Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([C:9]3[CH:10]=[CH:11][C:12]4[C:17]([C:8]=3[S:7](=[O:19])(=[O:18])[N:6]([CH3:20])[CH2:5]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:3]C1.Cl>CO>[CH3:20][N:6]1[CH2:5][C:4](=[O:3])[C:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]=2[S:7]1(=[O:18])=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CN1CC2(OCCO2)c2ccc3ccccc3c2S1(=O)=O
Agent: Cl
Solvent: CO
Product: CN1CC(=O)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 0.5 h

Procedure:
A suspension of 10.7 gm (0.35 mol) of 2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal in 200 ml of methanol and 200 ml of aqueous 9% hydrochloric acid wasrefluxed for 30 minutes. Then, the mixture was evaporated to dryness in vacuo, the residue was taken up in methylene chloride, and the solution wsneutralized and again evaporated to dryness. After recrystallization of theresidue from ethanol, 6.3 gm (69% of theory) of 2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide, m.p. 192°-193° C), were obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][CH3:8])[C:4](=[O:6])[CH3:5].[C:9](OC(=O)C)(=[O:11])[CH3:10].CO.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:7]([CH:3]([C:4](=[O:6])[CH3:5])[CH2:2][O:1][C:9](=[O:11])[CH3:10])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CO)C(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(COC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxymethyl-pentan-2-one (20.7 g) was dissolved in CHCl3 (150 mL) and cooled in an ice bath. Acetic anhydride (80 mL) was added, followed by DMAP (2.18 g), and the mixture was stirred overnight at room temperature. After cooling in an ice bath, MeOH (120 mL) was added dropwise, and the mixture was poured into a saturated aqueous NaHCO3 solution. After extraction with DCM twice, the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give 28.0 g of a light-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=8 Hz, 3H), 1.46-1.75 (m, 2H), 2.03 (s, 3H), 2.20 (s, 3H), 2.77 (quint., J=6.5 Hz, 1H), 4.20 (d, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@@H:12]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: CC(C)CBr
Reactant: Cc1cc(Br)ccc1N=C1N[C@@H](CC(C)C)CS1
Product: Cc1cc(Br)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Bromo-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-bromo -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-bromo-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:7][C:6]=1[F:23])[CH3:3]>Cl.CO>[NH:12]1[CH2:13][CH:10]([O:9][C:8]2[CH:21]=[CH:22][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[C:6]([F:23])[CH:7]=2)[CH2:11]1
Reactant: CN(C)Cc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1F
Agent: Cl
Solvent: CO
Product: CN(C)Cc1ccc(OC2CNC2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Intermediate 26B (1.2 g, 3.7 mmol) was dissolved in a 4.0 M solution of HCl in MeOH (20 mL) and the reaction mixture was stirred at RT over for four hours. The mixture was concentrated and the residue was dissolved in water. The aqueous solution was basified to pH=10 with aqueous NaOH (1.0 M) and extracted with DCM (4×30 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. There was obtained 0.71 g (86%) of 26C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.24 (s, 6H), 3.41 (s, 2H), 3.73-3.83 (m, 2H), 3.87-3.97 (m, 2H), 4.90-5.02 (m, 1H), 6.41-6.55 (m, 2H), 7.16-7.24 (m, 1H).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](=[O:13])[NH:9][N:8]=1)=[O:6])[C:2]#[CH:3]>C(#N)C.[Au](Cl)(Cl)Cl>[CH3:3][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][N:8]=2)=[N:4][CH:1]=1
Reactant: C#CCNC(=O)c1ccc(=O)[nH]n1
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1cnc(-c2ccc(=O)[nH]n2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
622 mg (2.05 mmol) of gold(III) chloride are added to a solution of 3.69 g (20.5 mmol) of N-prop-2-ynyl-6-oxo-1,6-dihydropyridazine-3-carboxamide in 41 ml of acetonitrile, and the mixture is stirred at room temperature for 3 days. A further 622 mg (2.05 mmol) of gold(III) chloride are added, and the mixture is stirred at room temperature for 7 days. The reaction mixture is evaporated and chromatographed on a silica gel column with dichloromethane/methanol as eluent: 6-(5-methyloxazol-2-yl)-2H-pyridazin-3-one as yellowish crystals; ESI 178.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OB(O)O)=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>C1(C)C=CC=CC=1.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.O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:24]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2cccnc2)cc1
