Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CC1(C)C(C)(C)OB(C2C=C([CH2:52][NH:53]C(=O)CCCC)C=CC=2)O1>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29]([C:30]5[N:53]([CH3:52])[CH:33]=[CH:32][CH:31]=5)=[O:34])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCCCC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCCC(=O)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(=O)c5cccn5C)c4)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-indole-7-carboxamide substituting 1-methyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1H-pyrrole-2-carboxamide (49 mg, 0.144 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Gilson Preparatory HPLC to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[N:10][C:9]([N:12]3[CH2:17][C@@H:16]4[CH2:18][C@H:13]3[CH2:14][NH:15]4)=[CH:8][CH:7]=2)=[CH:2]1.[CH:19](O)=O.C=O>>[NH3:10].[CH3:19][N:15]1[CH2:14][C@@H:13]2[CH2:18][C@H:16]1[CH2:17][N:12]2[C:9]1[N:10]=[N:11][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:7][CH:8]=1
Reactant: c1cc(-c2ccc(N3C[C@@H]4C[C@H]3CN4)nn2)cs1
Reactant: O=CO
Agent: C=O
Product: CN1C[C@@H]2C[C@H]1CN2c1ccc(-c2ccsc2)nn1
Product: N
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 2-[6-(3-thienyl)-3-pyridazinyl]-(1S,4S)-(+)-2,5-diazabicyclo-[2.2.1]-heptane (0.21 g, 0.81 mmol), formic acid (0.92 ml, 24.4 mmol) and formaldehyde (0.68 ml, 24.4 mmol) was stirred at 100° C. for 6 hours. The mixture was evaporated. Aqueous sodium hydroxide (30 ml, 1 M) was added followed by extraction with ethyl acetate (3×30 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as an oil. Yield 0.15 g, 77%.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)[CH3:19]>>[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1)[CH3:19]
Reactant: CCc1ccccc1B(O)O
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: CCc1ccccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-ethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][S:21][C:22]2[N:23]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:24]([C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=3)([CH3:29])[CH3:28])=[CH:25][N:26]=2)=[C:15]([Cl:46])[CH:14]=1)(=[O:12])=[O:11])(=[O:4])=[O:3].[CH3:47][N:48]1[CH:52]=[CH:51][N:50]=[CH:49]1>CC#N>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[Cl:46][C:15]1[CH:14]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][CH2:6][N+:50]2[CH:51]=[CH:52][N:48]([CH3:47])[CH:49]=2)(=[O:11])=[O:12])[CH:18]=[C:17]([F:19])[C:16]=1[CH2:20][S:21][C:22]1[N:23]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[C:24]([C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=2)([CH3:29])[CH3:28])=[CH:25][N:26]=1
Reactant: Cn1ccnc1
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Solvent: CC#N
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCC[n+]4ccn(C)c4)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Product: CS(=O)(=O)[O-]
Yield: 16 %

