Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C2C(C(=O)NC)=C(C3C=CC(F)=CC=3)OC=2C=CC=1C1C=C(C=CC=1C)C(O)=O.[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:39]2([NH2:42])CC2)=[N:37][CH:38]=1>>[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:39]#[N:42])=[N:37][CH:38]=1
Reactant: Cc1cnc(C2(N)CC2)cn1
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Product: Cc1cnc(C#N)cn1

Procedure:
This example was prepared from the coupling of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid with 1-(5-methylpyrazin-2-yl)cyclopropanamine (obtained from 5-methylpyrazine-2-carbonitrile by the reaction using Ti(OiPr)4/EtMgBr/BF3OEt2), and was isolated as a TFA salt after purification by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Sunfire Prep C18 19×100 Sum, Fraction Collection: 7.15-7.72 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 8.44 (s, 1H), 8.43 (s, 1H), 7.95 (m, 2H), 7.90 (dd, J=7.93, 1.83, 1H), 7.83 (s, 1H), 7.55 (d, J=8.55, 1H), 7.49 (d, J=7.93, 1H), 7.33 (d, J=8.24, 1H), 7.29 (t, J=8.85, 2H), 2.96 (s, 3H), 2.51 (s, 3H), 2.30 (s, 3H), 1.67 (m, 2H), 1.41 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=553.22, HPLC Rt=1.647 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.01 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.04 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=13.04 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][C@H:38]([CH3:41])[CH2:39][OH:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][C@H:38]([CH3:41])[CH2:39][OH:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.74 Hz, 3 H), 1.48-1.59 (m, 4 H), 1.59-1.75 (m, 4 H), 2.35-2.47 (m, 2 H), 3.33-3.42 (m, 4 H), 3.48 (t, J=5.05 Hz, 2 H), 3.99-4.12 (m, 1 H), 4.14-4.23 (m, 4 H), 4.97-5.02 (m, 1 H), 7.14 (ddd, J=8.95, 6.63, 2.11 Hz, 2 H), 7.24-7.54 (m, 2 H), 7.98 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.37 (d, J=8.00 Hz, 1 H), 17.24 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: [NH2:1]C1C=NC2C(C=1NCC(C)(O)C)=CC=C(OCC1C=CC=CC=1)C=2.C(OCC(Cl)=O)C.C(OCC(Cl)=O)(=O)C.[CH2:41]([O:48][C:49]1[CH:50]=[CH:51][C:52]2[C:53]3[N:61]([CH2:62][C:63]([CH3:66])([OH:65])[CH3:64])[C:60]([CH2:67][O:68][CH2:69][CH3:70])=[N:59][C:54]=3[CH:55]=[N:56][C:57]=2[CH:58]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[NH2:1][C:55]1[C:54]2[N:59]=[C:60]([CH2:67][O:68][CH2:69][CH3:70])[N:61]([CH2:62][C:63]([CH3:64])([OH:65])[CH3:66])[C:53]=2[C:52]2[CH:51]=[CH:50][C:49]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:58][C:57]=2[N:56]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Agent: CC(=O)OCC(=O)Cl
Agent: CCOCC(=O)Cl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O

Procedure:
1-{[3-Amino-7-(benzyloxy)quinolin-4-yl]amino}-2-methylpropan-2-ol, prepared as described in Parts A and B of Example 54, was treated according to the general methods described in Parts C and D of Example 54 with ethoxyacetyl chloride used in lieu of acetoxyacetyl chloride in Part C. The product, (7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, was treated according to the general methods of Parts F and G of Example 54 to provide (4-amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white powder, mp 215.1-215.5° C.
Reaction SMILES: C([O:5][NH:6][C:7](=[N:59]S(C1C(C)=C(C)C2OC(C)(C)CC=2C=1C)(=O)=O)[NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:41]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:13](=[O:40])[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:27][C:26]([C:36]([F:39])([F:38])[F:37])=[N:25]2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C)(C)C.N1CCCCC1>CN(C)C=O>[NH2:41][C@@H:12]([CH2:11][CH2:10][CH2:9][NH:8][C:7]([NH2:59])=[N:6][OH:5])[C:13]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:27][C:26]([C:36]([F:39])([F:38])[F:37])=[N:25]2)=[CH:22][CH:23]=1)(=[O:16])=[O:17])=[O:40]
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NC(=O)[C@H](CCCNC(=NS(=O)(=O)c3c(C)c(C)c4c(c3C)CC(C)(C)O4)NOC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NC(=O)[C@@H](N)CCCNC(N)=NO)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound (15a) is treated with 20-50% piperidine in N,N-dimethylformamide (0.1 M) to remove the Fmoc protecting group. The residue is purified by reverse phase chromatography (acetonitrile/water with 0.05% trifluoroacetic acid) and then dissolved in 95% trifluoroacetic acid-methylene chloride (0.1 M). The mixture is stirred at 25° C. for 6 h and then concentrated under reduced pressure. The residue is purified by reverse phase chromatography (acetonitrile/water with 0.05% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Si:10]([O:17][CH2:18][CH:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20]Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][CH2:18][CH:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[Cl:1])([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)OCC(CCl)OC1CCCCO1
Product: CC(C)(C)[Si](C)(C)OCC(Cn1cc([N+](=O)[O-])nc1Cl)OC1CCCCO1
Yield: 49.5 %

