Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl: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]([OH:13])=O)=[CH:9][CH:8]=1)=[O:5].Cl.C(N=C=N)C.O.ON1C2C=CC=CC=2N=N1.[NH2:37][CH2:38][CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:37][CH2:38][CH:39]([OH:40])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:13])=[CH:14][CH:15]=1)=[O:5]
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2Cl)cc1
Reactant: NCC(O)c1ccccc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCC(O)c1ccccc1)c1ccc(NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
under an N2 atmosphere, 4-(2-chlorobenzamido)benzoic acid (0.500 g, 1.81 mmol) was dissolved in N,N-dimethylformamide (10.0 ml) and the solution was treated with N-3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.696 g, 3.62 mmol), 1-hydroxybenzotriazole hydrate (0.491 g, 3.62 mmol), 2-amino-1-phenylethanol (0.498 g, 3.62 mmol), and triethylamine (0.506 ml, 3.62 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was diluted with ethyl acetate and washed with 0.5N HCl followed by 5% NaHCO3. The organic layer was dried (Na2SO4), and concentrated in vacuo. The resulting solid was triturated with a mixture of ethyl acetate and hexanes to afford 2-chloro-N-(4-(((2-hydroxy-2-phenylethyl)amino)carbonyl)phenyl)benzamide (0.578 g, 71.5%) after collecting the solid by filtration. ESI m/z=395.0 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reaction time: 4 h

Procedure:
2′,4′-Dichloro-biphenyl-4-carboxylic acid methyl ester (3 g) was dissolved in a mixture of THF (25 mL) and methanol (25 mL). 1 M NaOH (50 mL) was added and the mixture stirred for 4 hours by which stage a clear solution had formed. Conc. HCl was added and the precipitate was collected as a white solid. Toluene was added and the mixture was evaporated to dryness to give the title compound as a white solid. 1H NMR (CDCl3): δ 7.20 (2H, m), 7.52 (2H, m), 7.64 (1H, s) and 8.12 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:26])[CH2:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[CH:19][N:18]=3)[CH:16]=2)=[CH:4][CH:3]=1.[N:27]#[C:28][NH2:29].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>CN(C=O)C>[C:28]([NH:29][C:23]([C:21]1[CH:20]=[CH:19][N:18]=[C:17]([N:15]2[CH:16]=[C:12]([CH2:11][CH2:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH3:26])[CH:13]=[N:14]2)[CH:22]=1)=[O:25])#[N:27]
Reactant: N#CN
Reactant: CN(CCc1cnn(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCc1cnn(-c2cc(C(=O)NC#N)ccn2)c1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
A mixture of 2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxylic acid (70 mg, 0.2 mmol), cyanamide (17 mg, 0.4 mmol), HATU (113 mg, 0.3 mmol) and DIEA (59 mg, 0.6 mmol) in DMF (3 mL) was stirred at room temperature for 3 hours. The mixture was concentrated and purified by prep-HPLC to give the compound (15 mg, 20%). 1H NMR (400 MHz, DMSO-d6): 2.67-2.74 (3H, m), 2.94-2.98 (2H, m), 3.28 (1H, m), 3.43-3.45 (1H, m), 4.26-4.30 (1H, m), 4.44-4.48 (1H, m), 7.31-7.36 (2H, m), 7.59-7.61 (2H, m), 7.70-7.71 (1H, m), 7.76 (1H, s), 8.31 (1H, s), 8.42 (1H, d, J=5.2 Hz), 8.58 (1H, s), 9.56 (1H, br). [M+H] Calc'd for C20H19FN6O, 379. Found, 379.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[C:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)[C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[CH:36][CH:37]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: COc1ccc(C(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
