Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH2:22]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a suspension of morphine (10.0 g, 35.1 mmol) in THF (200 ml), was added benzyl bromide (5.5 ml, 98%, 45.3 mmol) and sodium hydroxide (1.48 g, 37.0 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction temperature rose gradually to rt during the process. THF in the reaction mixture was removed on a rotary evaporator. The residue was dissolved in CH2Cl2 (150 ml) and water (50 ml). The organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo to obtain a crude product (13 g), which was dissolved in CH2Cl2 and loaded onto a silica gel column (3×30 cm). The column was first eluted with 3% methanol in CH2Cl2, followed by 5% methanol in CH2Cl2. Pure fractions were combined to obtain 3-benzylmorphine (7.9 g, 60% yield). IR (KBr)(v, cm-1): 3540 (m, sharp, --OH), 3020 (m, sharp), 2900 (s, sharp), 1600 (m, sharp); NMR (δH)(CDCl3): 7.50-7.20 (5, m, --C6H5), 6.70 (1, d, J, 8.1, 2-H), 6.51 (1, dd, J, 8.1 & 0.9, 1-H), 5.65 (1, dm, J, 9.9, 7-H), 5.26 (1, dt, J, 9.9 & 2.5, 8-H), 5.12 (2, AB, OCH2Ph), 4.85 (1, dd, J, 6.6 & 1.2, 5-H), 4.22-4.05 (1, m, 6-H), 3.32 (1, dd, J, 6.2 & 3.3, 9-H), 3.02 (1, d, J, 18.6, 10-Hβ), 2.75-2.65 (1, m, 14-H), 2.75-2.65 (1, b, --OH), 2.58 (1, dm, J, 12.0, 16-He), 2.5-2.3 (1, m, 16-Ha), 2.42 (3, s, N--CH3), 2.27 (1, dd, J, 18.6 & 6.6, 10-Hα), 2.05 (1, td, J, 12.1 & 5.3, 15-Ha), 1.85 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([CH:22]=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.O[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]1([CH3:24])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([CH2:22][O:23][C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: Oc1cccnc1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(C=O)cc43)sc2C(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(COc5cccnc5)cc43)sc2C(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A mixture of Example 50 (0.050 g, 0.14 mmol), 3-hydroxypyridine (0.015 g, 0.14 mmol), and triphenylphosphine (0.042 g, 0.16 mmol) in THF (15 mL) was cooled to 0° C. Diethyl azodicarboxylate (0.03 mL, 0.16 mmol) was added, and the reaction mixture stirred for 30 minutes at 0° C., then at r.t. for 3 h. Further portions of 3-hydroxypyridine (0.015 g, 0.14 mmol) and triphenylphosphine (0.021 g, 0.08 mmol) were added, and stirring continued for 2 h. The mixture was concentrated in vacuo and the residue partitioned between DCM (50 mL) and water (50 mL). The organic fraction was washed with water (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 6) to give the title compound (0.0045 g, 8%) as a white solid. δH (CDCl3) 8.32 (2H, br. s), 8.06 (1H, d, J 1.7 Hz), 7.38-7.31 (2H, m), 7.13 (1H, dd, J 8.5 and J 1.9 Hz), 6.99 (1H, d, J 8.5 Hz), 5.07 (2H, s), 5.21 (1H, br. s), 4.38-4.32 (2H, m), 4.18-4.11 (2H, m), 2.88 (2H, s), 1.40 (6H, s). LCMS (ES+) 423.0 (M+H)+, RT 2.27 minutes (Method 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH2:9][NH:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:31]1([S:37]([N:10]([CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[OH:21])[CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(CNCC(O)c1cccc(Br)c1)Nc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN(CC(O)c1cccc(Br)c1)S(=O)(=O)c1ccccc1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a cooled suspension of 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-phenyl-acetamide (840 mg) and N,N-diisopropylethylamine (760 mL) in methylene chloride (20 mL) was added benzenesulfonyl chloride (0.31 mL). The mixture was stirred at 0° C. for 1 hour and at room temperature overnight. A 1M aqueous solution of KHSO4 was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, n-heptanelethyl acetate 1:1) to yield 2-{benzenesulfonyl-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-amino}-N-phenyl-acetamide (1.17 g, 99%) as a white foam, MS: 489.0 (M+H, 1Br)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:17][NH2:18])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2-c2ccc(F)cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN=C1c2ccccc2-c2ccc(F)cc21
