C.) suspension of starting material and sodium hydride in an inert solvent, e.g. dimethylformamide, and stirring the reaction mixture at ambient temperature until the reaction is complete.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][CH3:15])[NH:11][C:10](=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:19].C(=O)(O)[O-].[Na+]>>[Cl:19][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=[C:12]([CH2:14][CH3:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc(-c2cccc(Cl)c2)cc(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc(Cl)cc(-c2cccc(Cl)c2)n1
Temperature: 85 °C
Yield: 81 %

Procedure:
A mixture of 6-(3-chlorophenyl)-2-ethylpyrimidin-4(3H)-one (0.240 g, 1.0 mmol) and POCl3 (5 mL) was heated to 85° C. for 6 h. After this time, the reaction was cooled, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound as an off-white solid (0.210 g, 81%). MW=253.13. 1H NMR (CDCl3, 500 MHz) δ 8.10 (t, J=1.9 Hz, 1H), 7.96-7.92 (m, 1H), 7.55-7:41 (m, 3H), 3.03 (q, J=7.6 Hz, 2H), 1.55 (s, 1H), 1.42 (t, J=7.6 Hz, 3H); APCI MS m/z 254 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[N:32]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][N:34]=[CH:33]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:40]3[CH2:39][CH2:38][CH:37]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH2:42][CH2:41]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: c1cn(C2CCNCC2)cn1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCC(n4ccnc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
660 mg of N,N'-carbonyldiimidazole were added to a solution of 1.52 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 15 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 538 mg of 4-(imidazol-1-yl)piperidine in 5 ml of dry acetonitrile was then added to the solution, and the mixture was stirred at room temperature for 30 minutes and then at 40° C. for a further 7 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with an aqueous solution of sodium hydrogencarbonate, with water and with an aqueous solution of sodium chloride, in that order. The organic solution was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by reverse phase column chromatography through 200 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using a gradient elution method, with mixtures of acetonitrile and water ranging from 50:50 to 55:45 by volume as the eluent. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 1.45 g of the title compound, as a powder.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[CH:21]=C.[OH-].[Na+]>CN(C)C=O>[CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13])[CH:20]=[CH2:21]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC=O
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCNc1ccc([N+](=O)[O-])cc1C
Temperature: 70 °C
Yield: 96.2 %

Procedure:
60 g (0.33 mol) of N-formyl-2-methyl-4-nitroaniline were dissolved in 500 ml of dimethylformamide. 184 g (1.33 mol) of potassium carbonate were added, and the resultant solution was warmed to 50° C. 152.8 g (2 mol) of allyl chloride were added dropwise in the course of 50 minutes to the mixture at 50° C. When the alkylation reaction was complete, the resultant reaction mixture was warmed to 70° C. and 350 g of 1 N sodium hydroxide solution were slowly added dropwise. The resultant mixture was stirred at 70° C. for 2.5 hours and subsequently poured into 3 l of ice water. The precipitate was filtered off with suction, washed with water until neutral and subsequently dried at 50° C. under reduced pressure, to give 61 g of N-allyl-2-methyl-4-nitroaniline (yield: 95%), which was recrystallized as described under section 1.4 and then had the same physical chemical properties as the compound prepared in accordance with section 1.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:15][CH:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:15]([CH:16]([CH3:18])[CH3:17])=[O:27])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)Sc1cccc(-c2ccc(Cl)cc2Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)c1cccc(-c2ccc(Cl)cc2Cl)c1
Yield: 84.5 %

Procedure:
To 1.0 g (3.4 mmol) of [3-(2,4-dichlorophenyl)phenyl]isopropyl sulfide in 50 ml of chloroform, 0.7 g (4.1 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred for 2 hours. The reaction mixture was stirred at room temperature for another 12 hours, and 5% aqueous sodium bicarbonate was added for separation. The chloroform layer was washed with 5% aqueous sodium sulfite and water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.9 g of [3-(2,4-dichlorophenyl)phenyl]isopropyl sulfoxide (yield 85.0%) as a colorless dough (nD20 1.6169).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12](=[O:26])[C:13]([CH3:25])=[CH:14][C:15]=1[C:16]([NH:18][O:19][CH2:20][CH2:21][O:22]C=C)=[O:17]>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12](=[O:26])[C:13]([CH3:25])=[CH:14][C:15]=1[C:16]([NH:18][O:19][CH2:20][CH2:21][OH:22])=[O:17]
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Solvent: CO
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 0 °C

