Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)CCC=C)(=O)CCC=C.[Li+].[OH-].[CH2:16]([O:23][C:24](=[O:47])[C@H:25]([CH:44]([CH3:46])[CH3:45])[NH:26]C(=O)C(NC(OCC1C=CC=CC=1)=O)CC=C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1[C@H](N2C(=O)N=C(N)C=C2)O[C@H](COP(O)(O)=O)[C@H]1OP(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(O)=O>CN(C=O)C.C1COCC1>[CH2:16]([O:23][C:24](=[O:47])[C@H:25]([CH:44]([CH3:45])[CH3:46])[NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCC(NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: C=CCCC(=O)OC(=O)CCC=C
Agent: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)[C@H](N)C(=O)OCc1ccccc1
Yield: 94 %

Procedure:
N-(4-pentenoyl)valyl-pdCpA was prepared. Treatment of S-valine methyl ester with 4-pentenoic anhydride afforded the respective amide as a colorless oil in 73% yield. Following hydrolysis of the ester moiety (LiOH, aq THF), the derived intermediate was converted to the respective cyanomethyl ester (4). Admixture of 4 and pdCpA Robertson, et al., Nucleic Acids Res. 17:9649 (1989), in freshly distilled DMF afforded N-(4-pentenoyl)valyl-pdCpA (5) as a colorless solid in 94% yield. A sample of N-(2-nitroveratryloxycarbonyl)valyl-pdCpA was prepared as described, Robertson, et al., J. Am. Chem. Soc. 113:2722 (1991) for comparative purposes.
Reaction SMILES: [CH:1]1[C:6]2[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:5]=2[CH:4]=[CH:3][C:2]=1[C:17](=[O:19])[CH3:18].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(Cl)Cl.O>[N+:20]([C:3]1[C:2]([C:17](=[O:19])[CH3:18])=[CH:1][C:6]2[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:5]=2[CH:4]=1)([O-:22])=[O:21]
Reactant: CC(=O)c1ccc2c(c1)OCCOCCOCCO2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1[N+](=O)[O-])OCCOCCOCCO2
Temperature: 0 °C
Yield: 36.1 %

Procedure:
1-(6,7,9,10,12,13-Hexahydro-5,8,11,14-tetraoxa-benzocyclododecen-2-yl)-ethanone (200 mmol, 51.3 g) dissolved in DCM (750 ml) and the mixture cooled to 0° C. Nitric acid (90%, 300 mmol, 14 ml) was added dropwise to the cooled solution over 20 minutes. Sulfuric acid (96.2%, 300 mmol, 8.75 ml) was then added dropwise over 40 minutes at 0° C. Additional nitric acid (200 mmol, 9.4 ml) was added dropwise over 20 minutes. The reaction mixture was diluted with water (300 ml) and wash with water (3×200 ml), Sat. NaHCO3 (4×200 ml, or until neutral). The organic layer was dried over Na2SO4 and concentrated. The crude mixture was recrystallized with DMF to give 22.5 g of the nitro product. The DMF layer was concentrated and recrystallized with ethyl acetate to give additional 8.75 g of the product. The ethyl acetate layer was concentrated and purified on silica column using 20% EtOAc/hexanes to give another 4.75 g of the product. Total yield is 36 g, (−60%). 1HNMR (400 MHz, DMSO) δ 7.82 (s, 1H), 7.61 (s, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 2.71 (s, 3H). LC/MS Calcd for (M+H)−312.3. found 312.5.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20]S(C)(=O)=O)([CH3:18])[CH2:13]1.C([O-])([O-])=O.[K+].[K+].[CH2:31](O)[C:32]([F:35])([F:34])[F:33]>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:18])([CH2:19][O:20][CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:13]1
Reactant: OCC(F)(F)F
Reactant: CC1(COS(C)(=O)=O)CCCN(CC2COc3ccccc3O2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(COCC(F)(F)F)CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of methanesulfonic acid 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethyl ester (0.35 g, 0.98 mmol), K2CO3 (0.68 g) and trifluoroethanol (4 ml) was irradiated in a microwave reactor at 150° C. for 10 min. Water was added and the reaction mixture was extracted with DCM (2×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:36](=[O:37])[N:12]2[C:13]([C:30]([O:32]CC=C)=[O:31])=[C:14]([CH2:17][N:18]3[N:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:19]3(=[O:29])=[O:28])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:67].C(OCC)(=O)C.C(C(CCCC)C(O)=O)C>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.C(OCC)(=O)C>[O:29]=[S:19]1(=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[N:27][N:18]1[CH2:17][C:14]1[C@H:15]([CH3:16])[C@@H:11]2[C@@H:10]([C@H:8]([OH:7])[CH3:9])[C:36](=[O:37])[N:12]2[C:13]=1[C:30]([O-:32])=[O:31].[Na+:67]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3N=Cc4ccccc4S3(=O)=O)[C@H](C)[C@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(CN3N=Cc4ccccc4S3(=O)=O)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (29 mg, 0.055 mmol), triphenylphosphine (6.3 mg, 0.024 mmol), 0.5M sodium 2-ethyl-hexanoate in ethyl acetate (0.125 mL, 0.063 mmol), and 2-ethyl-hexanoic acid (0.0098 mL, 0.061 mmol) were dissolved in 1:1 dichloromethane-ethyl acetate (1 mL). Tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.0061 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with diethyl ether (7 mL) and extracted with water (2×1.5 mL). The aqueous extracts were washed with hexanes, concentrated under vacuum, and purified by preparative layer chromatography on a 1 mm×20 cm×20 cm RPSF plate, using 3:1 water-acetonitrile as the developing solvent. The product band was located by UV, removed and eluted with 4:1 acetonitrile-water. The eluent was concentrated under vacuum to remove the acetonitrile and lyophilized to afford the crude product (11 mg). This material was dissolved in ice cold water (1.5 mL) and applied to a small column of Amberchrom CG-161 resin (5 mm×5 cm). The column was eluted with cold water (20 mL) followed by 20% aqueous isopropanol in 2 mL fractions. The product containing, aqueous isopropanol fractions (2-7) were combined, concentrated under vacuum, and lyophilized to afford the title compound (5.6 mg) as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2ccc(O)cc21
Temperature: 80 °C
Yield: 94.1 %