Procedure:
Similar to Example 28, the objective compound was synthesized from 2-chloro-4-nitroimidazole (2.15 g) and 1-(tert-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane (12 g), there was obtained 1-[3-(tert-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-2-chloro-4-nitroimidazole (3.03 g, yield: 74.3%) as colorless liquid product.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH3:19][N:20]([CH3:30])[CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.CN(C)CCCC1C=NC=CC=1>[Ru](=O)=O>[CH:7]1[C:6]2[CH:5]([N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][N:20]([CH3:30])[CH3:19])[CH2:25]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CN(C)CCCC1CCCNC1
Agent: O=[Ru]=O
Agent: CN(C)CCCc1cccnc1
Product: CN(C)CCCC1CCCN(C2c3ccccc3Oc3ccccc32)C1

Procedure:
By the procedure of Example 1, reacting 9-acetoxyxanthene with 3-(3-dimethylaminopropyl)piperidine [prepared by hydrogenating 3-(3-dimethylaminopropyl)pyridine in the presence of ruthenium dioxide by the procedure of Example 12] gives 1-(9-xanthenyl)-3-[3-(dimethylamino)propyl]piperidine.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH3:10][O:11][SiH:12]([O:15][CH3:16])[O:13][CH3:14]>C([Si](C)(C)O[Si](C=C)(C)C)=C.[Pt].C1(C)C=CC=CC=1>[CH3:8][N:7]([CH3:9])[CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:12]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:10]
Reactant: C=CCOCCN(C)C
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CO[Si](CCCOCCN(C)C)(OC)OC
Reaction time: 24 h
Yield: 85.9 %