Yield: 25.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.65 g, 0.56 mmol), 4-formylphenylboric acid (2.81 g, 18.7 mmol), 2M aqueous sodium carbonate (18.7 ml, 37.4 mmol) and ethanol were added to the nitrogen-saturated solution of 3-bromopyridine (2.66 g, 16.8 mmol) in toluene and refluxed under nitrogen for 8 hrs. Water was added to the solution and extracted with ethyl acetate, washed with water and brine and dried. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1.5) to give 4-(3-pyridyl)benzaldehyde (0.78 g, 25%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1>>[C:1]1([CH2:7][O:8][C:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:31]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:30]=3[N:21]=[CH:22][CH:23]=[CH:24]4)(=[O:32])=[O:33])=[CH:17][CH:18]=2)=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: O=C(NCCc1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1)OCc1ccccc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from the Cbz amine from Example 3 and 8quinolinesulfonyl chloride: 1H NMR (400 MHz, d6 -DMSO) 9.94 (s, H), 9.12 (m, 1H), 8.49 (dd, 1H), 8.31 (dd, 1H), 8.24 (dd, 1H), 7.70 (m, 2H), 7.2-7.4 (m, 4H), 6.94 (d, 2H), 6.88 (d, 2H), 4.94 (s, 2H), 3.04 (m, 2H), 2.48 (t, 2H). FAB MS m/z 462 (M+1).
Reaction SMILES: C(OC([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[C:27]([O:33]C)(=O)[CH2:28][C:29]([CH3:31])=O>C(Cl)Cl>[C:16]([CH:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:27](=[O:33])[CH2:28][C:29]([CH3:31])=[N:8]2)[CH2:15][CH2:14]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)NNC1CCC(C(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(C2CCC(C(C)(C)C)CC2)C(=O)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To the N′-(4-tert-butyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester (7.61 g) in CH2Cl2 (30 mL) was added TFA (10 mL). After 5 h at RT, the solvent was removed under reduced pressure. The residue was dissolved in glacial acetic acid (100 mL), methyl acetoacetate (4.46 g, 38.4 mmol) was added and the reaction was heated to 100° C. for 18 h. After allowing the reaction to cool to RT, the solvent was removed under reduced pressure. Flash chromatography of the residue (50% to 80% EtOAc/hexanes, silica gel) gave the two isomers of 2-(4-tert-butyl-cyclohexyl)-5-methyl-2,4-dihydro-pyrazol-3-one as pale yellow oils. Isomer 1: 2.67 g; TLC Rf 0.30 (silica gel, 1:1 EtOAc/hexanes); MS (ES+) m/z 237.0 (M+H+). Isomer 2: 0.66 g; TLC Rf 0.15 (silica gel, 1:1 EtOAc/hexanes); MS (ES+) m/z 237.4 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[C:3]1=[O:13].C([O-])([O-])=O.[K+].[K+].CS(O[C@H:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])(=O)=O>CN(C=O)C>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([C@@H:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])[CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[C:3]1=[O:13]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: COC(=O)[C@@H](C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)n1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a suspension of 1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (20 g, 111 mmol) and K2CO3 (30.6 g, 222 mmol) in DMF (400 mL) was added (R)-methyl 2-((methylsulfonyl)oxy)propanoate (which may be synthesized according to the procedure described in PCT Pub No. WO/2005/059107 (40 g, 222 mmol). The reaction mixture was stirred at 20° C. for 20 h. The reaction mixture was then quenched with saturated NH4Cl(aq), diluted with water and extracted with CH2Cl2 (3×). The combined organic extracts were washed 3× with 10% LiCl (aq), dried over Na2SO4 and evaporated in vacuo. The residue was purified using silica gel column chromatography eluting first with PE:CH2Cl2 (1:1) followed by CH2Cl2:MeOH (50:1) to give 13.5 g (50.7 mmol, 45.7%, ee: 95%) of the (S)-product. The (S)-product was analyzed by chiral HPLC to determine it is at least 95% pure as the S-isomer (≧95% ee).