Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([F:34])=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH:31]([F:33])[F:32])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:34][C:5](=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[C:19]([CH:26]([CH3:27])[CH3:28])[C:18]=3[O:29][CH2:30][CH:31]([F:32])[F:33])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(F)=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=C(F)C(=O)O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 2-Fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid was isolated as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.1 Hz, 1H, Ar—H), 7.58 (d, J=7.3 Hz, 1H, Ar—H), 7.41 (d, J=3.0 Hz, 1H, furan-H), 7.34 (t, J=7.6 Hz, 1H, Ar—H), 7.31 (d, J=2.2 Hz, 1H, Ar—H), 7.17 (d, J=2.2 Hz, 1H, Ar—H), 5.52 (tt, J=55.2 Hz, J=4.1 Hz, 1H, O—CH2—CF2H), 3.52 (dt, J=13.6 Hz, J=4.1 Hz, 2H, O—CH2—CF2H), 3.41 (m, 1H, CH3—CH—CH3), 2.95 (m, 1H, CH3—CH—CH3), 2.56 (d, J=3.5 Hz, 3H, C═C—CH3), 1.31 (d, J=6.7 Hz, 6H, CH3—CH—CH3), 1.29 (d, J=6.8 Hz, 6H, CH3—CH—CH3).
Reaction SMILES: C([C@H]([C@@H](C(OCC)=O)O)O)(OCC)=[O:2].[CH3:15][C:16]([Si:19]([CH3:38])([CH3:37])[O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24]([CH2:35][OH:36])=[CH:23][CH2:22]1)([CH3:18])[CH3:17].C(OO)(C)(C)C.COC(C)(C)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:18][C:16]([Si:19]([CH3:38])([CH3:37])[O:20][CH:21]1[CH2:22][CH:23]2[C:24]([CH2:35][OH:36])([O:2]2)[CH:25]1[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:15])[CH3:17]
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC=C(CO)[C@@H]1COCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC1CC2OC2(CO)C1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 250-mL oven dried three necked round bottomed flask was equipped with a magnetic stir bar, argon inlet, and temperature probe charged with oven dried powdered molecular sieves 4A° (9.0 g). DCM (30 mL) was added to the flask and the resulting suspension was stirred room temperature for 5 minutes. Diethyl D-tartrate (2.13 g, 10.32 mmol) in DCM (18 mL) was added at room temperature and the mixture was cooled to −30° C. Keeping the temperature at −30° C., titanium (IV) isopropoxide (2.665 mL, 9.03 mmol) was added. The reaction mixture was stirred at −30° C. for 30 minutes followed by 15 minutes at −15° C. The mixture was cooled to −30° C. To this mixture, a solution of compound 16 (4.5 g, 12.9 mmol) in DCM (18 mL) was added. The mixture was stirred for 30 minutes at −30° C. followed by addition of a solution of tert-butyl hydroperoxide (5.0–6.0 M; 9.40 mL, 5.176 mmol). The reaction mixture was stirred between −30° C. to −20° C. for 3 hours to complete the reaction. The reaction was quenched by addition of water (45 mL). The reaction mixture was stirred with vigorous mixing and allowed to warm up to room temperature (15 to 20° C). When the temperature reached ˜15° C., 30% sodium hydroxide solution (10 mL) was added slowly to give a milky white slurry. This slurry was added into a 3.0-L Erlenmeyer flask containing tert-butyl methyl ether (1100 mL). The mixture was stirred for 30 minutes and then filtered on a bed of diatomaceous earth (Celite®). The aqueous layer was separated from the filtrate and discarded. The organic layer was washed with 10% aqueous sodium thiosulfate (100 mL) and water (2×160 mL). The combined organic layer was washed with water (100 mL), brine (50 mL), and dried over magnesium sulfate. The organic layer was concentrated in vacuo to give the title compound in quantitative yield (5.47 g) as an oil.
Reaction SMILES: [N:1]([C@@H:4]1[C:40]([CH3:42])([CH3:41])[C@H:39]2[C@@:7]3([O:35][C:11]4[C:12]5[CH2:13][N:14]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:15](=[O:27])[C:16]=5[CH:17]=[C:18]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:10]=4[CH2:9][C@:8]3([CH3:44])[C@@H:36]([CH3:43])[CH2:37][CH2:38]2)[CH2:6][CH2:5]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[NH2:1][C@@H:4]1[C:40]([CH3:42])([CH3:41])[C@H:39]2[C@@:7]3([O:35][C:11]4[C:12]5[CH2:13][N:14]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:15](=[O:27])[C:16]=5[CH:17]=[C:18]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:10]=4[CH2:9][C@:8]3([CH3:44])[C@@H:36]([CH3:43])[CH2:37][CH2:38]2)[CH2:6][CH2:5]1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N=[N+]=[N-])CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Yield: 91.2 %