Procedure:
The final product from Example 16 (25 mg) was placed in a Syn 10 (Radleys) reaction tube together with a magnetic stirrer, and the material was dissolved in methanol by the addition of one aliquot (1 mL) of methanol preheated to 50° C. with stirring. A further 5 mg of methanol was added to the reaction tube to ensure a super-saturated solution was produced on cooling. When the majority of the solid had dissolved, the resultant solution was filtered through a Pall 0.45 μm PTFE Acrodisc CR13 filter into a second tube at 50° C. in the Syn 10. The tube was then cooled to 0° C. at a rate of 3° C./min and held at 0° C. until the material had crystallized. The samples were filtered off, dried by suction then by standing in ambient conditions. The solids were carefully removed from the filter paper and examined by XRPD.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[NH2:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>CN(C)C=O>[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[NH:51][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 72 h
Yield: 95 %

Procedure:
5-Chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzotriazole monohydrate (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.95 g) were added to a solution of (±)-trans-N-tert-butoxycarbonyl-1,2-cyclohexanediamine (3.00 g) in N,N-dimethylformamide (10 ml) at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and dichloromethane (30 ml), a saturated aqueous solution (150 ml) of sodium hydrogencarbonate and water (150 ml) were added to the residue. After collecting colorless precipitate formed was collected by filtration and dried to obtain the title compound (5.21 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:20])[C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]1[O:20][C:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[N:7][N:6]=1
Reactant: O=C(NNC(=O)c1c(F)c(F)c(F)c(F)c1F)c1cc(Cl)ccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1c(F)c(F)c(-c2nnc(-c3cc(Cl)ccc3Cl)o2)c(F)c1F
Yield: 81 %

Procedure:
By the general method of Part B of Example 2, the reaction of 21.0 g (0.05377 mol) 2,5-dichloro-N′-(pentafluorobenzoyl)benzohydrazide in POCl3 gave a product which was recrystallized from ethanol/water to give 16.59 g (81% yield) of 2-(2,5-dichlorophenyl)-5-(pentafluorophenyl)-1,3,4-oxadiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29].C(=O)([O-])[O-]>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>[CH:28]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:21])=[O:22])[CH2:18][CH2:19]2)[CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: O=Cc1cccc(B(O)O)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-]
Solvent: O
Solvent: C1COCCO1
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C
Yield: 68.9 %

Procedure:
To a solution of 5-bromo-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (420 mg, 0.9 mmol) in dioxane (6.0 mL) and water (2.0 ml), (3-formylphenyl)boronic acid (750.0 mg, 5.0 mmol), Pd(PPh3)4 (100.0 mg, 10%) and cessium carbonate (800 mg, 1.8 mmol) were added. The reaction mixture was heated in a Smith synthesizer microwave at 160° C. for 20 min. All solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (300.0 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[CH2:26][C:25]3[C:20](=[C:21]([N+:27]([O-])=O)[CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:30])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>CO.C(OCC)(=O)C.CO.[Pd]>[NH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[C:19](=[O:30])[N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:26]2
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reaction time: 20 h
Yield: 53.7 %