Procedure:
After adding toluene (200 mL) to a round-bottom flask containing 2-(allyloxy)-N,N-dimethylethanamine (0.398 mol) and dissolving trimethoxysilane (0.398 mol), a commercially available platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane solution was added and the mixture was stirred for 24 hours under reflux. Upon completion of reaction, after removing the solvent through distillation under reduced pressure, 0.342 mol (yield: 86%) of the target compound was obtained by extracting with water and diethyl ether. 1H and 13C NMR spectroscopic data of the purified N,N-dimethyl-2-(3-(trimethoxymethylsilyl)propoxy)ethanamine are as follows.
Reaction SMILES: [C:1]([CH:8]([CH2:12][CH2:13][NH2:14])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]I.[H-].[Na+]>C1COCC1>[C:1]([CH:8]([CH2:12][CH2:13][NH:14][CH3:15])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(CCN)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCC(C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
To a 0° C. solution of 5.00 g (24.6 mmol) of BOC-4-aminobutyric acid in 75 mL of dry THF, was added 12.2 mL (197 mmol) of methyl iodide followed by 2.95 g (73.8 mmol, 60% dispersion in mineral oil) of sodium hydride, portionwise. The reaction was rapidly stirred at room temperature for 12 h and quenched by the careful addition of water. The mixture was partitioned between ether and water, and the organic phase extracted with 1 N aq sodium bicarbonate. The combined aqueous phases were chilled and acidified to pH 3 with 1 N sodium hydrogen sulfate, then extracted with two portions of ethyl acetate. The combined organics were washed successively with water, 5% aq sodium thiosulfate, water, brine, and then dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 5.00 g (94%) of BOC-4-(N-methylamino)butyric acid. 1H NMR: (300 MHz, CDCl3) δ 3.28 (2H, bt, J=7 Hz), 2.84 (3H,s), 2.36 (2H,t,J=7.5 Hz), 1.85 (2H, m), 1.45 (9H, s).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:6])[CH2:3][NH2:4].C(NCC)C>C(Cl)Cl>[NH2:1][C@H:2]([C:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:6])[CH2:3][NH2:4]
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)C(=O)OCc1ccccc1
Solvent: CCNCC
Solvent: ClCCl
Product: NC[C@H](N)C(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 1-L round bottom flask is charged with Fmoc-Dap-Z, CH2Cl2 (122 mL) and diethylamine (61 mL, Acros). The solution is stirred at room temperature and the completion monitored by HPLC. After 7 hours, the mixture is concentrated (bath temp. <30° C.). The residue is suspended in CH2Cl2 (300 mL) and concentrated. This is repeated twice. To the residue is added MeOH (20 mL) and CH2Cl2 (300 mL), and the solution is concentrated. The residue is suspended in CH2Cl2 (100 mL) and toluene (400 mL), concentrated, and the residue left under vacuum overnight to give product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Na]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])/[C:15](/[OH:21])=[CH:11]/[C:10](=[O:12])[C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[CH3:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A solution of 1-(4-trifluoromethoxy-phenyl)-ethanone (5 g, 24 mmol) and diethyl oxalate (3.25 ml, 24 mmol) in ethanol (5 ml) was added within 20 min to an ice cooled solution of metallic sodium (552 mg, 24 mmol) in ethanol (15 ml) under an argon atmosphere. The cooling bath was removed and the reaction stirred 30 min after reaching ambient temperature. After standing 14 h, the precipitated yellow solid was filtered. The solid was partitioned between 1 M HCl/ice water 1/1 and tert butyl methyl ether. The aqueous layer was extracted two times with tert butyl methyl ether, the combined extracts were washed with brine/ice water 1/1 and dried over sodium sulfate. Evaporation of the solid gave 7.2 g (23.8 mmol, 99%) of the title compound as orange crystals.
Reaction SMILES: [C:1]([C:3](=[C:9]([O:11][CH2:12][CH3:13])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[C:1]([C:3](=[C:9]([O:11][CH2:12][CH3:13])[CH:10]=[CH:16][N:17]([CH3:19])[CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(C#N)=C(C=CN(C)C)OCC
Temperature: 70 °C

Procedure:
A mixture of ethyl 2-cyano-3-ethoxybut-2-enoate (194 g theory, 1.06 mol) and N,N-dimethylformamide dimethyl acetal (160 g, 1.325 mol) was heated at 70° C. for 2 h. The mixture was concentrated under high vacuum to provide crude ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate. The residue was used directly without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:24]C3CCCCO3)[CH:14]=[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]1=2)[CH3:2].Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:24])[CH:14]=[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OCc3ccccc3)c21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Yield: 88.3 %

Procedure:
A solution of [4-benzyloxy-1-hydroxy-6-(tetrahydro-pyran-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (1.00 g, 2.35 mmol) in THF (10 mL) was treated with 6N HCl (0.3 mL) at 0° C. for 2 h. The mixture was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=2:3) to afford the title compound (710 mg, 89%). 1H NMR (300 MHz, CD3OD) δ 7.51-7.38 (m, 5H), 6.64 (s, 1H), 6.61 (s, 1H), 5.58-5.53 (m, 1H), 5.14 (s, 2H), 4.12 (q, 2H), 3.28-3.20 (m, 1H), 2.47-2.43 (m, 1H), 1.22 (t, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2>C(O)C.C(O)(=O)C.[C].[Pd]>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH2:33][CH2:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH2:39][CH2:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc2occc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(CCc1ccc2c(c1)CCO2)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 78.4 %

