Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[Cl:18][C:19]1[CH:25]=[C:24]([CH:26]2[CH2:35][CH2:34][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:28][CH2:27]2)[CH:23]=[CH:22][C:20]=1[NH2:21].C(OCC)(=O)C>C1COCC1>[Cl:18][C:19]1[CH:25]=[C:24]([CH:26]2[CH2:35][CH2:34][C:29]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:28][CH2:27]2)[CH:23]=[CH:22][C:20]=1[NH:21][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)cc1Cl)OCc1ccccc1
Yield: 72.2 %

Procedure:
Pyridine (2.18 mL, 26.9 mmol) and benzyl chloroformate (1.53 g, 8.96 mmol) were added sequentially, each in one portion, to a stirred solution of 2-chloro-4-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (2.40 g, 8.96 mmol) in THF (30 mL) at 5° C. and the reaction mixture was stirred at 10° C. for 3 h. Ethyl acetate (75 mL) was added and the mixture was washed with H2O (2×30 mL) and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a solid, which was purified by column chromatography, using a gradient of 20-50% ethyl acetate:isohexane as eluent, to give the title compound (2.6 g, 72%) as a white solid; 1H NMR δ 1.65-1.93 (8H, m), 2.49-2.6 (1H, m), 4.0 (4H, s), 5.25 (2H, s), 7.12 (1H, s), 7.15 (1H, dd), 7.25 (1H, d), 7.37-7.48 (5H, m), 8.08 (1H, d); MS m/e (M−H)− 400.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26](N(C)C)(=O)=O)=[C:22]([SH:32])[CH:21]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[S:8](N(C)C)(=O)=O.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(Cl)Cl.CCOC(C)=O>[SH:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([SH:26])=[C:22]([SH:32])[CH:21]=3)=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[SH:8]
Reactant: CN(C)S(=O)(=O)c1ccc(-c2ccc(-c3ccc(S(=O)(=O)N(C)C)c(S)c3)cc2)cc1S
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Sc1ccc(-c2ccc(-c3ccc(S)c(S)c3)cc2)cc1S
Temperature: 0 °C
Yield: 21.8 %

Procedure:
3,3″-dimercapto-4,4″-bis(N,N′-dimethylaminosulfonyl)-1,1′:4′,1″-terphenyl (508 mg, 1 mmol) synthesized in process 3-a is dissolved into 30 ml of absolute THF, lithium aluminium hydride (445 mg, 12 mmol, 12 eq) is added at the temperature of 0° C., then the reacting solution is refluxed for 24 hours. The obtained reaction mixture is poured into ice water, and adjusted the pH to 1 or less by adding hydrochloric acid, that is, acidified. Deposited green precipitate is removed by suction filtration, then the filtrate is washed by methylene chloride completely. After that, the filtrate is extracted by acid-base extraction (CH2Cl2), the separated organic phase is dried up using magnesium sulfate and recrystallized. Solvent is evaporated off under vacuum condition and the obtained crude product is isolated by a column chromatography (φ=20 mm, h=10 mm; AcOEt), further refined by recrystallization (CH2Cl2) and 3,3″,4,4″-tetramercapto-1,1′:4′,1″-terphenyl (78 mg, 22%) is obtained as a light yellowish crystal (compound J).
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.C(Cl)Cl.N1C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27](C)[C:28](Cl)=O)=[CH:23][CH:22]=1.Cl.C(O)C>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:28])[C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8])=[CH:23][CH:22]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C(=O)Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
In a round bottomed flask, to a suspension of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 2.91 g, 20.2 mmol) in methylene chloride (11.3 mL, 177 mmol) at −10° C. (internal temp) was added pyridine (4.00 mL, 49.5 mmol) over 10 minutes. To the resulting clear solution at −10° C., was added dropwise a solution of 2-(4-chlorophenyl)propanoyl chloride (4.10 g, 20.2 mmol) in methylene chloride (7.93 mL, 124 mmol) over 1 h. The reaction mixture was then stirred for 1 h at −10° C., and then for 1 hour at room temperature. The mixture was poured into hydrochloric acid (2.00M in water, 45.3 mL, 90.6 mmol) and ice, the layers were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with 1N HCl and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. To the crude residue was added ethanol (39.6 mL, 679 mmol) and the mixture was heated at reflux (89 degree bath temp) for 3 hours. After cooling to room temp, the volatiles were removed in vacuo. Residue was adsorbed onto silica using DCM and purified via column chromatography (gradient elution: 0 to 20% EtOAc/hexanes to afford ethyl 4-(4-chlorophenyl)-3-oxopentanoate (2.94 g, 92%) as a yellow oil. LCMS: (FA) ES+ 255; 1H NMR (400 MHz, DMSO)S 7.34-7.30 (m, 2H), 7.17-7.13 (m, 2H), 4.16-4.09 (m, 2H), 3.90 (q, J=7.2, 1H), 3.40 (d, J=15.6, 1H), 3.30 (d, J=15.6, 1H), 1.40 (d, J=6.8, 3H), 1.23 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClC(Cl)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:11][C:10]=1[F:17]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: C[C@H]1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H]1COCCN1Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
(S)-3-Methylmorpholine (119 mg, 0.86 mmol), 4-bromo-3-fluorobenzaldehyde (175 mg, 0.86 mmol) triethylamine (132 μl, 0.95 mmol) and sodium triacetoxyborohydride (274 mg, 1.29 mmol) were dissolved in dichloroethane (2.5 ml). The mixture was stirred at ambient temperature under argon atmosphere for 24 h. Hydrochloric acid (1M) was added until pH 1-2. The mixture was washed with dichloromethane. The aqueous phase was made alkaline with KOH (1M, aq) and extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give (S)-4-(4-bromo-3-fluorobenzyl)-3-methylmorpholine (220 mg, 89%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[S:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[C:23]([C@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[S:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 1 h
Yield: 67.7 %