Procedure:
A suspension of 2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-nitro-2,3-dihydro-isoindol-1-one (3.0 g, 6.9 mmol) and Pd/C (10% 350 mg) in methanol/ethyl acetate (150 mL each) was shaken under hydrogen (50-60 psi) in a Parr for 20 hours. The suspension was filtered thru a pad of Celite, and washed with acetone (300 mL). The solvent was removed in vacuo to give a solid. The solid was slurried in methanol (10 mL) for 3 hours. The suspension was filtered and washed with methanol to give 7-amino-2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one as a white solid (1.5 g, 55% yield): mp, 135-137° C.; 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.93 (s, 3H, CH3), 3.66 (dd, J=5, 15 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.06 (q, J=7 Hz, 2H, CH2), 4.13 (d, J=16 Hz, 1H, CHH), 4.22 (dd, J=10, 15 Hz, 1H, CHH), 4.35 (d, J=17 Hz, 1H, CHH), 5.19 (brs, 2H, NH2), 5.64 (dd, J=5, 10 Hz, 1H, NCH), 6.54 (d, J=8 Hz, 1H, Ar), 6.61 (d, J=7 Hz, 1H, Ar), 6.83 (d, J=8 Hz, 1H, Ar), 6.90-6.96 (m, 2H, Ar), 7.20 (t, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.59, 41.28, 48.01, 51.81, 55.87, 56.14, 64.48, 110.98, 111.38, 112.22, 113.41, 114.75, 119.23, 129.89, 133.08, 142.36, 146.02, 148.72, 149.45, 170.57; Anal Calcd for C20H24N2O5S: C, 59.39; H, 5.98; N, 6.93. Found: C, 59.04; H, 6.04; N, 6.74.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(Cl)cccc23)cc1
Yield: 49 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and cyclopentylbromide (0.107 mL, 1.0 mmol) to give the title compound (0.080 g) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[C:29]([Sn](CCCC)(CCCC)CCCC)=[N:28]1>CN(C=O)C.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.[Cu]I>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=4[N:27]([CH3:26])[N:28]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCC2
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCC2
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 22.1 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 234 μmol) and 1-methyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (99.5 mg, 234 μmol) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (13.5 mg, 11.7 μmol) and CuI (8.91 mg, 46.8 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (60 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give N-tert-butyl-2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 51.8 μmol, 22.1%) as an off-white solid. MS (M+Na)+=505; 1H NMR (CDCl3) δ: 9.12 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 5.73 (s, 2H), 3.90 (s, 3H), 3.54-3.68 (m, 2H), 3.06 (t, J=6.0 Hz, 2H), 2.63-2.78 (m, 2H), 1.91-2.06 (m, 2H), 1.77-1.90 (m, 2H), 1.62 (s, 9H), 0.95-1.02 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[N:7]2.I[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[N:7]2
Reactant: Cc1nc(-c2ccccc2)n2nc(N)ncc12
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2)n2nc(Nc3cccc(C(F)(F)F)c3)ncc12
Yield: 81.2 %

Procedure:
In a similar manner as described for Example 25, 5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride (26 mg, 0.1 mmol), 1-iodo-3-(trifluoromethyl)benzene (33 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol), 2-(di-t-butylphosphino)biphenyl (10 mg, 0.03 mmol) and sodium t-butoxide (25 mg, 0.23 mmol) in dioxane (0.80 mL) gave 5-methyl-7-phenyl-N-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (30 mg, 81%) as a yellow solid. 1H NMR (CDCl3): δ8.83 (s, 1H), 8.46-8.49 (m, 2H), 8.33 (s, 1H), 7.43-7.57 (m, 5H), 7.35 (d, J=7.51 Hz, 1H), 7.08 (s, 1H), 2.63 (s, 3H). MS m/z 369 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.CS(C)=O.CO.CO>[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:61]=[C:60]4[C:56]([CH:57]=[N:58][NH:59]4)=[C:55]([NH:62][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[O:10])[CH:54]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cc1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.2 %

Procedure:
To a solution of 5-methyl-2-pyridinecarboxylic acid (55 mg, 0.40 mmol, available from Synchem OHG) in DMF (2 ml) was added HATU (150 mg, 0.40 mmol) and DIPEA (0.211 ml, 1.21 mmol). The mixture was stirred at room temperature for 20 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the mixture stirred at room temperature for 18 h. The reaction mixture was added to the top of a 2 g aminopropyl cartridge that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The solvent was removed in vacuo to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with DCM/MeOH (1:1) and the solvent removed under a stream of nitrogen to give the title compound (20 mg) as a cream solid.