Procedure:
7-Hydroxy-3,4-dihydronaphthalen-1(2H)-one (0.75 g, 4.2 mmol) was dissolved in ethanol (30 mL) and water (10 mL), then the hydroxylamine hydrochloride (0.59 g, 8.5 mmol) and sodium acetate (0.70 g, 8.5 mmol) were added. The reaction was heated to 80° C. for 2 h. The reaction was allowed to cool to r.t., concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as oil. The oil was purified by flash chromatography on a silica gel column eluting hexane: ethyl acetate gradient to give 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one oxime (0.70 g, 95%) as a yellow green oil. Analytical LCMS (M+H)+: m/z=178.1.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH2:1]([N:8]([C@H:9]1[C@H:10]([OH:14])[CH2:11][O:12][CH2:13]1)[C:24](=[O:25])[CH2:23][Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1COC[C@H]1NCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N(Cc1ccccc1)[C@@H]1COC[C@H]1O
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(benzylamino)tetrahydrofuran-3-ol (4.1 g, 21.2 mmol) in CH2Cl2 (40 mL) at −40° C. was added triethylamine (5.9 mL, 42.4 mmol) followed by dropwise addition of 2-chloroacetyl chloride (1.6 mL, 21.2 mmol). The reaction was stirred at −40° C. for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 (40 mL) and extracted using CH2Cl2 (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 100% EtOAc/hexanes afforded trans-N-benzyl-2-chloro-N-(4-hydroxytetrahydrofuran-3-yl)acetamide. MS APCI calc'd for C13H16ClNO3 [M+H]+ 270. found 270.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].O[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[CH:21][CH:22]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1 g) in anhydrous tetrahydrofuran (20 mL) was cooled to 0° C. under a nitrogen atmosphere. 4-Hydroxybiphenyl (3 g) and triphenylphosphine (4.61 g) were added and the mixture was treated with di-isopropylazodicarboxylate (3.46 mL) dropwise. The mixture was stirred at 0° C. for 10 min then cooling was removed and the mixture stirred for a further 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (100 mL). The organic phase was separated, dried and evaporated. The residue was purified by flash chromatography, eluting with pentane/ethyl acetate 9:1 by volume to give a mixture of the title compound and 4-hydroxybiphenyl (1.8 g). This material was purified further by flash chromatography eluting with dichloromethane/methanol 99:1 by volume to give compound 17 as a white solid (200 mg). LCMS System A: Rt=4.2 mins.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.[F:14][C:15]([F:34])([F:33])[C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([CH2:31]Cl)[N:27]=2)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>>[F:34][C:15]([F:14])([F:33])[C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([CH2:31][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH3:13])[N:27]=2)[CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.49 (s, 1H), 7.94 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 5.87 (s, 2H), 2.51 (s, 3H); MS (ES) m/z 485 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:13][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]ccc2c1
Reaction time: 0.75 h