Yield: 60 %

Procedure:
A mixture of commercially available (Aldrich Chemical, Inc.) 2-fluoro-9-fluorenone (11) (10 g, 50.5 mmoL) and hydrazine monohydrate (10 mL , 200 mmoL, 4 eq) in ethanol (250 mL ) was refluxed for 1.5 h. The solution was then reduced in volume (to about a 100 mL) and chilled. The solid that separated was collected by filtration, washing with cold ethanol to provide 6.5 g (60%) of product (12): mp 161°-165° C.; IR (KBr) 3390, 3310, 3200, 1450 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.85 (bd, 1H, J=7.3Hz), 7.69 (bd, 1H, J=7.1Hz), 7.57 (dd, 1H, J=4.8, 8.1Hz), 7.36 (m, 3H), 7.02 (ddd, 1H, J=2.5, 8.3, 9.2Hz), 6.48 (bs, 2H); MS m/z 212 (M+), 183 (base peak).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:26][C:27]2[NH:31][CH:30]=[CH:29][N:28]=2)[CH2:39][C:35]2[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=2)=[CH:22][CH:23]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
The compound (608.7 mg) obtained in Example 103-5 was dissolved in anhydrous methanol (24 ml) and added with 1-methyl-2-imidazole carboxaldehyde (231.3 mg) and sodium cyanoborohydride (176.0 mg). The solution was adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 3 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform. The extract was dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (502.6 mg) as a colorless oily substance.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH2:2][CH3:3].[H-].[Na+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15]Cl)[CH:14]=1.O>CN(C=O)C>[Br:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:12]=[N:11][CH:10]=1
Reactant: ClCc1cncc(Br)c1
Reactant: CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)NCc1cncc(Br)c1
Yield: 82 %

Procedure:
To a solution of propionamide (146 mg, 2.0 mmol) in DMF (10 mL) was added NaH (61 mg, 2.4 mmol) at 0° C. and reaction mixture was stirred for 10 min before the addition of 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A], 412 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour before water was added. Then, the reaction mixture was extracted with EtOAc and combined organic layers were dried by anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography to give title compound (400 mg, 82%) as a solid.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[S:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[S:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: C=Cc1cc2c(nn1)SCCO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2c(nn1)SCCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.2 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]oxathiino[3,2-c]pyridazine (200 mg, 1.11 mmol) in 1,4-dioxane/water (10 ml/2 ml) was treated with an aqueous solution of osmium tetroxide (4% w/v, 1 ml) and sodium periodate (0.55 g), initially stirred in an ice-bath for 1.5 hours, then allowed to warm to room temperature. After 1.5 hours the mixture was treated with sodium bicarbonate solution, evaporated to dryness and dissolved in 1,4-dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (20 g), and chromatographed, eluting with 0-100% ethyl acetate in hexane, to afford a pale yellow solid (63 mg, 31%).