Procedure:
To the above Compound (44) (300 mg, 0.50 mmol) dissolved in 10 ml of THF were added 1.0 ml of water and 270 mg (1.03 mmol) of triphenylphosphine. The mixture was heated to reflux for 24 hours. After the addition of ethyl acetate, it was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was loaded onto a silica gel column (silica gel 20 g), followed by elution with 60 ml of ethyl acetate to remove nonpolar fractions. The polar fractions eluted with 120 ml of ethyl acetate and 80 ml of chloroform-methanol (20:1) mixture were combined, and concentrated under reduced pressure. The residue was further purified by a column chromatography (Merck, Lobar column, size B; chloroform:methanol=20:1-10:1) to give 262 mg (83%) of Compound (45a) as a powdery material.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]([CH3:19])[C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]2[C:17]=1[CH3:18])=[O:4].[F:22][C:23]([F:40])([F:39])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[CH3:18][C:17]1[N:9]2[CH:10]=[C:11]([NH:14][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:27]4[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:39])[F:40])=[CH:25][CH:26]=4)=[CH:35][CH:34]=3)=[O:37])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[N:5]([CH3:19])[C:3](=[O:4])[C:2]([F:21])([F:20])[F:1]
Reactant: Cc1c(N(C)C(=O)C(F)(F)F)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: Cc1c(N(C)C(=O)C(F)(F)F)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn12
Yield: 61.2 %

Procedure:
Operations similar to Example 1 were conducted using 2,2,2-trifluoro-N-methyl-N-(3-methyl-6-nitroimidazo[1,2-a]pyridin-2-yl)acetamide (580 mg) and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid (510 mg), to provide N-{3-methyl-2-[methyl(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}-4′(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamide (610 mg) as white solid.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:13]2([CH3:18])[O:17][CH2:16][CH2:15][O:14]2)[O:11][CH:12]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.O>[CH3:18][C:13]1([C:10]2[O:11][CH:12]=[C:8]([CH2:6][OH:5])[N:9]=2)[O:17][CH2:16][CH2:15][O:14]1
Reactant: CCOC(=O)c1coc(C2(C)OCCO2)n1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2nc(CO)co2)OCCO1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of 2-(2-methyl-[1,3]dioxolan-2-yl)-oxazole-4-carboxylic acid ethyl ester (5.05 g, 22.2 mmol) in dry THF (80 mL) was added an ice-cold solution of LiAlH4 (1.0 M in THF, 24.7 mL, 24.7 mmol). The reaction mixture was stirred at 0° C. until completion of the reaction. Water (2.0 mL) was carefully added at 0° C. followed by aq. 1 M NaOH (2.0 mL) and water (2.0 mL). The resulting suspension was stirred at rt for 1 h, filtered (+EA) and the filtrate concentrated under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.18. LC-MS-conditions 05c: tR=0.22 min; [M+H]+=186.30.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][P:8](=[O:15])([O:9][CH2:10][CH3:11])[O:12][CH2:13][CH3:14]
Reactant: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1cccc(N)c1)OCC
Yield: 95 %

Procedure:
A solution of the diethyl (3-nitrobenzyl)phosphonate prepared as described above, in MeOH (5 mL) was hydrogenated in the presence of 10% Pd/C (100 mg) overnight. The reaction mixture was filtered and the filtrate concentrated in vacuo to afford the desired product diethyl (3-aminobenzyl)phosphonate (0.690 g; yield: 95%), which was used directly in further chemistries without purification. 1H-NMR (CDCl3, 400 MHz): δ=1.24 (t, J=7.2 Hz, 6H), 3.04 (d, J=21.6 Hz, 2 H), 3.66 (s, br, 2 H), 4.01 (q, J=7.2 Hz, 4 H), 6.57 (d, J=8.8 Hz, 1 H), 6.67-6.68 (m, 2 H), 7.08 (t, J=7.6 Hz, 1 H). MS (ES+): m/z 244.00 (MH+). HPLC: tR=2.24 min (ZQ3, polar—5 min).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 4 of Example 60, from 3.15 g (9.77 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 80 mL of 1:1 methanol-water mixture and 0.28 g (11.7 mmol) of lithium hydroxide with a work-up consisting only of thorough evaporation of solvents.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][NH:14][C:13](=O)[C@@H:12]([CH2:17][CH3:18])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[AlH4-].[Li+].[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:11][C@H:12]([CH2:17][CH3:18])[CH2:13][NH:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H]1O[C@@H](COCc2ccccc2)CNC1=O
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]1CNC[C@H](COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.7 %