Procedure:
In 1 ml of acetic acid is dissolved 0.5 g of tert-butyl 3(R)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1 hour. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 20 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized by adding 2 ml of acetic acid, and purified by MCI-gel column chromatography (water:methanol=1:2). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.23 g of 3(R)-[1(R)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-])=O)=[C:6](/[CH:8]=[CH:9]/[C:10](=[O:23])[CH2:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:7]=1.OC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC=CC=2[N+]([O-])=O)=CC=1>>[NH2:24][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][C:6]=1/[CH:8]=[CH:9]/[C:10](=[O:23])[CH2:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1cc(O)ccc1[N+](=O)[O-]
Agent: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]
Product: Nc1ccc(O)cc1/C=C/C(=O)CC(=O)/C=C/c1ccc(O)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 349, but with (1E,6E)-1-(5-hydroxy-2-nitrophenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (26 mg, 73 μmol, synthesized in Example 106) as the starting material instead of (1E,6E)-1-(4-hydroxyphenyl)-7-(2-nitrophenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=60/40 to 30/70. The product was obtained as a solid (6.8 mg, 37%) having the following characteristics.
Reaction SMILES: C(C(C(=O)CC([O-])=O)C([O-])=O)C1C=CC=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[CH2:69]([O:71][C:72](=[O:89])[CH:73]([CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:74](=[O:81])[CH2:75][C:76]([O:78][CH2:79][CH3:80])=[O:77])[CH3:70]>C(OCC)(=O)C.CS(C)=O>[CH2:69]([O:71][C:72](=[O:89])[CH:73]([CH2:82][C:83]1[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=1)[CH:74]([OH:81])[CH2:75][C:76]([O:78][CH2:79][CH3:80])=[O:77])[CH3:70]
Reactant: CCOC(=O)CC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C([O-])CC(=O)C(Cc1ccccc1)C(=O)[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)C(Cc1ccccc1)C(=O)OCC

