Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=C)=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=[O:30])=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1
Reactant: CC(C)=O
Reactant: C=Cc1cc(C)c(Cc2ccc(-c3cn(C)nc3C)nc2)cc1C(=O)OC
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-vinylbenzoate (0.18 g) in a mixed solvent of acetone (2.80 mL)-acetonitrile (2.80 mL)-water (2.80 mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodium periodate (0.53 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.18 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11]2[C:10](=[O:13])[N:8]([CH3:9])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1)[CH3:2].[H-].[Na+].[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:1]([C:3]1[N:12]([CH2:27][CH2:26][CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]2[C:10](=[O:13])[N:8]([CH3:9])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Reactant: BrCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1CCCOc1ccccc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A suspension of 8-ethyltheophylline (20.8 g; 0.1 M) in dry dimethylformamide (100 ml) was added to an oil free suspension of sodium hydride (2.4 g; 0.1 M) in dry dimethylformamide (100 ml) and the mixture was stirred for 30 minutes. 3-Phenoxypropylbromide (21.5 g; 0.1 M) was added and the mixture was stirred at room temperature for 24 hours. The resulting suspension was poured into water and the precipitate was filtered off and dried. The solid was crystallised from ethanol to give 8-ethyl-7-(3-phenoxy propyl)theophylline as white prisms 23.6 g (69%) mp 107°-8°.
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[N:10][N:11]2C(OC(C)(C)C)=O)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:11]1[C:12]2[C:8](=[C:7]([CH2:6][O:5][C:4]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:3]=3[CH:1]=[O:2])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: COc1ccc(OCc2cccc3c2cnn3C(=O)OC(C)(C)C)c(C=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(OCc2cccc3[nH]ncc23)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To tert-butyl 4-((2-formyl-4-methoxyphenoxy)methyl)-1H-indazole-1-carboxylate (88 mg, 0.23 mmol) in DCM (5.0 mL) was added TFA (2.0 mL). The mixture was stirred at rt for 2 h and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde (50 mg, 77%) as a white solid. 1H NMR (400 MHz; CDCl3) δ=10.53 (s, 1H), 8.23 (s, 1H), 7.54 (d, 1H) 7.43 (t, 1H), 7.38 (d, 1H), 7.25 (d, 1H), 7.08-7.15 (m, 2H), 5.51 (s, 2H), 3.82 (s, 3H). LRMS (M+H+) m/z 283.1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11](O)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1.ClCCCl>[C:5]1([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: ClCCCl
Product: c1ccc(C(Cn2cncn2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
26.7 g (0.2 mole) of AlCl3 were added in portions to a solution of 18.9 g (0.1 mole) of 1-phenyl-2-(1,2,4-triazol-1-yl)-ethanol in 50 ml of benzene and 50 ml of 1,2-dichloroethane at -10° C. Thereafter, the mixture was warmed to room temperature in the course of 30 minutes, and was then heated to 80° C., until the evolution of gas was no longer observed. The mixture was poured onto 200 ml of ice-water, the organic phase was separated off and concentrated, and the residue was triturated with diisopropyl ether. Yield 21.4 g (86% ), m.p. 107°-108° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.624 g, 2.1 mmoles), 4-dimethylaminopyridine (27 mg, 0.2 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 100 mL acetonitrile. Valeryl chloride (1.08 mL, 8.9 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). After evaporation of the solvent, the product was further purified on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (85:15). The product containing fractions were combined, concentrated, and loaded onto preparative silica gel plates (20×20×0.2 cm). The plates were developed in a mixture of chloroform-acetone (80:20). The product was scraped from the preparative plate and eluted from the silica gel with ethanol. The product was then flash chromatographed on a silica gel column (2.5×40 cm) with a mixture of chloroform:acetone (95:5). Lyophilization afforded 0.463 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-((pentanoyloxy)methyl)-tetrahydro-2-furyl)-9H-purine as an oil (58% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
In a 200 ml-three-necked flask, 3.40 g (25.0 mmole) of 4-methylphenyl-boronic acid (made by Aldrich Co.), 4.09 g (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 mol of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.80 g (yield=51.1%) of 1-(4-methylphenyl)isoquinoline.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]([F:23])([F:22])[F:21])[C:9]([CH2:24]Cl)=[CH:8]2.CN(C=O)C.[N-:31]=[N+:32]=[N-:33].[Na+]>>[N:31]([CH2:24][C:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]([F:23])([F:22])[F:21])=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:2])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)Oc1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 8-chloro-3-(chloromethyl)-2-(2-(trifluoromethoxy)-phenyl)quinoline hydrochloride (0.6319 g, 1.546 mmol) in DMF (7.732 mL, 1.546 mmol) was added sodium azide (0.2011 g, 3.093 mmol) at room temperature and the mixture was stirred at room temperature. After 1 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 3-(azidomethyl)-8-chloro-2-(2-(trifluoromethoxy)phenyl)quinoline as a colorless syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (1 H, s), 8.11 (1 H, dd, J=8.2, 1.2 Hz), 8.02 (1 H, dd, J=7.6, 1.4 Hz), 7.54-7.74 (5 H, m), 4.52 (2 H, br. s.); LC-MS (ESI) m/z 379.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[C:20]([CH2:19][CH2:18][C:17]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:23])([OH:22])=[O:21]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2COCCOC(=O)CCC(=O)O)c(=O)[nH]1
Yield: 44 %

