Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:13]=[C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]1[CH2:24][C:25](O)=[O:26]>>[Br:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH:7][C:25](=[O:26])[CH2:24][N:15]2[C:16]3[C:21](=[N:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:14]2=[O:13])[S:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Nc1scc(Br)c1-c1nccs1
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1nccs1
Yield: 15.3 %

Procedure:
The title compound was prepared from 4-bromo-3-(thiazol-2-yl)thiophen-2-amine (90 mg, 0.35 mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (105 mg, 0.52 mmol) according to protocol A. The crude product was purified by HPLC to give N-(4-bromo-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (24 mg) as a white solid. LCMS m/z 449.0/451.0 and retention of 4.019 min using method [7]. 1H-NMR (300 MHz, CDCl3) δ 8.39 (d, J=5.2 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.4, 5.3 Hz, 1H), 7.34 (d, J=3.4, 1H), 6.94 (s, 1H), 4.09 (s, 2H), 3.49 (t, J=7.2 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[C:13]([Cl:20])[C:14]4[N:15]([CH:17]=[CH:18][N:19]=4)[CH:16]=[C:11]3[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:33]1([S:36](N)(=[O:38])=[O:37])[CH2:35][CH2:34]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[C:13]([Cl:20])[C:14]4[N:15]([CH:17]=[CH:18][N:19]=4)[CH:16]=[C:11]3[N:10]([S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])[C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=c1[nH]c2cn3ccnc3c(Cl)c2n1-c1ccc(Br)cc1Cl
Reactant: NS(=O)(=O)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(Cl)c3nccn3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the crude product (Step J) in 3 ml anhydrous THF was added LHMDS (0.4 ml, 0.4 mmol, 1M/THF) at 0° C. and the mixture was stirred for 5 min. The cyclopropyl sulfonamide (83 mg, 0.59 mol) was added neat and the mixture was warmed to room temperature and stirred for 15 h. The mixture was quenched with brine, diluted with H2O and extracted using a mixture of EtOAc/THF (3:1). The organic phase was washed with brine and dried with Na2SO4. Subsequent column chromatography (100% EtOAc) gave the title product as a brown oil (36 mg, 20% over the 2 last steps). Rf (100% EtOAc)=0.35. 1H-NMR (500 MHz, MeOH-D3): δ=8.80 (s, 1H), 7.89 (s, 1H), 7.86-7.85 (d, 1H), 7.68-7.66 (dd, 1H), 7.60-7.58 (d, 1H), 7.46 (s, 1H), 1.51-1.37 (m, 2H), 1.23-1.15 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cu][C:13]#[N:14].CN(C)C=O.C(OCC)(=O)C>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
A mixture of 7.7 g (0.040 mol) of 2,5-dichloronitrobenzene and 4.0 g (0.044 mol) of copper (I) cyanide in 4.0 ml (0.05 mol) of N,N-dimethylformamide was refluxed for 3.5 hours. The reaction mixture was poured slowly into 39 ml (0.40 mol) of ethyl acetate and followed by stirring for 10 hours at room temperature. The precipitate was filtered and washed with 3 ml of ethyl acetate. After concentration of the combined filtrate, the residue gave 4.6 g (63.0%) of 4-chloro-2-nitrobenzonitrile purified by the procedure of Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:8]=1)#[N:2].Cl.[OH-:26].[Na+]>CCOCC>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[C:11]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:26])=[CH:8][N:7]3[N:9]=2)=[CH:19][CH:20]=1
Reactant: [OH-]
Reactant: N#Cc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: NC(=O)c1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 6-cyano-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 52. 100 mg, 0.318 mmol) and concentrated hydrochloric acid (2 mL) were stirred at room temperature overnight. The mixture was diluted with ether, basified with 5N sodium hydroxide solution and extracted thoroughly with ethyl acetate several times. The combined organic layers were dried (MgSO4), filtered and evaporated to dryness. The title compound was isolated in 85% yield (90 mg). 1H NMR (d6-DMSO) δ 9.36 (s, 1H), 8.60 (d, 2H, J=5.2 Hz), 8.22 (bs, 1H), 7.81 (bs, 2H), 7.67 (bs, 1H), 7.58 (m, 2H), 7.28–7.37 (m, 4H). MS (ES+ve): 334 (25, M+2), 333 (100, M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([C:20]([CH2:27][CH3:28])([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])[CH3:19]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:21](=[O:22])[C:20]([CH2:27][CH3:28])([CH2:18][CH3:19])[C:24](=[O:25])[O:9]2)=[O:7])=[CH:10][CH:11]=1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)NO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(C)cc2)C1=O
Yield: 34.1 %