Titanium tetrachloride (0.50 mL, 4.53 mmol) was slowly added to a slurry of zinc powder (0.61 g, 9.31 mmol) in dry tetrahydrofuran (10 mL). The reaction mixture was heated at reflux for 2.5 h. A solution of 3,3,5,5-tetramethyl-cyclohexanone (0.64 mL, 3.67 mmol) and N-[4-(4-methoxy-benzoyl)-phenyl]-benzenesulfonamide (182) (0.45 g, 1.22 mmol) in dry tetrahydrofuran (10 mL) was added to the reaction mixture and heated at reflux for another 2 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) followed by 10% K2CO3 (10 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 55:45) to give 0.48 g (80%) of compound 183 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.81 (s, 6H), 0.84 (s, 6H), 1.21 (s, 2H), 1.75, (s, 2H), 1.85 (s, 2H), 3.68 (s, 3H), 6.79 (d, J=8.6 Hz, 2H), 6.95-6.98 (m, 6H), 7.47-7.50 (m, 2H), 7.55-7.58 (m, 1H), 7.69 (d, J=7.3 Hz, 2H), 10.17 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:45][O:46][CH:47]([CH3:49])[CH3:48].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:29][CH:30]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13](=[N:45][O:46][CH:47]([CH3:49])[CH3:48])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(C)ON
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc2c(=O)n(CC(=NOC(C)C)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), 2-(aminooxy)propane hydrochloride (0.052 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.18 g, 80%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1OS(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[PH3:37]=[O:38]>[Pd]>[PH2:37]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][S:3]([C:2]([F:1])([F:36])[F:35])(=[O:4])=[O:5])=[O:38]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12)C(F)(F)F
Reactant: O=[PH3]
Agent: [Pd]
Product: O=[PH2]c1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12

Procedure:
In detail, 2,2'-dihydroxy-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (3), which is obtained by hydrogenation of 1,1'-bi-2-naphthol in the presence of a platinum oxide catalyst, is reacted with trifluoromethanesulfonic acid anhydride (4) in accordance with the process described in Tetrahedron Letters, Vol. 31, pp. 6321-6324 (1990) to obtain 2,2'-bis(trifluoromethanesulfonyloxy)-5,5',6,6',7,7',8,8-octahydro-1,1'-binaphthyl (5). Compound (5) is reacted with phosphine oxide (6) in the presence of a palladium catalyst to obtain compound (7). Compound (7) is first reduced by trichlorosilane in the presence of triethylamine and then hydrolyzed or first hydrolyzed and then reduced to obtain 2- diphenylphosphino-2'-hydroxy-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (8). Compound (8) is reacted with a chlorophosphite derivative (9) in the presence of triethylamine to obtain an optically active phosphine compound of formula (II).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][NH:10][C:11](=[O:28])[C@H:12]([NH:16][C:17]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20]([C:26]#[N:27])=[CH:19][CH:18]=2)[C@@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[CH3:36][C:37]([Si:40](Cl)([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C>[Si:40]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:20]([C:26]#[N:27])=[CH:19][CH:18]=1)[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=1)=[O:28])([C:37]([CH3:39])([CH3:38])[CH3:36])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 4-cyano-N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (320 mg, 0.76 mmol) in DMF (10 mL) was added imidazole (208 mg, 3.06 mmol) and TBSCl (230 mg, 1.53 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by SiO2 column to afford N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(7-cyanobenzo[b]thiophen-4-ylamino)butanoyl)-4-cyanobenzohydrazide (380 mg, 93%). 1H NMR (400 MHz, CDCl3, δ in ppm) 9.28 (b, 1H), 8.63 (b, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.23 (d, J=5.6 Hz, 1H), 6.35 (d, J=8.2 Hz, 1H), 5.59 (d, J=5.9 Hz, 1H), 4.44 (m, 1H), 4.01 (m, 1H), 1.14 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: CO[C:3]1[CH:4]=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=C[C:8]=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH2:43][CH3:44])[CH:35]=1)=O.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH2:43][CH3:44])[CH:35]=2)=[CH:8][CH2:3][CH3:4])[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(OC)c2)ccc1OC
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Product: CCC=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OCC)c1

Procedure:
