Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:26]2[CH2:27][CH2:28][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25]2)[CH2:32][CH2:31]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.403 mmol), 1-methyl-4-piperidone (0.099 mL, 0.806 mmol), sodium triacetoxyborohydride (113 mg, 0.537 mmol) and glacial acetic acid (48 mg, 0.806 mmol) were mixed with 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (85:15) as mobile phase to give 1-[1-(1-methyl-4-piperidyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (148 mg, 78%). 1H NMR (DMSO-d6) δ 1.42 (m, 2H), 1.81 (m, 2H), 1.92 (m, 2H), 2.15 (m, 1H), 2.26 (m, 2, 3H), 2.28 (m, 2H), 2.75 (m, 4H), 2.86 (m, 1H), 3.22 (m, 1H), 5.36 (m, 1H), 7.16 (m, 5H), 7.44 (m, 2H), 7.67 (m, 2H), 8.24 (s, 1H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+ =470.4, Rt=2.01.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:32][C:31]=12
Reactant: c1ccc2c(c1)Cn1ccnc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. After-stirring for 3 minutes, 5 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, and brine. The solution is dried with Na2SO4 and the volatiles concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:19]([NH:21][C@H:22]([C:24]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=[O:36])[C:27]5=[C:37]([CH3:40])[CH:38]=[CH:39][N:26]5[N:25]=4)[CH3:23])=[N:18][CH:17]=[N:16][C:15]=3[N:14](COCC[Si](C)(C)C)[CH:13]=2)[CH:9]=[C:8]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:7]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.N>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([NH:49][S:50]([CH3:53])(=[O:51])=[O:52])[CH:9]=[C:10]([C:12]2[C:20]3[C:19]([NH:21][C@H:22]([C:24]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=[O:36])[C:27]5=[C:37]([CH3:40])[CH:38]=[CH:39][N:26]5[N:25]=4)[CH3:23])=[N:18][CH:17]=[N:16][C:15]=3[NH:14][CH:13]=2)[CH:11]=1)(=[O:3])=[O:4]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 82.8 %

Procedure:
(S)-3-(Methylsulfonamido)-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl methanesulfonate (169 mg, 0.19 mmol) was treated with trifluoroacetic acid (4.7 ml, 61 mmol) and a solution of ammonia (7N in methanol, 4.0 ml, 17 mmol) according to the method described in Example 27 to give 102 mg (83% yield) of the title compound. Purity 99%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)CC1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:2][NH:3][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1
Reactant: [H][H]
Reactant: CN(CCCCOc1cccc(C(F)(F)F)c1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCCCOc1cccc(C(F)(F)F)c1
Yield: 25.8 %

Procedure:
A mixture of intermediate 8 (0.019 mol) in methanol (150 ml) was hydrogenated with palladium on carbon (10%, 2 g) as a catalyst. After uptake of hydrogen gas (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the free base with a NaOH solution. The aqueous solution was extracted with toluene. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was converted into the hydrochloric acid salt (1:1) in DIPE. The precipitate was filtered off and dried, yielding 1.21 g (22.5%) of N-methyl-4-[3-(trifluoromethyl)phenoxy]-1-butanamine (intermediate 9).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:21])[CH:9]=[CH:10][CH:11]=1.Cl.O>O1CCCC1>[CH3:21][C:13]1[N:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[CH:2]=[O:1])[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: Cc1cc2ccccc2n1-c1cccc(C2OCCO2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2ccccc2n1-c1cccc(C=O)c1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 5.4 %

