Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3OC)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
4-(2-Iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxyquinoline (compound 116) (84 mg), 2-methoxyphenylboronic acid (152 mg), and tetrakistriphenylphosphine palladium (12 mg) were disssolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (23 mg, yield 29%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:14][CH2:15][CH:16]1[CH:20]([CH2:21]I)[O:19][C:18](=[O:23])[NH:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH2:7]([O:14][CH2:15][CH:16]1[CH:20]([CH2:21][N:4]2[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]2)[O:19][C:18](=[O:23])[NH:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(COCc2ccccc2)C(CI)O1
Reactant: Brc1cn[nH]c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(COCc2ccccc2)C(Cn2cc(Br)cn2)O1
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (2.33 g, 15.9 mmol), 4-[(benzyloxy)methyl]-5-(iodomethyl)-1,3-oxazolidin-2-one (5.00 g, 14.4 mmol), and potassium phosphate tribasic (9.17 g, 43.3 mmol) in DMF (50 mL) was stirred and heated to 90° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by reverse phase HPLC to afford 4-[(benzyloxy)methyl]-5-[(4-bromo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one. MS ESI calc'd. for C15H12BrN3O3 [M+H]+ 366 and 368. found 366 and 368. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.38-7.29 (m, 5H), 4.63-4.60 (m, 1H), 4.54 (s, 2H), 4.39 (d, J=5.6 Hz, 2H), 3.80-3.76 (m, 1H), 3.41 (d, J=4.8 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[O:12][CH3:13])[CH3:2].[F-].[K+].B1(C=C)OB([CH:25]=[CH2:26])OB(C=C)O1.C1C=CN=CC=1>O1CCOCC1.[Cl-].[Na+].O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH:25]=[CH2:26])=[CH:7][C:6]=1[O:12][CH3:13])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(Cl)cc1OC
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)N(CC)CC)c(OC)c1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirring degassed solution of N,N-diethyl-4-chloro-2-methoxybenzamide (65 mg, 0.35 mmol), potassium fluoride (134 mg, 2.3 mmol), and 2,4,6-trivinylcyclotriboroxane pyridine complex (132 mg, 0.35 mmol) in 1,4-dioxane (3 mL) was added bis(tri-t-butylphosphine)palladium (5 mg, 0.01 mmol). The reaction was heated to reflux for 5 h and then cooled to room temperature. The reaction was diluted with brine and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pale yellow oil. The oil was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to give 40 mg of the desired product as a colorless oil. MS (ESI) 234 (M+H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[C:6]([OH:10])(=O)[CH:7]=[CH2:8].[C:11](O)(=O)[CH:12]=[CH2:13].[C:16](O)(=O)[CH:17]=[CH2:18].[C:21](O)(=O)C=C.C(O)(=O)C=C.OCC(CO)(CO)CO.C(O)(=O)C=C.NC(OCC)=O.C1(=O)OCCCCC1.OCC(CO)(COCC(CO)(CO)CO)CO>C(O)(C)C>[CH2:11]1[CH2:8][CH2:7][C:6]([OH:10])([C:1]([C:2]2[CH:3]=[CH:21][CH:16]=[CH:17][CH:18]=2)=[O:5])[CH2:13][CH2:12]1
Reactant: C=CC(=O)O
Agent: CCOC(N)=O
Agent: O=C1CCCCCO1
Agent: OCC(CO)(CO)CO
Solvent: CC(C)O
Product: O=C(c1ccccc1)C1(O)CCCCC1

Procedure:
A protective layer coating solution was prepared by mixing 3 parts by mass of pentaerythritol hexaacrylate (KAYARAD DPHA, produced by Nippon Kayaku Co., Ltd.), 3 parts by mass of an urethane acrylate oligomer (ART RESIN UN-3320HA, produced by Negami Chemical Industrial Co., Ltd.), 3 parts by mass of an acrylic acid ester of dipentaerythritol caprolactone (KAYARAD DPCA-120, produced by Nippon Kayaku Co., Ltd.), 1 part by mass of a silica (P-526, produced by Mizusawa Industrial Chemicals, Ltd.), 0.5 parts by mass of a photopolymerization initiator (IRGACURE 184, produced by Nihon Ciba-Geigy K.K.), and 11 parts by mass of isopropyl alcohol, and sufficiently agitating and dispersing the mixture with the use of a ball mill, such that the average particle diameter became approximately 3 μm.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:25][C:23]([F:24])([F:26])[C:19]1[CH:18]=[C:17]([C@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3cccc(C(F)(F)F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