Reaction SMILES: [CH2:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:25]([O:24][C:22]([C:19]1[S:18][C:17]([N:7]2[CH2:6][C:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:4]=3[CH2:8]2)=[N:21][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC2=C(CNC2)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)s1
Yield: 64.3 %

Procedure:
tert-Butyl 3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.2 g, 5.7 mmol), ethyl 2-bromothiazole-5-carboxylate (1.69 g, 7.17 mmol) and triethylamine (1.09 ml, 7.84 mmol) were stirred at 100° C. in 70 ml of DMF for 7 h. The residue was filtered off, the filtrate was concentrated and the remaining residue was extracted with ethyl acetate. 1.34 g of crude product were obtained, which were reacted without further purification (M+H+: 366.14).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13]Cl)[CH:11]=[CH:12][C:4]=2[O:3]1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CS(C)=O>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: c1c[nH]cn1
Reactant: CC1Oc2ccc(CCl)cc2NC1=O
Solvent: CS(C)=O
Product: CC1Oc2ccc(Cn3ccnc3)cc2NC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
1.25 g (5.9 mmol) of (±)-2-methyl-3-oxo-6-chloromethyl-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 12.5 ml of dimethyl sulfoxide, mixed with 0.804 g (11.8 mmol) of imidazole and stirred for 8 hours at 70° C. After stirring overnight at room temperature, the reaction mixture is spun on an oil pump until dry, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol). 940 mg (65.7%) of the desired imidazole compound is obtained, melting point 219-222° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[N+:13]([CH3:16])([O-:15])=[O:14]>>[N+:13]([CH:16]=[CH:11][C:10]1[C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc2c1OCCO2
Product: O=[N+]([O-])C=Cc1cccc2c1OCCO2

Procedure:
In close analogy to the procedure described above, 2,3-Dihydro-benzo[1,4]dioxine-5-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[N:11][C:10]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)#[N:2].N[NH:24][C:25]([NH2:27])=[S:26].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[NH2:27][C:25]1[S:26][C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]=[N:11][C:10]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)=[N:2][N:24]=1
Reactant: N#CCCCCc1ccc(NC(=O)Cc2ccccc2)nn1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCCCc2ccc(NC(=O)Cc3ccccc3)nn2)s1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-phenylacetamide (14.7 g, 50.2 mmol) was charged into a 250 mL round bottom flask fitted with an open top reflux condenser. To the flask was added thiosemicarbazide (5.03 g, 55.2 mmol) and trifluoroacetic acid (88 mL). The reaction slurry was heated in a 65° C. bath for 2 h. After cooling to RT, H2O (150 mL) was added and stirred for 30 minutes. The mixture was then slowly transferred to a stirred 7.5% sodium bicarbonate solution (1400 mL) cooled in a 0° C. bath. The precipitate was collected by suction filtration, rinsed with water (2×200 mL), diethyl ether (2×200 mL) and dried under high vacuum overnight. The off-white solid was slurried in DMSO (200 mL) and heated in an 80° C. bath until the internal temperature reached 65° C. DMSO (105 mL) was used to rinse sides of flask. H2O (120 mL) was slowly added until the solution became slightly cloudy and then the mixture was removed from heat bath and allowed to cool to ambient temperature while stirring. The pale green precipitate was collected by suction filtration, rinsed with water (200 mL) and diethyl ether (2×200 mL). The solid was dried overnight under high vacuum to provide N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-phenylacetamide (1024, 15.01 g). 1H NMR (300 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.23 (d, J=8.916 Hz, 1H), 7.59 (d, J=8.826 Hz, 1H), 7.36 (m, 5H), 7.07 (s, 2H), 3.78 (s, 2H), 2.87 (t, J=6.799 Hz, 4H), 1.69 (bm, 4H)
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[B:30](OC)([O:33]C)[O:31]C.Cl>C1COCC1>[F:16][C:17]1[C:18]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[C:19]([F:23])[CH:20]=[CH:21][C:22]=1[B:30]([OH:33])[OH:31]
Reactant: Fc1cccc(F)c1-c1ccncc1
Reactant: COB(OC)OC