Procedure:
1-[3-(1,3-Dioxolan-2-yl)phenyl]-2-methyl-1H-indole (1.1 g, 3.94 mmol) synthesized according to the method described in J. Am. Chem. Soc., 2002, vol. 124, pp. 11684-11688 was dissolved in tetrahydrofuran (40 mL), 5 N hydrochloric acid (10 mL) was added to the solution, and the mixture was stirred at 50° C. for 40 min. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:6) to give the title compound (50 mg, yield 5%) as a pale-yellow oil. MS: m/z 236 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:23][N:22]([CH3:31])[N:21]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.FC1C=C(O)C=CC=1C1C(C2C=CN=CC=2)=CN(C[C:51]([F:54])([F:53])[F:52])N=1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:23][N:22]([CH2:31][C:51]([F:54])([F:53])[F:52])[N:21]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2F)n1
Solvent: CC(C)=O
Product: Fc1cc(OCc2ccc3ccccc3n2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[3-Fluoro4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 3-Fluoro4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol and acetone as the solvent provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (m, 2 H), 7.80 (s, 1H), 7.31 (t, J=8.3 Hz, 1H), 7.24 (m, 5 H), 6.72 (dd, J=8.3, 2.5 Hz, 1 H), 6.50 (dd, J=11.6, 2.1 Hz, 1 H), 4.81 (q, J=8.4 Hz, 2H); MS: (M+H m/z=479.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](Cl)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH:27][CH3:26])=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(Cl)nccc3c2)CC1
Product: CNc1nccc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc12

Procedure:
154 mg (0.42 mmol) of 4-(1-Chloro-isoquinolin-6-yloxy)-piperidine-1-carbocyclic acid tert-butyl ester (162) were heated in 15 ml of an aqueous methylamine-solution (41%)) at 110° C. in a sealed tube. After 7 h the reaction mixture was evaporated and the residue was taken up in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and the solvent was removed i. vac. The residue was purified by silica gel chromatography (ethyl acetate/methanol 5:1). Yield: 45 mg. Rt=1.14 min (Method #4). Detected mass: 358.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7]([Cl:25])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)O)c2)c1
Product: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Cl)c2)c1