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[O:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47].[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:46]([C:42]3[O:41][CH:45]=[CH:44][CH:43]=3)(=[O:48])=[O:47])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccco2)c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and furan-2-sulfonyl chloride (125 mg) were added dropwise and the mixture was further stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a colorless oil (yield 193 mg, 91%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=[C:6]1[CH:15]([N:18]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH2:16][CH3:17].O[NH:41][C:42](=[NH:44])[CH3:43].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][CH2:29][CH2:28][N:18]([C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH:15]([C:6]1[N:5]([CH2:4][C:3]2[O:2][N:44]=[C:42]([CH3:43])[N:41]=2)[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=1)[CH2:16][CH3:17])([CH3:37])([CH3:38])[CH3:36]
Reactant: CCC(c1nn2cccc2c(=O)n1CC(=O)OC)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(c1nn2cccc2c(=O)n1Cc1nc(C)no1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a mixture of (±)-(2-{1-[(3-tert-butoxycarbonylaminopropyl)-(4-methylbenzoyl) amino]propyl}-4-oxo-4H-pyrrolo[2,1-f][1,2,4]triazin-3-yl)acetic acid methyl ester (Example 7 A, 26 mg, 0.05 mmol) and N-hydroxyacetamidine (Tyger Scientific, 6 mg, 0.08 mmol) in DMF (1 mL), under Ar, was treated with sodium hydride (6.5 mg as 60% dispersion in mineral oil, 0.15 mmol) and stirred at ambient temperature overnight before being diluted with ethyl acetate. The organic layer was washed twice with water and once with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC (YMC S5 ODS, 20×250 mm, 30 minute gradient from 66–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (5 mg, 18%): 1H NMR (CDCl3) δ 7.45 (m, 1H), 7.21–7.08 (m, 4H), 7.07 (m, 1H), 6.59 (m, 1H), 5.97 (m, 1H), 5.83 (m, 1H), 5.47 (m, 1H), 3.92 (m, 1H), 3.36 (m, 2H), 2.74 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.30–1.98 (m, 2H), 1.74–0.80 (m, 14H); MS (ESI+) 564.20 (M++H).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:58])([CH3:57])[C@H:7]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:8](=[O:48])[NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@H:13]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:17][C:18](=[O:21])[O:19][CH3:20])(=O)C.[OH-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C>[C:53]([O:52][C:50]([NH:49][C@@H:7]([C:6]([CH3:58])([CH3:57])[CH2:5][OH:4])[C:8]([NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@@H:13]([NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:25])([CH3:23])[CH3:24])[NH:17][C:18]([O:19][CH3:20])=[O:21])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:30][CH:29]=1)=[O:48])=[O:51])([CH3:54])([CH3:55])[CH3:56]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)COC(C)=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)CO)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product of Example 174F (0.020 g, 0.025 mmol) in a mixture of dioxane (0.250 mL) and water (0.100 mL) was added an aqueous solution of lithium hydroxide (0.028 mL, 1 N), and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate and washed with brine, dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1
Reactant: CSc1ccccc1B(O)O
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Product: CSc1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-(methylthio)phenylboronic acid. colorless crystals (yield 39%). MS (APCI−): 377 (M−H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([OH:19])=[O:18])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]1COCC1>>[CH2:1]([O:8][C:9]1[N:13]([C:14]2[CH:15]=[C:16]([C:17]([O:19][CH3:23])=[O:18])[CH:20]=[CH:21][N:22]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc(-n2nccc2OCc2ccccc2)c1