Procedure:
Whole cell reductions of 2-benzyl-3-ketoglutarate were carried out using E. coli cells expressing the gene encoding KRED 1008. Cells were grown overnight at 30 C in 400 mL of a Luria Broth/glucose (2 g/L)/ampicillin (100 mg/L) media. The cells were isolated by centrifugation and re-suspended in 400 mL of a minimal salt (M9) solution containing isopropylthiogalactoside (IPTG, 0.5 mM), glucose (5 g/L), ampicillin (100 mg/L), and 2-benzyl-3-ketoglutarate diethyl ester. In independent experiments, the concentration of 2-benzyl-3-ketoglutarate diethyl ester was varied over the range of 1 gram/liter to 7.5 grams/liter. Cells continued to grow at 30 C after addition of the ketodiester substrate. Samples were removed at regular time intervals and analyzed for product formation using gas chromatography until complete reaction was observed. Although the 2-benzyl-3-ketoglutarate diethyl ester substrate did not completely dissolve in the aqueous buffer, and although no DMSO co-solvent was used, the reduction reactions were complete after 20–40 hours. In reactions that were allowed to proceed for more that 24 hours, another portion of glucose (1–3 g) and IPTG (0.4 mL of a 0.5 M solution) were added. The product 2-benzyl-3-hydroxyglutarate diethyl ester was isolated by removal of the cells by centrifugation and extraction of the reaction mixture with ethyl acetate. The yield of 2-benzyl-3-hydroxyglutarate diethyl ester in all cases was greater than 80%.
Reaction SMILES: [CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][C:9]([C:13]4[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=4[C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>[Pd].CO>[CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][C:9]([C@H:13]4[C@@H:17]([C:18]5[C:26]6[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=6)[NH:20][CH:19]=5)[C:16](=[O:27])[NH:15][C:14]4=[O:28])=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1cc2c3c(ccn3CCC2)c1
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cc3c4c(ccn4CCC3)c2)[C@H]1c1c[nH]c2ccccc12
Yield: 100.4 %

Procedure:
3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (753 mg, 2.05 mmol) and 5% palladium on carbon (100 mg) in methanol (40 ml) were stirred under hydrogen at 60 psi for 15 hours at room temperature. The reaction mixture was filtered through a bed of celite and the filtrate evaporated to dryness to afford (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione (760 mg) which was used without further purification. LCMS: 370 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)Oc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CC(C)Oc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [BrH:1].BrBr.[NH:4]1[CH2:9][CH2:8][C:7]([OH:11])(O)[CH2:6][CH2:5]1>C(O)(=O)C>[BrH:1].[Br:1][CH:6]1[C:7](=[O:11])[CH2:8][CH2:9][NH:4][CH2:5]1
Reactant: OC1(O)CCNCC1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1CCNCC1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.7 mL 33% HBr in acetic acid, 11.4 g bromine in 30 mL acetic acid was added slowly to a stirred solution of 10 g piperidine-4,4-diol in 60 mL acetic acid at RT. The reaction mixture was stirred additional 45 min at ambient temperature and the acetic acid was completely removed under reduced pressure. The residue was dissolved in 200 mL acetone and refluxed for 1 hour, cooled, filtered and washed with acetone and dried to give 15.2 g of the desired product
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.[O:21]=[C:22]1[CH:27]([N:28]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1>>[O:21]=[C:22]1[CH:27]([N:28]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]2=[O:14])[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1
Reactant: Cc1ccc(CNc2cccc(C(=O)O)c2C(=O)O)o1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: Cc1ccc(CNc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)o1
Yield: 20 %

Procedure:
3-[(5-Methyl-furan-2-ylmethyl)-amino]-phthalic acid (5 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The residue was purified by preparative HPLC (Symmetry C18, isocratic, 35/65 acetonitrile/water) to give 0.31 g (20%) of product as a yellow solid: mp 305–307° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.93 (t, J=6.0 Hz, 1H), 6.22 (d, J=2.9 Hz, 1H), 5.98 (d, J=1.9 Hz, 1H), 5.07 (dd, J=5.3 and 12.5 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.97–2.82 (m, 1H), 2.62–2.44 (m, 2H), 2.22 (s, 3H), 2.06–1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 170.02, 168.77, 167.21, 151.04, 150.02, 145.80, 136.04, 132.08, 117.57, 110.96, 109.63, 108.27, 106.34, 48.55, 38.94, 30.95, 22.10, 13.24; Anal. Calcd. For C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 61.75; H, 4.71; N, 11.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(Cl)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(Cl)cc2)n1