Procedure:
190 mg (0.562 mmol) of [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetic acid (5-3) was refluxed in an excess of thionyl chloride for 5 hours. After this time the reaction was cooled and the thionyl chloride was removed in vacuo and the resultant oil solidified upon storage under reduced pressure to yield the desired product 5-4. 1H NMR(CDCl3): 4.94 (s, 2H), 6.49 (m, 1H), 6.71 (m, 1H), 6.74 (m, 1H), 7.16 (m, 1H), 7.23 (m, 1H), 7.41 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:13][O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
To a solution of methyl 2-hydroxy-4-methylbenzoate (3 g; 18.2 mmol) in DMF (36 mL) was added potassium carbonate (5 g; 36.4 mmol) and methyl iodide (3.35 mL; 182 mmol) dropwise. The reaction mixture was stirred at room temperature for 24 hours. The insoluble's were filtered, washed with ethyl acetate and the volatiles were removed under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate (1 to 30%) in heptane to furnish 2.78 g of the methyl 2-methoxy-4-methylbenzoate (85%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][N:11]([C:14]4[C:15](=[O:28])[NH:16][C:17]5[C:22]([N:23]=4)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=5)[C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1.N1C=CC=CC=1.[O:35](S(C(F)(F)F)(=O)=O)[S:36]([C:39]([F:42])([F:41])[F:40])(=O)=[O:37]>ClCCl>[O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][N:11]([C:14]4[C:15]([O:28][S:36]([C:39]([F:42])([F:41])[F:40])(=[O:37])=[O:35])=[N:16][C:17]5[C:22]([N:23]=4)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=5)[C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (140 mg, 0.37 mmol) in dichloromethane (80 ml) was added pyridine (175 mg, 2.21 mmol) and Tf2O (510 mg, 1.81 mmol). The reaction was stirred overnight under atmosphere of nitrogen at room temperature. Then the reaction mixture was quenched with water (200 ml), extracted with dichloromethane (3×20 ml), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-5(6H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a red oil (150 mg, crude), which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:23])=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[N:6][CH:7]=1.[S-:24][C:25]#[N:26].[K+].BrBr>C(O)(=O)C>[C:18]([O:17][C:16](=[O:22])[NH:15][C:13]1[CH:14]=[C:9]([O:8][C:5]2[N:6]=[C:7]3[S:24][C:25]([NH2:26])=[N:1][C:2]3=[CH:3][CH:4]=2)[CH:10]=[CH:11][C:12]=1[F:23])([CH3:19])([CH3:20])[CH3:21]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)ccc1F
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl {5-[(5-aminopyridin-2-yl)oxy]-2-fluorophenyl}carbamate (3.00 g, 9.4 mmol) and potassium thiocyanate (3.93 g, 40 mmol) in acetic acid (40 mL) was added dropwise bromine (2.40 g, 15 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (3.20 g, 90%) as a pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCCCC)=O>C(#N)C>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:11]=[N:24][NH:5]2
Reactant: CCCCCON=O
Reactant: COc1ccc(N)c(C)c1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: COc1ccc2[nH]ncc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 3-bromo-4-methoxy-2-methylaniline (19.06 g) in acetonitrile (250 mL) was slowly added acetic anhydride (18.9 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added potassium acetate (2.60 g) and pentyl nitrite (22.3 g), and the mixture was heated under reflux for 8 hr. The reaction mixture was concentrated, and to the residue was added 6M hydrochloric acid (200 mL), and the mixture was heated under reflux overnight. The reaction mixture was neutralized with 8M sodium hydroxide, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was dissolved in tetrahydrofuran, and the solution was treated with activated carbon. The activated carbon was filtered off, the filtrate was concentrated, and the obtained residue was crystallized from diisopropyl ether. The crystals were collected by filtration, washed with diisopropyl ether, and dried to give the title compound (10.42 g, yield 52%) as yellow crystals. melting point 178-180° C. MS: 229 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-nicotinic acid (2.3 g, 8.5 mmol) was dissolved in DMF (75 mL). To the solution was added TBTU (2.99 g, 9.3 mmol), N,N-diisopropylethyl amine (7.2 mL, 42 mmol) and (trans)-2-amino-cyclohexanol (1.4 g, 9.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 2.5 g of the title compound as a white solid, MS (ISP) 368.9, 371.0 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][OH:6].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C1C=CN=CC=1.O1CCOCC1>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:18])[N:1]1[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: NC(CCCO)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1C(CCCO)c1ccccc1
Temperature: 155 °C

Procedure:
Heat a solution of δ-aminobenzenebutanol (7.32 g), phthalic anhydride (6.57 g) and 4-(dimethylamino)pyridine (0.050 g) in dioxane (100 ml) under a nitrogen atmosphere at reflux for one hour. Evaporate the solvent at atmospheric pressure and heat the residue at 155° C. under a nitrogen atmosphere for 21/2 hours. After cooling, dissolve the residue in EtOAc (400 ml). Wash the solution with 10% aqueous citric acid (50 ml) followed by saturated aqueous NaHCO3 (50 ml) and brine (50 ml). Dry the organic layer over Na2SO4, filter and vacuum evaporate the solvent to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[CH2:23]([N:25]([CH2:33][CH:34]=[CH2:35])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24]>>[CH:15]1([CH2:14][C:13]([NH:12][C:8]2[C:7]([CH3:22])=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([CH2:35][CH2:34][CH2:33][N:25]([CH2:23][CH3:24])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:3]3)=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=CCN(CC)C(=O)OC(C)(C)C
Reactant: Cc1ccc2nc(Cl)ccc2c1NC(=O)CC1CCCCC1
Product: CCN(CCCc1ccc2c(NC(=O)CC3CCCCC3)c(C)ccc2n1)C(=O)OC(C)(C)C
Yield: 44 %