(2R,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.155 g, 0.42 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 3.30 mL, 18.83 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (43 mg, 33%). 1H NMR (600 MHz, dmso) δ 1.35 (q, 1H), 1.47 (dq, 1H), 1.87 (d, 1H), 2.00 (d, 1H), 2.69-2.77 (m, 1H), 2.83-2.91 (m, 1H), 3.08-3.14 (m, 1H), 3.75 (d, 1H), 5.74 (s, 1H), 7.50-7.55 (m, 1H), 7.55-7.59 (m, 1H), 7.64-7.68 (m, 1H), 7.71 (s, 1H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1144
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[CH3:45][N:46]1[CH:50]=[CH:49][N:48]=[C:47]1[Sn](CCCC)(CCCC)CCCC>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.C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([C:47]2[N:46]([CH3:45])[CH:50]=[CH:49][N:48]=2)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccccc3)c(Cl)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(-c3nccn3C)c(Cc3ccccc3)c(Cl)c2c1
Temperature: 110 °C

Procedure:
A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1.01 g, 1.86 mmol, Example 109), 1-methyl-2-(tributylstannyl)-1H-imidazole (1.42 g, 3.68 mmol), Pd(PPh3)4 (206 mg, 0.180 mmol), and toluene (10 mL) was sparged with N2 for about 10 minutes, then heated at 83° C. for 16 hours and 110° C. for 3 hours. After cooling down to room temperature, the mixture was concentrated in vacuo and DCM was added. The precipitated solid was filtered and dissolved in DMSO and MeOH. A few drops of TFA were added to improve solubility. The mixture was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 9.06 (s, 1H), 8.94 (s, 1H), 8.86 (d, J=2.02 Hz, 1H), 8.54 (d, J=2.02 Hz, 1H), 8.22 (d, J=9.09 Hz, 1H), 8.16 (dd, J=2.02, 8.08 Hz, 1H), 7.90-7.94 (m, 2H), 7.64 (d, J=1.52 Hz, 1H), 7.19-7.26 (m, 3H), 7.18 (d, J=1.52 Hz, 1H), 6.86-6.90 (m, 2H), 4.54 (s, 2H), 3.74 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH3:6].[NH:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:8]([C:13](N(C)OC)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11].Cl>C1(C)C=CC=CC=1.C1COCC1.C(OC(=O)C)C>[NH:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:8]([C:13]([CH2:3][CH2:4][CH2:5][CH3:6])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CCCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Magnesium (0.330 g, 13.6 mmol) was activated by suspending in toluene for 30 min under N2. The toluene was removed and the Mg was dried under N2. To the suspension of Mg in THF (20 mL) was added bromobutane (1.46 mL, 13.6 mmol) dropwise and the mixture was heated at reflux. When all the magnesium was dissolved, Boc-Leu-N(OCH3)CH3 in THF was added dropwise and the reaction was stirred for 2 h at 0° C. 1M HCl (150 mL) was added followed by ethylacetate (100 mL). The organic layer was washed with 1M potassium hydrogen sulfate, water, dried (Na2SO4) and concentrated in vacuum. The expected product was purified by silica gel column chromatography. The product was characterized by 1H-NMR and 13C-NMR. ESI-MS: calcd. 