Procedure:
A mixture of 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenylsulfonamido)propyl methanesulfonate (50 mg, 0.064 mmol) and 1-methylimidazole (0.1 mL) in CH3CN was refluxed in sealed tube for 3 h. After cooling and evaporation of volatiles, the residue was purified by column chromatography (DCM/MeOH=5:1) to give the title compound (8 mg, 16% yield). 1H NMR (400 MHz, CD3OD) δ 8.98-8.94 (m, 1H), 7.66 (d, J=1.95 Hz, 1H), 7.61 (t, J=1.73 Hz, 2H), 7.47-7.39 (m, 1H), 7.24 (s, 1H), 6.99-6.89 (m, 1H), 6.83 (t, J=8.63 Hz, 2H), 6.65-6.56 (m, 1H), 6.56-6.48 (m, 1H), 6.32 (dd, J=8.88, 4.80 Hz, 2H), 4.37 (t, J=6.77 Hz, 3H), 4.02 (d, J=1.33 Hz, 3H), 3.95 (s, 4H), 3.73 (d, J=3.60 Hz, 4H), 2.99-2.88 (m, 3H), 2.69 (d, J=3.79 Hz, 14H), 2.15-2.05 (m, 3H), 1.51 (s, 9H); MS (EI) m/z 704 (M+).
Reaction SMILES: C(OC(=O)C)(=O)C.[S:8]1[C:12]2=[N:13][C:14]([C:20]([OH:22])=[O:21])=[C:15]([C:17]([OH:19])=O)[CH:16]=[C:11]2[CH:10]=[CH:9]1.N#N.N1C=CC=CC=1>C(COC)OC>[S:8]1[C:12]2=[N:13][C:14]3[C:20](=[O:21])[O:22][C:17](=[O:19])[C:15]=3[CH:16]=[C:11]2[CH:10]=[CH:9]1
Reactant: O=C(O)c1cc2ccsc2nc1C(=O)O
Agent: N#N
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1OC(=O)c2nc3sccc3cc21
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Acetic anhydride (37.4 g, 0.366 mol) is added to a stirred suspension of thieno[2,3-b]pyridine-5,6-dicarboxylic acid (21.52 g, 0.096 mol) in dimethoxyethane (175 mL) in an inert N2 atmosphere. Upon addition of pyridine (16.78 g, 0.21 mol) at room temperature an exotherm to 45° C. is observed and a homogeneous solution results. The reaction mixture is then stirred at room temperature and the resulting solid filtered off, washed with ether and air dried to give 14.8 g (75%) of thieno[2,3-b]pyridine-5,6-dicarboxylic acid anhydride.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH2:8])=[CH:5][N:6]=1.CS[C:11](=[N:14][N+:15]([O-:17])=[O:16])[NH:12][CH3:13]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:11]([NH:12][CH3:13])=[N:14][N+:15]([O-:17])=[O:16])=[CH:5][N:6]=1
Reactant: NCc1cnc(Cl)s1
Reactant: CNC(=N[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Yield: 71.3 %

Procedure:
A mixture of 0.48 g of 2-chloro-5-thiazolemethanamine, 0.31 g of S-methyl-N-methyl-N'-nitroisothiourea prepared by the method described in the Journal of Medical Chemistry., 1977, Vol. 20, No. 7, P. 905 and 3 ml of ethanol was heated under reflux for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Solvent: Chloroform/Methanol =20/1) to obtain 0.37 g of the title compound as crystals. This compound is No. 8 in Table 1. m.p.: 151.0°-153.0° C.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=1)=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:32][CH3:33]>CN(C=O)C>[CH2:32]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH3:33]
Reactant: Cc1cc(C=CC#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C(=O)c2cc(C)cc(C=CC#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a stirred solution of 3-[3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (Compound 55) (323 mg, 1 mmol) and anhydrous powdered potassium carbonate (165 mg, 1.2 mmol) in DMF at room temperature, was added iodoethane (97 μL, 1.2 mmol). After stirring overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to give 190 mg (54%) of 3-[3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (73) as a white solid. The product was recrystallized from chloroform-ether. m.p. 174-176° C.; 1H-NMR (200 MHz, CDCl3) δ 1.12-1.30 (9H, m), 2.29 (1H, m), 2.51 (3H, s), 3.25 (1H, m), 3.90 (1H, m), 6.06 (1H, d, J=16.8 Hz), 7.47 (1H, d, J=16.8 Hz), 7.64 (1H, s), 7.80 (1H, s), 7.92 (1H, s), 10.08 (1H, s); m/z (EI) 351 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([N:14]=[C:15](SC)[S:16][CH3:17])#[N:13]>CO>[C:12]([NH:14][C:15](=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[S:16][CH3:17])#[N:13]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=NC#N)SC
Solvent: CO
Product: CSC(=NCCSCc1ccccn1)NC#N
Reaction time: 0.5 h

Procedure:
A solution of 2-[(2-pyridyl)methylthio]ethylamine (from the dihydrobromide, 20.0 g; 60.6 mmoles) and dimethyl cyanodithioimidocarbonate [prepared according to the procedure described in J. Org. Chem., 32, 1566 (1967)] (8.86 g; 60.6 mmoles) in methanol (150 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 16 hours and then a reflux temperature for 0.5 hours to complete the reaction. The reaction mixture was evaporated under reduced pressure and the crude product was recrystallized from acetonitrile to give N-cyano-N'-{2-[(2-pyridyl)methylthio]-ethyl}-S-methylisothiourea; mp 85°-86.5° C.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO.O>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=[N:24][OH:25])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCn1c(=O)c(C=NO)c(OC)c2cc(C)ccc21