Procedure:
A mixture consisting of 1.51 g (0.0100 mol) of 4-methylbenzohydroxamic acid, mp 148-150° C. (dec.) (lit. mp 148° C. dec. , Beilstein Handbook of Organic Chemistry, series H, vol 9, p. 491), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 1.977 g (0.0100 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 2 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 mL portions of water, three times with 50 mL portions of 5% hydrochloric acid, and two times with 50 mL portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 0.94 g (34.2%) of crude 2-(4-methylbenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from methanol gave pure 2-(4-methylbenzoly)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 92-93° C.; IR (Nujol) 1805 (s,C=0), 1747 (s, C=0) 1695 cm-1 (s, C=0);H1NMR (400 MHz, CDCl3) δ7.70 (d,2H), 7.29 (d,2H), 2.43 (s,3H), 1.95 (q. 4H), 1.00 (t, 6H); High resolution MS, calc'd for: C15H17NO4 : 275.1157. Found: 275.1163. Anal. Calc'd for: C15H17NO4 : C, 65.44; H, 6.23; N 5 09. Found: C, 65.24; H, 6.45; N, 5.28.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][CH2:9][C:8]=2[CH:15]=1)(=[O:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Na].C[Si](Cl)(C)C.[Br:31]Br>C1COCC1>[Br:31][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][CH2:9][C:8]=2[CH:15]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)COC(C)(C)O2
Reactant: BrBr
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reaction time: 1 h

Procedure:
To the product of step (b) (23.4 g, 0.113 mol) in 600 mL of THF at −78° C. was added 135 mL of 1.0 M sodium hexamethyldisilazane in THF (Sigma-Aldrich). After 1 hour, trimethylsilyl chloride (15.8 mL, 0.124 mol) was added. After another 30 minutes, bromine (5.82 mL, 0.113 mol) was added. After 10 minutes, the reaction was quenched by diluting the reaction mixture with diethyl ether and pouring it onto 500 mL of 5% aqueous Na2SO3 premixed with 500 mL of 5% aqueous NaHCO3. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an oil that solidified upon storage in the freezer.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:29]=[CH:28][N:27]=[N:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:29]=[CH:28][N:27]=[N:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnnc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2ccnnc2)cc1F
Yield: 95.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(pyridazin-4-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.04 g, 0.07 mmol) prepared in Example 53c, triethylsilane (0.06 mL), trifluoroacetic acid (0.07 mL) and dichloromethane (0.74 mL), to yield the title compound (30 mg, 94%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)([CH3:3])=[CH2:2].[Cl:11]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:11][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)=[CH2:3]
Reactant: C=C(C)c1cccc(C)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
A mixture of 4.7 g of 2-isopropenyl-6-methylpyridine, 4.7 g of N-chlorosuccinimide and 10 ml of carbon tetrachloride was stirred at 150° to 160° C. for 30 minutes. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1). to obtain 2.0 g of the objective compound.
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=O)[CH:2]([CH3:4])[CH3:3].[CH:16](/[S:24]([NH2:27])(=[O:26])=[O:25])=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:4][CH:2]([CH3:3])[CH2:1][CH:5]([C:6]([NH:27][S:24](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:25])=[O:26])=[O:8])[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)/C=C/c1ccccc1
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Product: CC(C)CC(C(=O)O)C(=O)NS(=O)(=O)/C=C/c1ccccc1
Yield: 96.6 %

Procedure:
In the same manner as in Example 1 (1), the object compound was obtained using diethyl isobutylmalonate (10.0 g). This and trans-β-styrenesulfonamide (2.91 g) were condensed in the same manner as in Example 152 (3). The condensed product was subjected to hydrolysis in the same manner as in Example 1 (3) to give the title compound (4.99 g) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](CCCC3CCCCC3)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:38].[CH2:39]([OH:41])[CH3:40]>>[ClH:38].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:41][CH2:39][CH2:40][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:20]([C:33]([F:34])([F:35])[F:36])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCC3CCCCC3)c(C(F)(F)F)c2)COC(C)(C)OC1
Reactant: CCO
Agent: Cl
Product: NC(CO)(CO)CCc1ccc(OCCCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 9-2 (760 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (525 mg) as a white powder. MS(ESI)m/z: 404[M+H]
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[N:13](COC)[C:12]([C:18]([NH2:20])=[O:19])=[CH:11]3)[CH2:3][CH2:2]1.O.O.C(O)(=O)C(O)=O.CO>O>[CH:1]1([CH2:4][N:5]([S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:23])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:18]([NH2:20])=[O:19])=[CH:11]3)[CH2:3][CH2:2]1
Reactant: COCn1c(C(N)=O)cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c21
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: NC(=O)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 70 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A mixture of 7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1-(methoxymethyl)-1H-indole-2-carboxamide (390 mg), oxalic acid dihydrate (351 mg), methanol (15 mL) and water (15 mL) was stirred at 70° C. for 1 hr, and further at 90° C. for 14 hr. The reaction mixture was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed successively with water, a diethyl ether-hexane mixture and hexane, and dried to give the title compound (286 mg, yield 81%) as crystals. melting point 229-231° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11]>C(N(CC)CC)C>[CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCCCC(C=O)CC
Reactant: C=O
Solvent: CCN(CC)CC
Product: CCCCC(C=O)(CC)CO
Temperature: 100 °C