271. found 293.3 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:15][CH2:16][CH:17]=O)[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH2:1]([O:8][CH2:9][C@H:10]([O:15][CH2:16][CH:17]=[N:25][OH:26])[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=CC[C@H](COCc1ccccc1)OCC=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC=CC[C@H](COCc1ccccc1)OCC=NO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of {[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}acetaldehyde (C11) (207 g, ≦0.63 mol) and sodium acetate (342 g, 4.17 mol) in aqueous ethanol (2:1 ethanol/water, 2.1 L) was added hydroxylamine hydrochloride (207 g, 2.98 mol). The reaction mixture was stirred at 60° C. for 18 hours, then concentrated in vacuo and extracted with ethyl acetate (2.0 L). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography on silica gel (Eluent: ethyl acetate in petroleum ether) to afford the product as a brown oil. By 1H NMR, this was assigned as a mixture of geometric isomers at both the oxime and olefin functional groups. Yield: 117 g, 0.444 mol, 70% over three steps. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ [7.42-7.48 (m) and 6.88-6.92 (m), total 1H], 7.20-7.36 (m, 5H), 5.29-5.61 (m, 2H), [4.48-4.54 (m) and 4.41-4.45 (m), total 3H], 2.13-2.32 (m, 2H), 1.54-1.65 (m, 3H).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH2:22]O)[CH:18]=[CH:19][C:20]=3[CH3:21])=[CH:12][CH:13]=2)[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])[CH3:41].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:27][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=3[CH3:21])[CH2:22][N:46]3[CH2:47][CH2:48][N:43]([C:40](=[O:42])[CH3:41])[CH2:44][CH2:45]3)=[CH:12][CH:13]=2)[N:8]([CH3:24])[S:7]1(=[O:25])=[O:26]
Reactant: Cc1ccc(CO)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Reactant: CC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(Cc2ccc(C)c(-c3ccc4c(n3)N(C)S(=O)(=O)N4CC3CC3(F)F)c2)CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylphenyl)methanol (39-1) (7.3 g, 18.4 mmol, 1.0 eq) was dissolved in NMP (90 mL) and triethylamine (7.7 mL, 55.2 mmol, 3.0 eq) was added followed by mesyl chloride (1.6 mL, 20.3 mmol, 1.1 eq). After 20 minutes, 1-acetylpiperazine (3.3 g, 25.7 mmol, 2.0 eq) and DIPEA (9.0 mL, 51.3 mmol, 3.0 eq) were added. The resulting mixture stirred at 80° C. for 2 hours minutes. The mixture was cooled, diluted with EtOAc (300 mL), washed with sodium bicarbonate (50 mL), water (6×50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (330 g SiO2, 0-20% IPA in DCM) to afford 1-[4-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazin-1-yl]ethanone (39-2) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 7.36 (d, J=8.0 Hz, 1 H); 7.35 (s, 1 H); 7.25 (s, 2 H); 7.08 (d, J=8.0 Hz, 1 H); 3.97 (d, J=6.8 Hz, 2 H); 3.56 (s, 2 H); 3.54 (dt, J=5.2, 20.4 Hz, 4 H); 3.38 (s, 3 H); 2.46 (dt, J=5.2, 18.8 Hz, 4 H); 2.35 (s, 3 H); 2.21 (m, 1 H); 2.07 (s, 3 H); 1.67 (m, 1 H); 1.43 (m, 1 H). HRMS m/z (M+H) 506.2029 found, 506.2032 required.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C(=O)([O-])[O-:16].[Na+].[Na+].OO>CO>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH2:8])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: COC(Cc1ncccc1C#N)OC
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COC(Cc1ncccc1C(N)=O)OC
Reaction time: 4.5 h
Yield: 85 %

Procedure:
The product from Example 228b (1.46 g, 7.6 mmol) was dissolved in methanol (20 mL) to which was added at room temperature sodium carbonate as a 3N solution (35 mL) followed by hydrogen peroxide as a 15% solution (35 mL). The reaction was allowed to stir for 4.5 hours then partitioned by the addition of ethyl acetate and solid sodium chloride. The aqueous phase was extracted several times with ethyl acetate and the combined organics stirred with solid sodium bisulfite followed by drying over MgSO4, filtered and concentration under vacuum to give the title compound (1.36 g, 85%) sufficiently pure for use as isolated.