1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)but-1-ene was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-3′-ethoxy-4′-methoxybenzophenone (1 g, 3.2 mmol), propyltriphenylphosphonium bromide (1.34 g, 3.5 mmol) and lithium hexamethyldisilazide (2.7 mL, 3.5 moll, 1.3M) with a reaction time of 2.5 hours at room temperature. The crude mixture was purified by chromatography (silica gel, methylene chloride) followed by a Kugelrohr, distillation to yield 0.77 g (71%) of a mixture of the E and Z, isomers as an oil: 1H NMR (CDCl3) δ 6.92–6.65 (m, 12H), 6.02–5.89 (m, 2H), 4.12–3.96 (m, 4H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.22–2.04 (m, 4H), 1.51–1.38 (m, 6H), 1.14–0.98 (m, 6H); 13C NMR (CDCl3) δ 148.5, 148.1, 147.8, 147.7, 140.4, 140.4, 136.0, 135.9, 133.0, 132.9, 130.1, 130.0, 122.2, 119.8, 114.6, 113.1, 112.0, 111.0, 110.7, 110.4, 64.3, 64.2, 55.9, 23.2, 14.8, 14.7; Anal. Calcd for C21H26O4. Theoretical: C, 73.66; H, 7.65. Found: C, 73.32; H, 7.26.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2SCCCS2)=[CH:6][C:5]([N:14]2[C:18](=[O:19])[N:17]([CH:20]([F:22])[F:21])[C:16]([CH3:23])=[N:15]2)=[C:4]([F:24])[CH:3]=1.BrN1C(=[O:31])CCC1=O.S(=O)(O)[O-].[Na+].C(Cl)Cl>CC(C)=O.C(#N)C.O.CCCCCCC>[Cl:1][C:2]1[C:7]([CH:8]=[O:31])=[CH:6][C:5]([N:14]2[C:18](=[O:19])[N:17]([CH:20]([F:22])[F:21])[C:16]([CH3:23])=[N:15]2)=[C:4]([F:24])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(-c2cc(C3SCCCS3)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O
Product: Cc1nn(-c2cc(C=O)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2.0 g (0.0051 mole) of 1-[4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 25 mL of acetone and 25 mL of acetonitrile is added slowly to a stirred, cold (0° C.) solution of 5.5 g (0.031 mole) of N-bromosuccinimide in 80 mL of acetonitrile and 20 mL of water. The reaction mixture is stirred at 0° C. for about one hour. Approximately 15 mL of an aqueous, saturated sodium bisulfite solution is added. A mixture of 25 mL of methylene chloride and 25 mL of n-heptane is added, and the mixture is shaken in a separatory funnel. The organic phase is removed and is washed in succession with an aqueous, saturated sodium bicarbonate solution, water, and an aqueous, saturated sodium chloride solution. The washed organic phase is dried over anhydrous magnesium sulfate and is filtered. The filtrate is evaporated under reduced pressure to leave a residue. This residue is purified by column chromatography on silica gel to yield 1-(4-chloro-2-fluoro-5-formylphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].N12CCCN=C1CCCCC2.CN(C)C=O.[CH2:29]([C:33]1[N:34]=[C:35]([CH3:63])[N:36]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[C:37](=[O:56])[C:38]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=2[C:48](=[N:50][OH:51])[NH2:49])=[N:44][CH:45]=1)[CH2:30][CH2:31][CH3:32]>O>[CH2:29]([C:33]1[N:34]=[C:35]([CH3:63])[N:36]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[C:37](=[O:56])[C:38]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=2[C:48]2[NH:49][C:1](=[O:2])[O:51][N:50]=2)=[N:44][CH:45]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
Process 3: 1,1′-Carbonyldiimidazole (490 mg, 3.02 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (460 mg, 3.02 mmol) were added to dimethylformamide solution (25 mL) of 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (430 mg, 0.918 mmol) and stirred for 3 hours at room temperature. Once the reaction is completed, the reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were purified by silica gel column chromatography (ethyl acetate) to give 3-{2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one (160 mg, 35%, two step yield) as weak yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[N:6]([CH2:16][CH3:17])[CH:5]=[N:4][C:3]=1[C:7]#[N:8]
Reactant: N#Cc1nc[nH]c1N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1cnc(C#N)c1N