Procedure:
To a solution of 1H-indole-5-carboxylic acid (5 g, 31.0 mmol) in 70% methanol/methylene chloride (105 mL) at 0° C. was added 1M trimethylsilyldiazomethane in hexanes (46 mL, 46 mmol). After 45 min., the reaction mixture was concentrated to afford 1H-indole-5-carboxylic acid methyl ester (5.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[C:5]([NH2:25])=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:25]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)[NH:26]2)=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:12][CH2:13]2)[N:7]=1
Reactant: Nc1nc(N)c(N)c(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)n1
Reactant: O=Cc1ccc(F)cc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Yield: 83 %

Procedure:
This compound was synthesized from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]pyrimidine and 4-fluorobenzaldehyde, yielding the pure title compound in 83% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].[C:15]([CH2:19][CH2:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:22](=[O:23])[CH:21]([CH3:25])[CH2:20][CH2:19][C:15]([O:17][CH3:18])=[O:16])=[O:4]
Reactant: COC(=O)CCC(C)C(=O)Cl
Reactant: COC(=O)C1CCc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(C)C(=O)N1c2ccccc2CCC1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1.0 g of 1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester (Ber. 61,2377), 0.87 g of 4-carbomethoxy-2-methylbutanoyl chloride, 1.44 g of powdered potassium carbonate and 20 ml of methylene chloride is stirred at room temperature overnight. It is cooled with ice, and 50 ml of water are added. The organic layer is separated, washed with N-hydrochloric acid and water, dried and evaporated, to yield the 1-(4-carbomethoxy-2-methylbutanoyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester, showing NMR-peaks at 0.85, 1.25, 3.35, 3.65 and 3.75 ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M41) (269 mg, 0.561 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (161 mg).
Reaction SMILES: C(OC([C:11]1[NH:15][C:14]([CH3:16])=[C:13]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]=1[CH3:23])=O)C1C=CC=CC=1>CC(C)=O.[Pd]>[CH3:22][O:21][C:19]([CH2:18][CH2:17][C:13]1[C:12]([CH3:23])=[CH:11][NH:15][C:14]=1[CH3:16])=[O:20]
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CC(C)=O
Product: COC(=O)CCc1c(C)c[nH]c1C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Methyl 5-(benzyloxycarbonyl)-2,4-dimethyl-3-pyrrolepropionate (3.1 g, 9.8 mmol) was dissolved in acetone (100 mL). This solution was added with 10% Pd—C, and stirred at room temperature under hydrogen gas. When the starting material disappeared, the reaction mixture was filtered, and the filtrate was distilled under reduced pressure. The residue was added with trifluoroacetic acid (10 mL), and heated at 40° C. for 10 minutes under an argon flow. The reaction mixture was added with chloroform, and washed once with water, and the aqueous layer was extracted twice with chloroform. The organic phases were combined, washed once with aqueous Na2CO3 and once with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: CH2Cl2) to obtain the target compound as brown liquid (1.6 g, yield: 90%).
Reaction SMILES: C1(C[O:8][C:9](=[O:51])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48](=[O:50])[NH2:49])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1.[H][H].CN(C=O)C>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48](=[O:50])[NH2:49])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:51])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of 2.2 g of N-[(3-carbamoyl)-5-(octadecyloxy)phenyl-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 3 hours. DMF (150 ml) was added and the mixture was heated to dissolve the precipitated product. The hot mixture was filtered to remove the catalyst and the filtrate was concentrated at reduced pressure to a solid. Recrystallization from THF gave 1.1 g (69% yield, mp 213°-216°) of N-(carboxymethyl)-N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1>>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: NCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCCCCN

Procedure:
In a manner similar to that in Reference Example 1, 4-amino-1-butanol was reacted with tert-butyldimethylsilyl chloride in the presence of imidazole to give 4-(tert-butyldimethylsilyloxy)-1-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22](O)=[O:23])[N:21]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:15][CH2:16]1)(=[O:10])=[O:9]
Reactant: O=C(O)c1csc(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Cl)N1CCN(c2nc(CO)cs2)CC1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
2-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)thiazole-4-carboxylic acid (77 mg, 0.02 mmole) was dissolved in 1 mL of anhydrous THF under nitrogen protection. 0.4 mL of LiAlH4 (1.0M solution in THF) was added to the solution through a syringe at −78° C. After 30 minutes, the reaction mixture was quenched with MeOH, evaporated to dryness, and extracted with EtOAc and 0.1 N tartaric acid solution in water. The organic layer was then dried over Na2SO4, and the solvent was removed. The title compound was obtained in 77% yield after purification using preparative HPLC. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.33 (M, 4 H), 3.47 (dd, J=6.19, 3.92 Hz, 4 H), 4.31 (s, 2 H), 6.63 (s, 1 H), 7.54-7.62 (m, 1 H), 7.65-7.75 (m, 2 H), 7.95-8.02 (m, 1H); ESI-MS: m/z 374.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:41]O.[OH-].[Na+]>CO>[C:35]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([OH:41])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OO
Reactant: CC1(C)OB(c2ccc3c(c2)C2(CO3)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(O)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
A mixture of 1′-(diphenylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (4.50 g, 8.50 mmol), hydrogen peroxide (4.86 mL, 30% solution, 42.5 mmol), sodium hydroxide (16.38 mL, 10% solution, 40.82 mmol) in methanol was stirred at 0° C. for 30 min and ambient temperature for 16 h. The reaction mixture was quenched with sodium bisulfite. The pH of the reaction mixture was adjusted to 4 using 14% hydrochloric acid. The mixture was extracted with ethyl acetate (3×250 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was triturated with hexane (20.0 mL), followed by ether (15.0 mL) to give the title compound (3.20 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.45-7.38 (m, 10H), 7.13 (dd, 1H), 7.07-6.91 (m, 3H), 6.79 (d, 1H), 6.63 (dd, 1H), 6.50 (d, 1H), 6.12 (d, 1H), 4.96 (d, 1H), 4.69 (d, 1H); MS (ES+) m/z 420.23 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.F[C:22]1[C:27]([CH:28]2[CH2:32][N:31]([CH3:33])[C:30](=[O:34])[CH2:29]2)=[CH:26][CH:25]=[CH:24][N:23]=1>CN1C(=O)CCC1>[CH3:33][N:31]1[CH2:32][CH:28]([C:27]2[C:22]([O:20][C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)=[CH:15][CH:16]=3)=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:29][C:30]1=[O:34]
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: CN1CC(c2cccnc2F)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1=O
Temperature: 100 °C

Procedure:
To a mixture of cesium carbonate (0.559 g, 1.72 mmol), 4-(pyridin-2-ylamino)phenol (0.320 g, 1.72 mmol), and 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.110 g, 0.566 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 100° C. for 2 h. The reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with 1 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (30% to 100% EtOAc (10% MeOH) in hexanes) gave 1-methyl-4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)pyrrolidin-2-one as a white solid and a 1:1 mixture of enantiomers. MS (ESI, pos. ion) m/z: 361.1 (M+1). IC50 (uM) 0.01406.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][CH2:17][CH2:16][CH2:15][N:10]1[CH:11]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: ClCCCBr
Reactant: O=c1[nH]cc(-c2cccs2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.5 %

Procedure:
A mixture of 5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep22, 1 g, 5.15 mmol), 1-bromo-3-chloropropane (0.81 g, 5.15 mmol) and potassium carbonate (0.71 g, 5.15 mmol) in DMF (10 ml) was stirred at room temperature for 7 hours, then the mixture was diluted with water and extracted with ethyl acetate. Organic phase was evaporated and the crude was purified by a FC (eluent P:E=3:1, 1:1) to afford the title compound (300 mg, y=21%)