Procedure:
A mixture of 9-(2-hydroxyethoxymethyl)guanine (0.25 g), succinic anhydride (0.55 g) and pyridine (50 ml) was heated under anhydrous conditions on a steam bath overnight. The solvent was evaporated under reduced pressure at <40° C., the last trace being removed azeotropically with toluene. The residue was triturated with acetone and the product removed by filtration. Recrystallization from methanol afforded 9-{2-(3-carboxypropionyloxy)ethoxymethyl}guanine, m.p. 203°-207° C. (sinter 190° C.), in 44% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH2:13]>C(#N)C.[Cl-].[Na+].O>[CH3:12][NH:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in acetonitrile (60 ml) is added dropwise to a stirred solution of aqueous methylamine (65 mL, 40 wt. %, 0.75 mol) in acetonitrile (50 mL) at 0° C. After stirring an additional 15 minutes, the solution is poured into brine and extracted 2× with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(methylaminomethyl)nitrobenzene (4.04 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[I:28]I.[OH-].[K+]>N1C=CC=CC=1.O1CCCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([I:28])=[CH:4][N:3]=1
Reactant: II
Reactant: Nc1nccc2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1ncc(I)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12

Procedure:
As shown in the Scheme above, 1-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea ((1), prepared as described in WO2005/10009), in a mixture of pyridine and tetrahydrofuran can be treated with iodine at room temperature, followed by treatment with potassium hydroxide at elevated temperature to provide 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2). Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be prepared by reacting 1-(4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (2) with carbon monoxide gas in the presence of a catalyst such as but not limited to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, and a base such as but not limited to triethylamine. The reaction is typically performed under pressure and at an elevated temperature. Methyl 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylate (3) can be reacted with aqueous lithium hydroxide to provide 4-amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4). The reaction is typically performed at elevated temperature in a solvent such as but not limited to tetrahydrofuran and methanol. 4-Amino-3-(4-(3-(3-fluorophenyl)ureido)phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (4) can be reacted with N,N-diethyl-1,3-propanediamine in the presence of a coupling agent such as but not limited to 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, an auxiliary coupling reagent such as but not limited to 1-hydroxybenzotriazole hydrate, and a base such as but not limited to N-methylmorpholine to provide 4-amino-N-[3-(diethylamino)propyl]-3-(4-{[(3-fluorophenyl)carbamoyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxamide (5). The reaction is typically performed in a solvent such as but limited to N,N-dimethylformamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C(N(CC)CC)C>CC(O)C>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)C1

Procedure:
A mixture of tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (1.073 g, 4.682 mmol) as prepared in the previous step and commercially available 4-chloro-6-(trifluoromethyl)quinazoline (990 mg, 4.256 mmol) were stirred in anhydrous iPrOH and triethylamine at 90° C. under argon for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a yellow solid after drying under high vacuum.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH3:12])[CH2:9][CH2:8][N:7]1[CH3:13])=[O:5])C.[OH-].[Na+].Cl.CCOCC>CCO>[CH3:13][N:7]1[CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CN(C)CCN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CN1CCN(C)C(C(=O)O)C1
Yield: 48.2 %