Reaction SMILES: [O:1]=[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].[O:13]=[CH:14][C@@H:15]([C@H:17]([C@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])O.[OH:25][CH2:26][C:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])=[O:28]>>[OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([O:8][C@@H:23]2[O:24][C@H:15]([CH2:14][OH:13])[C@H:17]([OH:18])[C@H:19]([OH:20])[C@H:21]2[OH:22])[C@H:5]([OH:6])[C@H:3]1[OH:4].[OH:25][CH2:26][C:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])=[O:28]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
The reaction mixture was subjected to purification by the column chromatography using active charcoal. Thus, the column was loaded with the oligosaccharide and elution of the adsorbed oligosaccharide was conducted by successively increasing the concentration of ethyl alcohol eluant. The eluate fraction obtained with 15% ethyl alcohol as the eluant was concentrated by evaporation and subjected to desalting and decoloration using active charcoal and an ion exchange resin followed by freeze-drying to give 2.7 g of the transglycosidation product B having a purity of 98%. A portion of this transglycosidation product B was taken and subjected to the fractionating high-performance liquid chromatography to give a chromatogram having a single peak as is shown in FIG. 3. Hydrolysis of the transglycosidation product B indicated that it was composed of glucose, galactose and fructose. The enzymolytic hydrolysis of the same with the β-fructofuranosidase gave lactose and fructose in equal molar amounts. FIG. 4 shows a 13C-NMR spectrum of the transglycosidation product B.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[F:38][CH:36]([F:37])[O:35][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:39])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(morpholine-4-sulfonyl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.16 g), tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.32 mL) was stirred at room temperature for 2 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of mixture was adjusted to 4 by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue triturated with a mixture of acetonitrile and water to afford title compound, 0.083 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc(N)cc2)c1-c1ccccc1

Procedure:
5-Methyl-1-(4-nitrophenyl)-2-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester of Example 36 (4 mmol, 1.5 g) was dissolved in ethanol, and treated with 5% Pd/C (0.15 g). The mixture was hydrogenated with H2 (g) at 45 psi. Upon completion of the reaction, the mixture was filtered through Celite, and the solvents removed under vacuum. Analysis of the resulting solid showed it was the named product (m.p. 181° C.-183° C.).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][C:19]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)[N:25]=5)=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)=[O:13])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][C:19]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][NH:31][CH3:32])[N:25]=5)=[CH:20][CH:21]=4)[CH:16]=[CH:15]3)=[O:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCn1nc(NC(=O)n2ccc3cc(Oc4ccnc(CN(C)C(=O)OC(C)(C)C)n4)ccc32)cc1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nc(NC(=O)n2ccc3cc(Oc4ccnc(CNC)n4)ccc32)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate (33 mg, 0.062 mmol) in DCM (2 mL) at 0° C. is added TFA (0.7 mL, 9.1 mmol). The reaction is stirred for 30 minutes at 0° C. and is then placed at room temperature for an additional 20 minutes. The reaction mixture is then concentrated in vacuo to near dryness and then diluted with DCM and water. The mixture is neutralized by the addition of saturated aqueous NaHCO3 and the resulting layers are separated. The aqueous layer is extracted two additional times with DCM. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-20% MeOH)/DCM) to give the title compound. MS (ESI) m/z 432.2 (M+1). (DMSO-d6) δ ppm 0.62-0.71 (m, 2H) 0.93-1.02 (m, 2H) 1.37 (t, J=7.20 Hz, 3H) 1.86-1.99 (m, 1H) 2.30 (s, 3H) 3.71 (s, 2H) 4.15 (q, J=7.24 Hz, 2H) 6.16 (s, 1H) 6.71 (d, J=4.29 Hz, 1H) 6.87 (d, J=5.56 Hz, 1H) 7.12 (dd, J=9.09, 2.27 Hz, 1H) 7.46 (d, J=2.27 Hz, 1H) 8.17 (d, J=3.79 Hz, 1H) 8.31 (d, J=9.09 Hz, 1H) 8.61 (d, J=5.56 Hz, 1H) 10.64 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: Nc1cc(Cl)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
In a 2 L 3-neck round bottom flask, the stirred solution of (2-amino-4-chlorophenyl)methanol 2 (32 g, 203.82 mmol) in DCM (765 mL), manganese (IV) oxide (150 g, 1.724 mol) was added at rt. The resulting reaction mixture was stirred at rt under argon atmosphere for 40 h. On completion of reaction the reaction mixture was filtered through CELITE™ pad and solid residue was washed thoroughly with DCM (1000 mL). The combined filtrate was concentrated under reduced pressure to give 2-amino-4-chlorobenzaldehyde as orange solid. Yield: 24 g (76.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@H:21]([N:23]=[N+]=[N-])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N=[N+]=[N-])[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](N)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A mixture of 80C (410 mg, 1.10 mmol) and 10% Pd/C (100 mg) in MeOH:EtOAc (2:1, 15 mL) was stirred under hydrogen atmosphere for 2 h. The reaction was filtered through a pad of celite. The filtrate was concentrated and purified by flash chromatography (10 g ISCO silica gel cartridge, 0-20% MeOH/DCM) to the title compound 80D (284 mg): MS (ES) m/z 345 [M+H]+.