Procedure:
A solution of 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 1 g), hydroxylamine hydrochloride (0.3 g) and sodium acetate (0.3 g) in methanol (20 ml) was stirred for 3hrs. The mixture was then diluted with water and extracted with methylene chloride. The extracts were dried, evaporated and the resulting solid was crystallized from ether-hexane to give 1 -hexyl-3-oximinomethyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 316 (M+); NMR (CDCl3): δ3.98 (s, 3H, OCH3), 8.54 (s, 1H, CH=N).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:44][CH2:45][Cl:46]>CC#N.O>[Cl:46][CH2:45][CH2:44][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24]
Reactant: ClCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cn(CCCl)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
To a solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (275 mg, 0.56 mmol) in dry MeCN (8.0 mL) was added cesium carbonate (182 mg, 0.56 mmol) and 1-bromo-2-chloroethane (80 mg, 0.56 mmol). The reaction mixture was heated at 50° C. for 10 h, diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (gradient from 0% to 2% MeOH/CH2Cl2) to provide the title compound (170 mg, 54%). 1H NMR (DMSO-d6) δ 8.46 (d, J=1.6 Hz, 1H), 8.26 (dd, J=8.0, 1.6 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.36-7.33 (m, 3H), 7.27-7.25 (m, 2H), 5.16 (s, 2H), 4.08-4.03 (m, 4H), 3.93 (s, 1.5H), 3.77-3.73 (m, 3.5H), 3.50-3.40 (m, 2H), 1.50-1.45 (m, 4H), 1.35-1.10 (m, 4H), 0.92-0.75 (m, 6H); MS(ESI+) m/z 555.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[CH2:12]2.[Li:20]CCCC>CCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[CH-:12]2.[Li+:20]
Reactant: Cc1ccccc1-c1cccc2c1C=C(C(C)C)C2
Reactant: [Li]CCCC
Solvent: CCCCC
Product: Cc1ccccc1-c1cccc2[cH-]c(C(C)C)cc12
Product: [Li+]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2-methylphenyl)-2-isopropylindene (6.6 g, 26.5 mmol) was dissolved in 80 mL of pentane. To this solution was added 10.6 mL of n-BuLi (2.5M in hexane) and the reaction was allowed to stir 4 hours at room temperature. A white solid precipitates from solution and was collected by frit filtration and washed with additional pentane. Yield was 5.8 g (88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]4[C:16]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[N+:37]([O-])=O)=[CH:26][CH:25]=4)=[N:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(O)(=O)C>C(O)C.[Pd]>[NH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:17]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:23])[N:14]([C@H:11]3[CH2:12][CH2:13][C@@H:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)[N:15]=2)=[CH:29][CH:28]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5[N+](=O)[O-])cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A mixture of cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2-nitrophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.059 g, 0.091 mmol, 1 equiv), glacial acetic acid (0.03 mL, 0.5 mmol, 5 equiv), and 10% Pd-C (0.024 g, 0.4 wt/wt equiv) in ethanol (1 mL) was stirred at room temperature under a positive pressure of H2 for 16 h. Solids were removed by filtration with the aid of CH2Cl2 (10 mL) and the filtrate was concentrated to afford a yellow oil. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford cis-3-[4-(2-aminophenoxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid (0.018 g, 0.036 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.22 (1H, s), 7.59 (2H, d, J=8.6 Hz), 7.05 (2H, d, J=8.7 Hz), 6.85-6.98 (3H, m), 6.58-6.61 (1H, m), 4.93 (2H, bs), 4.78-4.80 (1H, m), 2.20-2.50 (11H, m), 2.14 (3H, s), 2.05-2.09 (2H, m), 1.55-1.70 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.00 min. MS: MH+ 499.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:13]=2)=[CH:8][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].N1(C(N2C=CN=C2)=O)C=CN=C1>ClCCl>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:35](=[O:36])[CH2:34][C:32]#[N:33])[CH2:23]3)[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (210 mg, 0.50 mmol, 1.00 equiv) in dichloromethane (50 mL), 2-cyanoacetic acid (63 mg, 0.74 mmol, 1.50 equiv), and 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (120 mg, 0.74 mmol, 1.50 equiv). The resulting solution was stirred for 24 h at room temperature and then diluted with dichloromethane. The resulting mixture was washed with NH4Cl and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 150 mg (62%) of 3-[(3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26][CH2:27][N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30].Cl.[C:35](=[O:38])(O)[O-:36].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:20][C:19]([F:22])([F:21])[C:35]([OH:36])=[O:38].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([C:19]([F:21])([F:20])[F:22])=[CH:14][C:15]([C:17]([NH2:18])=[O:36])=[CH:16][C:11]=3[N:10]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:9]2=[O:23])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCn1c(=O)n(-c2ccc(Cl)cc2)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
1-(4-Chlorophenyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (0.1767 g) was dissolved in N,N-dimethylformamide (5 ml), and to the solution was added sodium hydride (27.2 mg). The mixture was stirred at room temperature for 5 minutes. To the mixture were added 2-chlorotriethylamine hydrochloride (117.1 mg) and triethylamine (0.109 ml), and the mixture was stirred at 60-70° C. for 1 hour. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was dissolved in 2-methyl-2-propanol (15 ml) and heated at 50° C. To the solution was added powdered potassium hydroxide (0.7340 g), and the mixture was stirred for 1 hour. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by HPLC using condition 1 to give the title compound (90.4 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[CH:10])=[CH:4][CH:3]=1.[C:11]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[C:11]([O:17][CH2:18][N:19]1[CH:10]=[C:9]([C:5]2[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:21]=[N:20]1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)nc1C
Product: Cc1nc(Cl)ccc1-c1cn(COC(=O)C(C)(C)C)nn1