Procedure:
Ethyl 1,4-dimethylpiperazin-2-yl carboxylic acid (1.86 g) was dissolved in EtOH (10 mL) and 5M aqueous NaOH (20 mL) added. The mixture was refluxed for 2 hours, allowed to cool, 10M HCl (9.1 mL) added to give pH4 and the mixture evaporated to dryness. The white solid was stirred with MeOH (25 mL), CH2 Cl2 (10 mL) added and the filtrate evaporated to give, after trituration with Et2O, the title compound as a grey solid (761 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[CH2:14][CH2:15][CH2:16][Cl:17].O>C1COCC1>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: ClCCCCc1ccncc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
4-Methylpyridine (8.4 g, 90 mmol) and THF (40 mL) were mixed in dry glassware, flushed with nitrogen and cooled to −60° C. n-BuLi (1.6 M solution, 61.9 mL, 99 mmol) was added dropwise over 1.5 h. The temperature was not allowed to exceed −50° C. The mixture was then allowed to reach rt, THF (20 mL) was added and the mixture was then stirred at 45° C. for 2 h. Additional THF (20 mL) was added. This mixture was cooled to 0° C. and added dropwise through a cooled dropping funnel to a 65° C. solution of 3-bromo-1-chloropropane (14.9 g, 94.5 mmol) in THF (15 mL). The reaction mixture was slowly allowed to reach 0° C. overnight. Water (90 mL) was added, and the mixture was stirred for 10 min. The organic layer was separated and dried (Na2SO4) to give the sub-title compound in 97.6% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C1C(O)=CC=C(C)C=1.CS(O[CH:30]([C:44]#[N:45])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)(=O)=O>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH:30]([C:44]#[N:45])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:32]=3)=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC2C(C(=O)O)C2(C)C)cc1
Reactant: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Agent: Cc1ccc(O)cc1
Product: Cc1ccc(OC2C(C(=O)OC(C#N)c3cccc(Oc4ccccc4)c3)C2(C)C)cc1

Procedure:
Following the procedure of Example 2, 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylic acid is prepared from 4-cresol, which is then reacted with α-cyano-m-phenoxybezyl methanesulfonate to yield α-cyano-m-phenoxybezyl 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([N:23]([CH3:22])[CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: CNCCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 160 °C
Yield: 14.1 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), N-methyl-2-phenylethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. for in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (50 mg) as a yellow solid. LC-MS (ES) m/z=360 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.85 (t, J=7.6 Hz, 2H), 3.0 (s, 3H), 3.76 (t, J=7.6 Hz, 2H), 5.37 (s, 2H), 6.04 (s, 2H), 6.39 (s, 1H), 7.19-7.23 (m, 1H), 7.30-7.32 (m, 4H), 7.53 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH:2]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1ccc2ccc(C=O)cc21
Yield: 42.4 %

Procedure:
A solution of 6-hydroxymethyl-1H-indole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 31; 5.10 g, 20.6 mmol) and o-iodoxybenzoic acid (prepared by the literature procedure: Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022; 8.00 g, 28.6 mmol) in dimethylsulfoxide (25 mL) was stirred at room temperature for 4 h. Water (200 mL) was added and the solution was extracted with dichloromethane (3×100 mL). The combined extracts were washed with brine (200 mL), dried (MgSO4), filtered, evaporated in vacuo. The residual material was chromatographed over silica gel (20-30% ethyl acetate/hexanes) to give 6-formyl-1H-indole-1-carboxylic acid, 1,1-dimethylethyl ester (2.14 g, 42% yield) as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]1)=[O:7].Cl>CO.O1CCOCC1>[NH2:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)c2nccs2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H]1CCN(C(=O)c2nccs2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 1c (5.5 g, 18.52 mmol) in MeOH (30 mL) was added an HCl solution in dioxane (4M, 50 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation. Ether (100 mL) was added to the residue. The resultant white solid was collected by filtration, washed with hexanes, and dried under reduced pressure. The crude compound 1d was used in the next reaction without further purification. MS m/z (M+H+) 198.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1([C:29]#[N:30])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:29]([C:26]1([NH:25][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:23])[CH2:28][CH2:27]1)#[N:30]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: N#CC1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C#N)CC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (90 mg, 0.29 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (41 mg, 0.348 mmol), EDCI (110 mg, 0.58 mmol) and DMAP (75 mg, 0.58 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered to give the crude product which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 40% acetonitrile/60% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-cyanocyclopropyl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (25 mg, 23%) as a white solid. MS: (M+H)+=376; 1H NMR (300 MHz, DMSO): δ 12.95 (s, 1H), 9.10 (s, 1H), 8.87 (s, 1H), 8.56-8.53 (m, 2H), 6.69 (d, 1H, J=8.7 Hz), 7.26 (t, 1H, J=8.7 Hz), 4.15 (s, 3H), 1.70 (brs, 2H), 1.64 (brs, 2H).