Procedure:
To a stirred solution of (2R,6R)-6-((benzyloxy)methyl)-2-ethylmorpholin-3-one (362.2 mg, 1.453 mmol) in THF (2 mL) was added 1 M lithium tetrahydroaluminate in THF (2 mL, 2 mmol) dropwise at rt over a 2-min period. The reaction was stirred at rt for 2.5 h after which time it was cooled to 0° C. followed by a dropwise addition of water (0.6 mL) and then 1 M sodium hydroxide in water (0.04 mL). The quenched reaction was warmed to rt, stirred until a granular solid was formed and filtered over a Celite 545 pad rinsing with EtOAc (5 mL), DCM (5 mL) and ethyl ether (5 mL). The filtrate was concentrated and the resultant crude product was purified over silica gel (Biotage, eluting with a gradient of 5-10% MeOH in DCM) followed by combining the desired fractions, concentration and drying in vacuo to provide (2R,6R)-2-((benzyloxy)methyl)-6-ethylmorpholine (50.2 mg, 0.213 mmol, 14.6% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][C:28]#[N:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH2:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CC#N)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN)CC1
Reaction time: 0.33 h
Yield: 125.3 %

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1-cyanomethyl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.94 mmol; 392.9 mg) in methanol (20 mL). Add nickel dichloride (1.03 mmol; 135 mg). Add sodium tetrahydroborate (18.8 mmol; 717 mg) portion-wise. Evaporate and partition between water/DCM and stir 20 min. Add Celite®, stir 30 min and filter. Rinse solids with DCM, 10% MeOH/DCM. Add 2 mL 2M NH3-MeOH to organic layer and evaporate. Dissolve the residue in DCM, wash with brine, dry over MgSO4, filter through Celite® and evaporate to provide the title compound (498 mg; 125%). MS (ES): m/z=423 (M+H).
Reaction SMILES: C(O[CH2:6][C@H:7]([CH3:19])[CH2:8][CH2:9][CH2:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(C)(C)C.[BrH:20]>>[Br:20][CH2:6][C@H:7]([CH3:19])[CH2:8][CH2:9][CH2:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)COC(C)(C)C
Reactant: Br
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CBr