Reactant: C1CCOC1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of compound 2-(5-(benzyloxy)-1H-pyrazol-1-yl)isonicotinic acid (32 mg, 011 mmol, 1.0 eq.) in THF was added CH2N2 (˜10 eq.), the mixture was stirred for 30 min; the solvent was removed to obtain the desired product (25 mg). 1H NMR (400 MHz, CDCl3): δ 3.88 (3H, s), 5.18 (2H, s), 5.69 (1H, s), 7.28-7.39 (5H, m), 7.51 (1H, s), 7.69 (1H, d, J=4.4 Hz), 8.28 (1H, s), 8.65 (1H, s). [M+H] Calc'd for C17H15N3O3, 310; Found, 310.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][N:11]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:12]2=[O:17])=[O:6].[C:26](O)(=[O:48])[CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH3:47].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.CCOC(C)=O>[O:25]=[C:19]1[CH:18]([N:11]2[CH2:10][C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:26](=[O:48])[CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH3:47])[C:12]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The HCl salt of 3-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide (0.1 mmol) is taken up in 5 mL of DMF along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 0.1 mmol), HATU (0.11 mmol) and DIEA (0.3 mmol). The resulting reaction mixture is stirred at room temperature for 4 h and then diluted with EtOAc (20 mL). The organic layer is washed with water (3×5 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) affords (4Z,7Z,10Z,13Z,16Z,19Z)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropyl)docosa-4,7,10,13,16,19-hexaenamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(OCC)C>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reaction time: 0.25 h

Procedure:
Cool the 1-(t-butoxycarbonyl)-4-(1-(4-fluoro-benzyl)-1H-benzoimidazole-2-carbonyl)-piperidine in an ice bath. Add trifluoroacetic acid and mix. After 15 minutes, add diethyl ether to give a residue. Collect the residue by filtration and dry under vacuum. Recrystallize from ethanol/ether and dry resulting solid under vacuum to give the title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:21]([OH:23])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1>[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:21]([OH:23])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Pd]
Product: O=C(O)[C@H](Cc1c[nH]cn1)NCC(O)C(O)C(O)C(O)CO

Procedure:
The manufacture took place from D-glucose and L-(-)-histidine using palladium/activated carbon (10%) as a catalyst and yielded a product having a melting point of 165° to 170° C. (decomposition).
Reaction SMILES: S([O-])(=O)(=O)C.[N-]=[N+]=[N-].[Na+].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][C@@H:19]1[C@H:24]([N:25]=[N+:26]=[N-:27])[CH2:23][C@H:22]2[CH2:28][C@@H:20]1[C:21]2([CH3:30])[CH3:29]>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][C@H:19]1[C@H:24]([N:25]=[N+:26]=[N-:27])[CH2:23][C@H:22]2[CH2:28][C@@H:20]1[C:21]2([CH3:30])[CH3:29]
Reactant: CC1(C)[C@H]2C[C@@H](N=[N+]=[N-])[C@@H](CCOC3CCCCO3)[C@@H]1C2
Agent: CS(=O)(=O)[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC1(C)[C@H]2C[C@@H](N=[N+]=[N-])[C@H](CCOC3CCCCO3)[C@@H]1C2

Procedure:
Diethyl azadicarboxylate (20 g) was added dropwise to a suspension of the alcohol 1(2R-c) (6.11 g), triphenylphosphin (30 g) and zinc dimethanesulfonate (5.83 g) in benzene (350 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 3 h, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel in hexane ethyl acetate (5:1) to give the crude mesylate (6.7 g). The mesylate was treated with sodium azide by the same procedure cited for the preparation of 15 (IV-2, Example 2 (2)), 2.05 g, 31.3%. nmr δ (CDCl3) 0.86 (3H,s), 1.21 (3H,s), 1.28 (1H,d,J=10 Hz), 1.40-2.50 (14 H), 3.22-4.00 (5H), 4.57 (1H,m).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:27]([O:28]C(=O)C)[C@H:26]([O:32]C(=O)C)[C@@H:25]([CH2:36][O:37]C(=O)C)[O:24][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:6]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:32])[C@H:27]([OH:28])[C@H:5]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(N)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2ccc(N)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 90.4 %

Procedure:
To a solution of 5-amino-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.19 g) in methanol (3.5 mL) was added sodium methoxide (28% methanol solution, 0.064 mL), and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The resulting precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give 5-amino-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.12 g).