Procedure:
Prepared according to the method of example 1(b), using N-(2-chloro-6-methyl-5-quinolinyl)-cyclohexaneacetamide (Example 15 (a)) (400 mg) and ethyl(2-propenyl)-carbamic acid, 1,1-dimethylethyl ester (Example 15 (b)) (277 mg). Purification (SiO2, ethyl acetate:isohexane 20:80 as eluant) gave the sub-title compound (260 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: Nc1cccnc1
Product: Clc1nccc(-c2cccc(CNc3cccnc3)c2)n1

Procedure:
Intermediate 1 was coupled with 3-aminopyridine following procedure B. LC-MS showed the product had the expected M+H+ of 297.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]2)=[CH:14][CH:15]=3)[CH:5]=[CH:4][CH:3]=1.[CH:30]1([C:33]#[N:34])[CH2:32][CH2:31]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[N:24]1([C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:16]([C:13]3[N:12]=[C:11]4[N:29]=[C:8]([C:6]5[N:7]=[C:2]([C:30]6([C:33]#[N:34])[CH2:32][CH2:31]6)[CH:3]=[CH:4][CH:5]=5)[NH:9][C:10]4=[CH:15][CH:14]=3)[CH2:17]2)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C([C@@H]1CCCN(c2ccc3[nH]c(-c4cccc(Br)n4)nc3n2)C1)N1CCCC1
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(-c3nc4nc(N5CCC[C@@H](C(=O)N6CCCC6)C5)ccc4[nH]3)n2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a stirred solution of (R)-(1-(2-(6-bromopyridin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (300 mg, 0.658 mmol) in toluene was added cyclopropane carbonitrile. The mixture was cooled to 0° C. then a 1M solution of sodium bis(trimethylsilyl)amide in THF was added dropwise. The reaction mixture was stirred for 16 h at room temperature. The mixture was quenched with water and then was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified via preparative TLC (twice) to afford (R)-1-(6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)cyclopropanecarbonitrile (20 mg, 7%) MS (ES+APCI) (M+H) 442.2; LCMS retention time 2.969 min (Method C1); 1H NMR (400 MHz, CDCl3) δ 1.24-1.31 (m, 4H), 1.65-1.71 (m, 2H), 1.78-2.04 (m, 6H), 2.69 (m, 1H), 3.01 (t, 1H), 3.07-3.18 (m, 1H), 3.43-3.56 (m, 3H), 3.60-3.72 (m, 1H), 4.35 (br s, 1H), 4.54 (d, 1H), 6.72 (d, 1H), 7.48 (d, 1H), 7.79-7.95 (m, 2H), 8.58 (d, 1H), 10.28 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:7][CH:8]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C#N)n1-c1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C#N)n1-c1ccc(COS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
to a solution of 1-(4-hydroxymethylphenyl)-5-methylpyrrole-2-carbonitrile (890 mg) in dichloromethane (9 ml) was added triethylamine (794 μl) and methanesulfonyl chloride (343 μl) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for an hour and then dichloromethane was added therein. The mixture was stirred and washed with water twice and brine, dried over magnesium sulfates and concentrated in vacuo to give 1-(4-methanesulfonyloxymethylphenyl)-5-methylpyrrole-2-carbonitrile (1.19 g).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28]C)=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C.[OH-].[Na+]>CO.C1COCC1>[C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)([OH:28])=[O:27]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2c(Oc3ccc(C(=O)O)nc3)cc(C(=O)O)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.8 %

Procedure:
To a solution of 5-(6-methoxycarbonyl-2,2-dim ethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (110 mg, 0.275 mmol) in 2 mL MeOH and 1 mL THF was added 1N aqueous NaOH (0.55 mL, 0.55 mmol). The mixture was stirred at room temperature overnight, heated at 60° C. for 6 hr, then concentrated, acidified to pH˜3 with 1N aqueous HCl, extracted with 3×EtOAc, dried over Na2SO4, and concentrated to give 113 mg white solid. LCMS for C17H15NO6 m/z 330.00 (M+H+).