Procedure:
60 mg (82.3%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (45.74 mg, 0.165 mmol), 1-(2-fluorophenyl)piperazine (39.16 mL, 0.247 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6](OC3C=CC=CC=3)[C:5]=2[N:19]=1.C([O-])(=O)C.[NH4+:33].Cl>C(Cl)(Cl)Cl.CO.C(OCC)C>[NH2:33][C:6]1[C:5]2[N:19]=[C:2]([CH3:1])[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:4]=2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCNS(C)(=O)=O)c2c1C
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc(N)c2nc(C)n(CCCCNS(C)(=O)=O)c2c1C
Temperature: 150 °C
Yield: 59.1 %

Procedure:
N-[4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide (4.20 g, 10.4 mmol) and ammonium acetate (42 g) were combined and then heated in a sealed tube at 150° C. for 36 hrs. The reaction mixture was allowed to cool and then it was dissolved in chloroform. The solution was extracted with 10% aqueous sodium hydroxide solution. The aqueous layer was separated and then extracted multiple times with chloroform. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in methanol and combined with 1M hydrochloric acid in diethyl ether (10.4 mL). The resulting white precipitate was isolated by filtration and dried. The solid was dissolved in water and the solution was adjusted to pH 10 with solid sodium carbonate. The resulting white precipitate was isolated by filtration, washed with diethyl ether and then dried in a vacuum oven at 80° C. to provide 2.00 g of N-[4-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide, m.p. 228-230° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:11]=[C:12]([CH:20]=2)[C:13]([O:15]C(C)(C)C)=[O:14])=[N:6][CH:7]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[C:27]([OH:29])([C:26]([F:31])([F:30])[F:25])=[O:28].[CH3:24][O:23][C:21]([C:10]1[CH:11]=[C:12]([CH:20]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:9]=1)[C:13]([OH:15])=[O:14])=[O:22]
Reactant: COC(=O)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reaction time: 16 h

Procedure:
To a solution of tert-butyl methyl 5-(5-methylpyridin-2-yl)isophthalate in dichloromethane (75 mL) was added 25 mL of trifluoroacetic acid. After 16 h, the reaction was concentrated and dried under vacuum to give TFA salt of the title compound (6.5 g). MS 272.1 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:34][CH:35]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
Product: CN1CCN(Cc2ccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Yield: 40 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (125 mg, 0.43 mmol) and 1-(4-bromobenzyl)-4-methylpiperazine (129 mg, 0.48 mmol) in a manner analogous to Example 77 to yield [5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine (82 mg, 40%) as a yellow powder following purification on a 4 g Isco silica gel column using methanol in dichloromethane (0-20%) as eluent. MP=207-208° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.64 (s, 1H), 8.33 (d, J=8.0 Hz, 2H), 8.14 (d, J=8.0 Hz, 2H), 7.68 (m, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.30 (d, J=7.0 Hz, 1H), 7.18 (d, J=7.5 Hz, 2H), 3.40-3.33 (m, 5H), 2.46-2.18 (m, 8H), 2.14 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[CH2:44]([O:51][NH:52][C:14](=[O:16])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Yield: 59 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propanoic acid (2.84 g, 6.85 mmol), carbonyldiimidazole (1.22 g, 7.52 mmol) and O-benzylhydroxylamine hydrochloride (1.32 g, 8.27 mmol) in tetrahydrofuran (15 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propionamide as a yellow solid (2.1 g, 59% yield): mp, 159.0-161.0° C.; 1H NMR (DMSO-d6) δ1.30 (t, J=6.9 Hz, 3H, CH3), 3.03 (dd, J=7.7, 14.8 Hz, 1H, CHH), 3.15 (dd, J=8.0, 14.9 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 3.96 (q, J=6.9 Hz, 2H, CH2), 4.64 (s, 2H, PhCH2), 5.66 (t, J=7.8 Hz, 1H, NCH), 6.87-6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.23-7.41 (m, 5H, Ar), 8.06 (t, J=7.7 Hz, 1H, Ar), 8.14-8.18 (m, 1H, Ar), 8.26-8.31 (m, 1H, Ar), 11.24 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.66, 34.09, 50.62, 55.46, 63.72, 76.69, 111.86, 112.46, 119.83, 122.47, 126.94, 128.18, 128.67, 130.28, 133.08, 135.79, 136.38, 144.36, 147.69, 148.68, 162.99, 165.69, 166.18. Anal. Calcd for C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.12; H, 4.92; N, 7.82.