Procedure:
The title compound was prepared as described in Example 413 Step 2 using 6-chloro-3-ethynyl-2-methylpyridine (Example 432, Step 1) (315 mg, 2.08 mmol) and azidomethyl pivalate (327 mg, 2.08 mmol) as starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=3[N:15]=[C:14](N)[C:13]=2[N:12]=[C:11]1[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cccnc1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNC(=O)OC(C)(C)C
Product: CCCCc1nc2cnc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Yield: 83.2 %

Procedure:
tert-Butyl[2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.09 g, 30.5 mmol) and 3-pyridylboronic acid (4.31 g, 35.0 mmol) were coupled according to the method described in Part G of Example 386. The reaction was heated for 2.5 hours. The crude product was triturated with toluene (15 mL/g) at 123° C. and isolated by filtration to provide 11.31 g of tert-butyl{2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:14]=1[CH:15]=[N:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:40][NH:41]2)C1C=CC=CC=1)C>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4]([NH:41][CH3:40])=[O:24])=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ncc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ncc12

Procedure:
3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide CXCIX was prepared from 3-(7-methoxy-1H-indazol-4-yl)-3-phenyl-propionic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4). Part of the crude 3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide CXCIX was used without further purification for the next step. A second portion of 3-(7-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-propionamide was purified on chiral HPLC by multiple injections onto 20×250 mm Chiralpak AD preparative column using a mixture of 70/30 hexane/EtOH at 7 ml/min in order to separate the enantiomers CXCIX-A and CXCIX-B.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19](C(O)=O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN([C:28]([O:32]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:63])[C:53]([NH2:62])([C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1)[CH3:54])[CH3:50]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH2:20][CH:21]1[C:28](=[O:32])[NH:62][C:53]([C:55]1[CH:56]=[CH:57][C:58]([Br:61])=[CH:59][CH:60]=1)([C:52]([O:51][CH2:49][CH3:50])=[O:63])[CH3:54])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C(C)(N)c1ccc(Br)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(NC(=O)C1CCCN1C(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 58.8 %

Procedure:
N,N-diisopropylethylamine (4.1 mL, 23.6 mmol) was added dropwise to a mixture of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.7 g, 3.2 mmol), HATU (1.2 g, 3.2 mmol) and 2-amino-2-(4-bromo-phenyl)-propionic acid ethyl ester (0.8 g, 2.9 mmol) in DMF (20 mL), and stirred at ambient condition for 3 hours. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a colorless oil (0.8 g, 58%). m/z 490.9, 492.9 (M+Na)+.