Procedure:
A mixture of 1 g. (3.7 mmoles) of (2R,6R)-(+)-1-tert. butoxy-2,6,10-trimethylundecane and 10 ml. of 48% aqueous HBr was stirred and heated at reflux for 5.75 hours. The resulting mixture was cooled and worked up by ether extraction in the manner of Example 1 giving 0.9 g. of crude product. This material was chromatographed on 30 g. of silica gel. Elution with 49:1 parts by volume hexane-ether gave the (2R,6R)-(-)-1-bromo-2,6,10-trimethylundecane which was evaporatively distilled yielding 0.748 g. (73.4%) of a colorless oil, b.p. 83°-85° C. (bath temperature) (0.15 mm Hg).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.S(Cl)(Cl)=O.[CH3:18][C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[C:21]([Cl:26])[C:20]=1[OH:27].CN(C)C1C=CC=CC=1.C(OC1C(=CC=CC=1)C(Cl)=O)(=O)C>CC(C)=O>[Cl:26][C:21]1[CH:22]=[C:23]([CH:24]=[C:19]([CH3:18])[C:20]=1[OH:27])[NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Cc1cc(N)cc(Cl)c1O
Agent: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: Cc1cc(NC(=O)c2ccccc2O)cc(Cl)c1O
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
Acetylsalicyclic acid (1.39g.) was converted to its acid chloride by conventional method using thionyl chloride and put in solution in acetone (25 ml.). 2-Methyl-4-amino-6-chlorophenol (1.35 g.) and N,N-dimethylaniline (about 1 ml.) were dissolved in acetone to which, with stirring in the cold at 1° to 2° C., the above-prepared acetone solution of acetylsalicyloyl chloride was added dropwise over 20-30 minutes, and reaction was continued for 1-2 hours. Then under reduced pressure the acetone was evaporated off, and the residue was put in solution in 2 N sodium hydroxide by stirring several hours at room temperature. Addition of 2 N hydrochloric acid to make the pH of the solution lower than 1 resulted in the formation of a precipitate which was recrystallized from aqueous acetone to give white crystals (1.08 g.) of 3'-chloro-2,4'-dihydroxy-5'-methylbenzanilide. Yield: 45.4%. Melting point: 192°-194° C.
Reaction SMILES: C([O:4][C@H:5]1[C@H:18]([O:19]C(=O)C)[C@@H:17]([CH2:23][O:24]C(=O)C)[O:16][C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:6]1[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(=O)C.C(OCC)(=O)C.C(O)C.CCCCCC>CO.C[O-].[Na+]>[C:29]1(=[O:38])[N:28]([C@@H:6]2[C@@H:5]([OH:4])[C@H:18]([OH:19])[C@@H:17]([CH2:23][OH:24])[O:16][C@H:7]2[O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CC(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1[C@H]1[C@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
Benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (6) (40.6 g, 84 mM) in 750 ml of dry methanol and 30 ml of 0.5M sodium methoxide was added to a 2 liter round bottomed flask equipped with magnetic stirring bar, septum inlet and bent tube adapter and the contents stirred at room temperature for 18 hours. TLC indicated completion of the reaction. (The TLC solvent was 10:2:10 ethyl acetate: ethyl alcohol:hexane). To the mixture was added 15 g of Bio-Rad (Bio-Rad Laboratories, P.O. Box 708, 220 Maple Ave., Rockville Center, NY 11571) ion exchange resin AG-50W-X-8 (prewashed with H2O, methanol, and dried) and stirred for 5 minutes (pH should be≤7.0). The mixture, after filtration followed by the removal of solvent, furnished benzyl 2-deoxy-2-phthalimido-β-D-glucopyranoside (7), 30 g (89.4% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:31]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[N:32]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:36][C:33]3[NH:32][N:31]=[CH:35][CH:34]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=Cc1cc[nH]n1
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ccn[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (72.0 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with pyrazole-3-carboxaldehyde (24.5 mg) and sodium cyanoborohydride (35.9 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (52.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:52]1([CH:58]2[CH2:62][CH2:61][CH2:60][NH:59]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:59]3[CH2:60][CH2:61][CH2:62][CH:58]3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCCC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The following was added sequentially to DCM (2 mL): 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (50 mg, 0.126 mmol), DIPEA (0.07 mL, 0.378 mmol), EDC (30 mg, 0.151 mmol), HOBT (24 mg, 0.151 mmol), and 2-phenylpyrrolidine (0.023 mL, 0.151 mmol). The mixture was stirred for 18 h at rt, at which time the solution diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with 1M HCl (1×), 10% aq. sodium carbonate (1×) and brine (1×). The organic phase was dried with magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in EtOAc and precipitated out hexanes, and then collected over a filter and washed with diethyl ether to give the title compound as a white solid. (Yield: 20 mg, 0.038 mmol, 30%) 1H NMR (400 MHz, CDCl3) 7.61, 7.43-7.05, 7.09-6.94, 6.58, 5.41, 5.06-4.82, 4.33, 3.83-3.60, 3.11-2.88, 2.50-2.22, 2.06-1.58, 1.16-0.82
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.9 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.20 g), 3-hydroxypyridine (816 mg), and potassium carbonate (2.38 g) in DMF (12 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (430 mg).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(-c2ccnn2C)csc1C(=O)NC(Cc1ccccc1)CN(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccnn2C)csc1C(=O)NC(CN)Cc1ccccc1
Reaction time: 5 h

Procedure:
To a solution of 1,1-dimethylethyl[2-({[3-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (51 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction was stirred over 5 h, concentrated and purified by reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) to afford the bis-TFA salt of the title compound. (16 mg, 41%): LC-MS (ES) m/z 355 (M+H)+. NMR (d4-MeOD, 400 MHz) δ ppm 7.64 (s, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.36-7.30 (m, 4H), 7.28-7.21 (m, 1H), 6.30 (d, J=2.0 Hz, 1H), 4.58 (m, 1H), 3.69 (s, 3H), 3.27-3.13 (m, 2H), 3.07-2.93 (m, 2H), and 2.13 (s, 3H).