Procedure:
2'-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxyacetophenone (1268 mg) and benzo[b]furan-5-carbaldehyde (911 mg) are treated in the same manner as in Example 1 to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone. This product is dissolved in a mixture of ethanol (20 ml) and acetic acid (2 ml), and the mixture is subjected to catalytic hydrogenation by using 10% palladium-carbon (0.5 g) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue are added ethyl acetate and water, and the mixture is stirred. The organic layer is collected, washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and evaporated to remove the solvent. The residue is pulverized with chloroform-diisopropyl ether, and the obtained powder is collected by filtration and dried to give 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(2,3-dihydro-5-benzo[b]furanyl)propiophenone (920 mg).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:29])[C:16]3[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:20][N:19]([CH3:28])[C:17]=3[N:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1.Cl[CH2:33][CH2:34][N:35]=[C:36]=[O:37]>O>[CH:22]1([C:21]2[C:16]3[C:15](=[O:29])[NH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:6]5[CH2:33][CH2:34][NH:35][C:36]5=[O:37])=[CH:8][C:9]=4[O:30][CH3:31])=[N:18][C:17]=3[N:19]([CH3:28])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CCNC2=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.9 %

Procedure:
To a 4 ml tetrahydrofuran solution of 150 mg (0.425 mmol) of the compound obtained in Example 44, 71 μl (0.829 mmol) of 2-chloroethyl isocyanate was added, and the mixture was stirred at room temperature for 20 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 4 ml of ethanol and 2 ml of a 1M aqueous solution of sodium hydroxide were added, and the mixture was stirred at room temperature for 15 hours. Then, the reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid, and extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/1) to obtain 95 mg (53%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:20][C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([C:22]1[CH:23]=[N:24][N:25]([CH3:26])[C:21]=1[OH:20])=[O:5]
Reactant: CC(C)c1noc(-c2c(Cl)ccc(C(=O)Cl)c2Cl)n1
Reactant: Cn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)c1noc(-c2c(Cl)ccc(C(=O)c3cnn(C)c3O)c2Cl)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
At 5-10° C., 2.00 g (6.3 mmol) of 2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoyl chloride in 10 ml of dimethoxyethane were added dropwise to 0.62 g (6.3 mmol) of 5-hydroxy-1-methyl-1H-pyrazole and 1.74 g (12.6 mmol) of potassium carbonate in 20 ml of dimethoxyethane. After 2.5 hours of stirring at room temperature, the mixture was heated under reflux for 2 hours and then once more stirred at room temperature for 12 hours. The reaction mixture was then taken up in water and washed with methylene chloride or toluene; the aqueous phase that remained was adjusted to pH=3 using hydrochloric acid and the precipitate that had formed was filtered off with suction and dried. 1.90 g (79% of theory) of 4-[2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](F)=[C:14]([F:19])[CH:13]=1)=[O:11]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH3:9])[CH:17]=[CH:16][C:15]=1[O:8][CH:4]([CH3:3])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(C)O
Reactant: CC(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(C)Oc1ccc(C(C)=O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml of DMF, and the solution was stirred at room temperature for 1 hour. Then 0.312 g of 3,4-difluoroacetophenone was added, and the mixture was stirred at room temperature overnight. The reaction solution was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting compound was reacted further without further purification.
Reaction SMILES: OCC1C=C(C=C(OC)C=1)C(NC1CCNCC1)=O.C[O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([CH2:31][OH:32])[CH:24]=1.[Li+].[OH-]>C1COCC1.CO>[OH:32][CH2:31][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([O:29][CH3:30])[CH:26]=1)[C:22]([OH:33])=[O:21]
Reactant: COC(=O)c1cc(CO)cc(OC)c1
Agent: COc1cc(CO)cc(C(=O)NC2CCNCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CO)cc(C(=O)O)c1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxymethyl-5-methoxy-N-piperidin-4-yl-benzamide [prepared by i) saponification of 3-hydroxymethyl-5-methoxy-benzoic acid methyl ester [Synthetic Communications, 31(12), 1921-1926; 2001] with LiOH in THF/MeOH (2:1) to give 3-hydroxymethyl-5-methoxy-benzoic acid in analogy to the procedure described in example 53; ii) subsequent condensation with 4-amino-piperidine-carboxylic acid tert-butyl ester to give 4-(3-hydroxymethyl-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester, using N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride and N,N-dimethyl-4-aminopyridine in MeCl2 in analogy to the procedure described in example 60d); iii) Boc cleavage with TFA in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 461.1 (MH+).