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution/suspension of 5-amino-1H-imidazole-4-carbonitrile (2.16 g) in tetrahydrofuran/N,N-dimethylformamide under an atmosphere of nitrogen was added potassium carbonate (3.3 g) and iodoethane (1.9 mL). The reaction mixture was stirred at room temperature for 60 hours, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 2-5% methanol in dichloromethane afforded the title compound as an off-white solid (0.60 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30].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>CN(C=O)C.O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:29](=[O:30])[CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:21])[CH2:2][CH2:3]3)=[N:11]1
Reactant: Cc1ccccc1CC(=O)O
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine.2HCl (70 mg, 0.206 mmol), (2-methylphenyl)acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed the reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered, dried to give the product.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].C1(C)C=CC=CC=1.[CH3:15][O:16][C:17](=[O:31])[C:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=1[NH2:30].N1C=CC=CC=1>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:31])[C:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]([C:26]([F:28])([F:27])[F:29])=[CH:20][C:19]=1[NH:30][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: C=Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=Cc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Add a 1.0 M solution of isopropyl chloroformate in toluene (183.0 mL, 183.0 mmol) to a 0° C. cooled solution of 2-amino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (34.47 g, 140.58 mmol) and pyridine (35.0 mL, 429.20 mmol) in methylene chloride (500 mL). Allow the mixture to stir for 2 h at 0° C. then 16 h at room temperature under an atmosphere of N2. Wash the mixture with saturated aqueous sodium bicarbonate solution (2×200 mL) followed by aqueous 2 N HCl solution (2×200 mL). Wash the combined organic extracts with brine (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as an off-white solid (40.50 g, 87%): TLC Rf 0.62 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.32-1.33 (m, 6H), 3.89 (s, 3H), 5.21-5.27 (m, 1H), 5.41-5.44 (m, 1H), 5.63-5.70 (m, 1H), 7.03-7.11 (m, 1H), 8.23 (s, 1H), 8.89 (s, 1H), 10.32 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([I:22])=[C:16]2[C:15]([CH:23]([CH3:25])[CH3:24])=[N:14]1)[C:8]#[N:9])[CH3:3].[OH:26]O.[OH-].[Na+].O>CS(C)=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([I:22])=[C:16]2[C:15]([CH:23]([CH3:25])[CH3:24])=[N:14]1)[C:8]([NH2:9])=[O:26])[CH3:1]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2CN(C)C)c2nccc(I)c12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C(N)=O)cc2CN(C)C)c2nccc(I)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
Compound (125a) (0.500 g), 2-picoline-borane complex (0.166 g), and dimethylamine (0.216 mL) were dissolved in acetic acid (1.0 mL) and methanol (10 mL), followed by stirring at room temperature for 12 hr. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.213 g, 40%). This 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (1.6 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.132 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (0.144 g, 65%). According to Example 97(2), compound (126) (64%) was prepared as a white solid using 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:95]=[C:96]([F:98])[CH:97]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([F:84])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:98][C:96]1[CH:95]=[C:49]([CH:48]=[C:47]([F:46])[CH:97]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([F:84])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cc2F)CC1
Yield: 81.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenyl)piperidine-1-carboxylate (101 mg, 0.136 mmol) was hydrolyzed by lithium hydroxide (57 mg, 1.363 mmol) in THF/methanol/water (12/4/4 ml) to yield 65 mg (81% yield) of the titled compound. MS: m/z=588.4 (M+1).