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (3.10 ml, 18.4 mmol) in THF (80 ml) was cooled to −20° C., then treated with a 2.5 M solution of butyllithium in hexanes (7.03 ml, 17.6 mmol). After stirring at −20° C. for 10 min, the mixture was cooled to −78° C. and treated with a solution of 4-(2,6-difluorophenyl)pyridine (3.20 g, 16.7 mmol) in THF (20 ml). The mixture was stirred at −78° C. for 1.5 h before adding trimethyl borate (3.78 ml, 33.5 mmol). The mixture was allowed to warm to room temperature before adding 5 N aqueous HCl (20 ml). After stirring for 12 h, the solvent was removed in vacuo and the residue was partitioned between 1 N aqueous HCl (100 ml) and diethyl ether (100 ml). The organic layer was then extracted with 1 N aqueous NaOH and the aqueous layer was acidified to pH 8 with 5 N aqueous HCl. The resulting solid was collected by filtration, washed with water and dried to afford 3.20 g (81%) of 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid as a white solid: MS (ES+) m/z 235 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:13])[CH3:12]
Reactant: Cc1ccc(C#N)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1C#N
Yield: 97.2 %

Procedure:
To a solution of 2-Hydroxy-4-methylbenzonitrile (0.563 g, 4.23 mmol) in CH2Cl2 (21 mL) was added acetic anhydride (0.60 mL, 6.36 mmol) followed by triethylamine (1.20 mL, 8.61 mmol) and the resultant solution was stirred at room temperature for 30 minutes. The mixture was diluted with CH2Cl2 (60 mL), washed with saturated aqueous NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried (Na2SO4) and concentrated and provided 0.72 g (97%) of (2-cyano-5-methyl-phenyl) acetate as a white solid. 1H NMR (CDCl3) δ 2.38 (s, 3H), 2.43 (s, 3H), 7.08 (s, 1H), 7.13 (d, 1H, J=9 Hz), 7.54 (d, 1H, J=9 Hz).
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].Cl.[CH3:14]O>>[CH3:14][O:1][C@H:2]1[O:10][CH:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Agent: Cl
Product: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
In a manner similar to that described in Example 3, 300 parts by weight of D-glucose obtained from used paper was added to 1,100 parts by weight of a methanol solution containing hydrochloric acid at a concentration of 0.25 wt % and was then refluxed for 72 hours, whereby 160 parts by weight of methyl-D-glucopyranoside was obtained. The measurement results are shown below.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2c(Cl)ccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(Cl)ccnc12
Yield: 75 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-chloro-quinolin-8-ylamine (Intermediate 464) (1.5 g, 8.43 mmol), 2-nitrobenzene-1-sulfonyl chloride (2.43 g, 11.0 mmol), DMAP (cat), pyridine (2 ml, 25.28 mmol) in DCM (70 ml) for 3 h at room temperature gave the title compound (2.3 g, 74%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 89.2 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.39 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]1[O:16][C:15](=[O:17])[CH:14]([C:18](O)=O)[CH:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C=O.C(NCC)C>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]1[O:16][C:15](=[O:17])[C:14](=[CH2:18])[CH:13]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1C(=O)OC(CCCOCc2ccccc2)C1c1ccccc1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCNCC
Product: C=C1C(=O)OC(CCCOCc2ccccc2)C1c1ccccc1
Temperature: 100 °C
Yield: 76.9 %

Procedure:
5-(3-Benzyloxypropyl)-2-oxo-4-phenyltetrahydro-3-furancarboxylic acid (1 g) was dissolved in a solution (5 ml) prepared from sodium acetate (105 mg), acetic acid (4 ml), formalin (2.92 ml) and diethylamine (1 ml), and the solution was heated on a water bath (100° C.) for 30 minutes. After cooling, the reaction mixture was poured into ice water and extracted with ether. The extract was washed with 5% sodium bicarbonate and water and dried over magnesium sulfate. The solvent was then distilled off to give 5-(3-benzyloxypropyl)-3-methylene-4-phenyltetrahydro-2-furanone (0.7 g) as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10][C:11]([OH:13])=O.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:11](=[O:13])[CH2:10][C:4]2[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cc1c(F)cccc1F
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c(F)cccc1F
Yield: 37.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,6-difluorophenyl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 95, (2S,4R)-4-benzyl-1-(2-(2,6-difluorophenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (12.3 mg, 37.6%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.92 (s, 1H), 7.53 (m, 3H), 7.28 (m, 3H), 7.24-7.14 (m, 6H), 6.97-6.91 (m, 4H), 4.46 (m, 1H), 3.82 (m, 1H), 3.70 (m, 2H), 3.37 (m, 1H), 2.70 (m, 3H), 1.19 (m, 2H). MS (EI) for C32H27F3N2O3. found 545.6 (MH+).