Procedure:
A one liter Parr autoclave was charged with 2-ethylhexanal (334 g, 406 mL, 2.6 mole), 44% aqueous formaldehyde (136.4 g, 122 mL, 2.0 mole) and varying amounts of triethylamine to determine the effect of increasing triethylamine concentration on reaction rate. After purging with nitrogen, the autoclave was sealed and heated at 100° C. for one hour. The autoclave was cooled and the contents were analyzed for formaldehyde (HCHO) by calorimetric analysis and for 2-ethyl-2-(hydroxymethyl)hexanal (EHMH) by gas chromatography analysis. The yield of EHMH was calculated based on the 2-ethylhexanal consumed which was determined after correcting the gas chromatograph area for methanol and excess 2-ethylhexanal. Table I sets forth the amount of triethylamine (TEA, g/mL), the concentration by weight of triethylamine based on the total weight of the materials charged (TEA, %), the mole percent of formaldehyde converted (HCHO Conv.) and the percent yield of EHMH obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.CO[CH:33]1[CH2:37][CH2:36][CH:35](OC)O1>C(O)(=O)C>[N:1]1([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13](=[O:30])[C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[CH:16][CH:15]=3)[CH2:5][CH2:4][CH2:3]2)[CH:33]=[CH:37][CH:36]=[CH:35]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(n3cccc3)c3ccccc32)cc1

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in acetic acid (10 ml) is added dropwise 2,5-dimethoxytetrahydrofuran (0.19 ml), and the mixture is refluxed for 1 hour. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from ethyl acetate/n-hexane to give 5-(1-pyrrolyl)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.31 g) as colorless prisms, m.p. 208°-210° C.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:32])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]([NH2:31])=[O:30])[O:24][CH2:23]2)[CH:17]([CH:33]([OH:35])[CH3:34])[C:16]3=[O:36])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:41].O>[Pd].O1CCOCC1>[Na+:41].[NH2:31][C:29]([O:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:32])[CH:18]3[N:15]([C:16](=[O:36])[CH:17]3[CH:33]([OH:35])[CH3:34])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)=[O:30]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COC(N)=O)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.126 gof product from Example 20, 0.0223 g of sodium bicarbonate, 1.4 ml of water, 7.8 ml of dioxane, and 0.070 g of 10% palladium/carbon to give 0.055 g of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](C(=O)C)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)=[O:26].OO>C1(C)C=CC=CC=1>[OH:26][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: O=CO
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: OO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
4-n-Octyloxy-4'-acetylbiphenyl (38.5 g, 0.119 mol), formic acid (23.8 g, 5.17 mols) and toluene (200 ml) were heated to 60° C., followed by dropwise adding a 35% H2O2 aqueous solution (160.7 g, 1.04 mol) over 1.5 hour while keeping the liquid temperature at 70°~75° C., thereafter heating at 60°~70° C. for 3 hours with stirring, cooling down to room temperature, extracting with toluene (1.5 l), washing with water till the washing water became neutral, drying, removing toluene, adding ethanol (200 ml), heating under reflux, somewhat cooling, adding a 40% NaOH aqueous solution (80 ml ), again heating under reflux for 2 hours, pouring the solution in 6N hydrochloric acid (1 l), stirring, collecting the resulting solids by suction filtering, adding toluene (300 ml), withdrawing water and recrystallizing to obtain 4-hydroxy-4'-n-octyloxybiphenyl (18.5 g). Yield: 50.6%. M.P.: 153.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:26]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccn1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 75.8 %

Procedure:
A solution of 2.8 g of 2-aminopyridine and 4.2 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 190 ml of toluene was refluxed for 16 hours in a soxhlet apparatus containing 10 g of 4Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 1:1 ethyl acetate-hexane as the eluent) to yield 3.7 g (73%) of 1,2-dihydro-4-hydroxy-1-phenyl-N-(2-pyridyl)-3-quinolinecarboxamide, m.p. 145° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C=O)C.CO>[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c(=O)n(C4CC4)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 53.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (79 mg) was added to a solution of 1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (17.96 mg) in DMF (2 ml) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][C:13](=[O:18])[CH2:12]5)[CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Nc1cccc(Nc2ccc3c(c2)CC(=O)N3)c1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)CC(=O)N5)c3)cc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 5-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (20 mg, 0.083 mmol) in DMF (2 ml) is added 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (31 mg, 0.1 mmol), N,N-diisopropylethylamine (54 mg, 0.42 mmol), EDCI (32 mg, 0.17 mmol) and HOBt (11 mg, 0.083 mmol). The reaction is stirred for 12 hours and concentrated. The residue is purified by HPLC to afford the desired compound: LC-MS: 456.2 (MH+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2)[N:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.45 mmol), formaldehyde (30% solution in water, 0.16 mL, 1.60 mmol) and sodium triacetoxyborohydride (430 mg, 2.03 mmol) were mixed in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 3-iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (275 mg, 53%). 1H NMR (DMSO-d6) δ 1.85 (m, 2H), 2.09 (m, 4H), 2.22 (s, 3H), 2.88 (m, 2H), 4.75 (m, 1H), 8.19 (s, 1H), 8.32 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ 359.0, Rt 0.46 min.