Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]5[O:28][CH2:29][O:30][C:23]=45)=[N:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:31][CH3:32])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:33]=O.[OH-].[Na+]>C(O)=O>[OH:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]5[O:28][CH2:29][O:30][C:23]=45)=[N:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:31][CH3:32])[CH2:7][CH2:6][N:5]([CH3:33])[CH2:4][CH2:3]1
Reactant: C=O
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCN(C)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-[2-(4-hydroxypiperidin-4-yl)ethoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline (0.065 g), formaldehyde (40% aqueous solution; 0.2 ml) and formic acid (2 ml) was stirred and heated to 100° C. for 1.5 hours. The mixture was basified to pH9.5 by the addition of 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using an 80:17:3 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.021 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.8 (m, 4H), 2.05 (m, 2H), 2.8 (s, 3), 3.15 (m, 2H), 3.3 (m, 2H), 4 (s, 3H), 4.35 (m, 2H), 6.05 (s, 2H), 6.95 (m, 3H), 7.4 (s, 1H), 8.1 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 453.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:2]1([CH2:1][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([O:20][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(=O)OCC)c(O)c2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(=O)OCC)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Yield: 109.4 %

Procedure:
Benzylbromide (2.95 ml, 24.7 mmol) was added to a stirred solution of diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate (3 g, 9.87 mmol) and potassium carbonate (3.40 g, 24.7 mmol) in acetone (100 ml). The reaction mixture was refluxed for 18 hours under an atmosphere of argon. The resulting mixture was evaporated and the reaction mixture triturated with water. The resulting tan coloured solid was collected by filtration and washed with water then dried under vacuum to give the title compound (5.23 g, 10.8 mmol). LC/MS: Rt=4.13, [MH]+ 485.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[O:47][C:48]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:49]=2[CH:50]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]1[C:48]2[O:47][C:46]([CH2:45][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([CH2:13][O:12][C:11]5[CH:14]=[C:15]6[C:19](=[CH:20][C:10]4=5)[CH2:18][CH2:17][O:16]6)[C:2]3=[O:21])=[CH:50][C:49]=2[CH:51]=[CH:52][CH:53]=1
Reactant: Fc1cccc2cc(CBr)oc12
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cc3cccc(F)c3o2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-7-fluorobenzofuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 192-193° C.; 1H NMR (300 MHz, CDCl3) δ7.31-7.24 (m, 2H), 7.22-6.96 (m, 5H), 6.77-6.74 (m, 1H), 6.56 (s, 1H), 6.43 (s, 1H), 5.31-5.23 (m, 1H), 5.03-4.95 (m, 2H), 4.75-4.68 (m, 1H), 4.59-4.49 (m, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 161.8, 161.2, 152.8, 147.8 (d, JC-F=249.7 Hz), 141.9 (d, JC-F=11.3 Hz), 141.4, 132.7, 131.6 (d, JC-F=3.2 Hz), 128.8, 123.9, 123.7, 123.6, 120.1 (d, JC-F=5.2 Hz), 119.0, 116.6 (d, JC-F=3.9 Hz), 110.8 (d, JC-F=16.1 Hz), 109.0, 105.6 (d, JC-F=2.1 Hz), 93.2, 80.4, 72.4, 57.7, 37.5, 29.0; MS (ES+) m/z 428.3 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2
Reactant: O=C(N[C@@H]1CCCC[C@@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-cis-N1-[(5-chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-carbonyl]-1,2-cyclohexanediamine hydrochloride (100 mg) was dissolved in pyridine (3 ml), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and dichloromethane and 1N hydrochloric acid were added to the residue to separate an organic layer. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol 100:1) to obtain the title compound (79 mg) as a pale yellow foamy substance.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:33])[C:13]#[C:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2/[C:17](=[CH:25]/[C:26]2[NH:27][CH:28]=[CH:29][C:30]=2[O:31][CH3:32])/[C:18](=[O:24])[NH:19]3)=[CH:8][C:7]=1[O:34][CH3:35].O[Li].O>C1COCC1.O>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][NH:27][C:26]=1/[CH:25]=[C:17]1\[C:18](=[O:24])[NH:19][C:20]2[C:16]\1=[C:15]([C:14]#[C:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]([O:34][CH3:35])[CH:8]=1)[OH:33])[CH:23]=[CH:22][CH:21]=2
Reactant: COC(=O)COc1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)ccc1OCC(=O)O

Procedure:
rac-(Z)-[4-[3-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]-2-methoxyphenoxy]acetic acid methyl ester(28 mg, 0.057 mmol) (from Example 47) was hydrolyzed with LiOH.H2O (55 mg, 1.15 mmol) in THF (0.5 mL) and H2O (0.5 mL) at room temperature for 20 h according to Method F above to yield rac-(Z)-[4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]-2-methoxyphenoxy]acetic acid. (Yield 22 mg, 81%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=O.Cl.[CH3:23][NH:24][CH3:25].Cl>C(O)(C)C.C(O)C>[C:1]1([C:7]2[O:8][C:9]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:23][N:24]([CH3:20])[CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: CNC
Reactant: CC(=O)c1c(-c2ccccc2)oc2c(Cl)cccc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CN(C)CCC(=O)c1c(-c2ccccc2)oc2c(Cl)cccc12

Procedure:
To a suspension of 23 grams of the 2-phenyl-3-acetyl-7-chlorobenzofuran that was thus produced in 60 milliliters of isopropanol were added 3.9 grams of paraformaldehyde, 10.4 grams of dimethylamine hydrochloride, and 8 milliliters of a saturated solution of hydrogen chloride in ethanol and the mixture was heated under reflux for a period of 8 hours. The solvent was then evaporated under vacuum and the residue was taken up in water and the remaining water-insoluble material was extracted from the resulting solution with ethyl ether. A 5% aqueous solution of sodium hydroxide was then added to the aqueous solution until it was alkaline and the oily base had precipitated. Ethyl ether was then added to the aqueous solution to extract the oily base and the aqueous phase was separated therefrom. The ether extract was then dried over anhydrous sodium sulfate and a solution of hydrogen chloride in ethanol was then added thereto, producing a precipitate of the hydrochloride of the compound named in the heading of this example. The hydrochloride was then separated by suction filtration and recrystallized from ethanol, yielding 21.7 grams of crystals having a melting point of 163°-164° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][CH2:13][OH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[Br:15]Br.C(=O)([O-])[O-].[K+].[K+].[C:23]([OH:26])(=O)[CH3:24]>O>[Br:15][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][CH2:3][C:2]2([CH2:12][CH2:13][O:14][C:23](=[O:26])[CH3:24])[CH3:1]
Reactant: BrBr
Reactant: CC1(CCO)CCOc2ccccc21
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)OCCC1(C)CCOc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2.5 g (13 mmol) of 2-(4-methylchroman-4-yl)ethanol in 15 mL of acetic acid was added 7.5 mL of a 2.7 M solution of bromine in acetic acid. After 30 minutes, the reaction was poured onto an ice cold slurry of potassium carbonate in water and extracted with diethyl ether. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was passed through a pad of silica gel using ethyl acetate-hexanes (0-30% gradient) to afford 3.6 g (90%) of acetic acid 2-(6-bromo-4-methylchroman-4-yl)ethyl ester as an oil. The ester was treated with 0.96 g (23 mmol) of lithium hydroxide in 45 mL of 4:1 mixture of methanol-water. After stirring overnight, the reaction was concentrated in vacuo to remove methanol and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3 g (96%) of 2-(6-bromo-4-methylchroman-4-yl)ethanol as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].C(C1C=CC([CH:20]([O:24]C(C2C=CC(C#N)=CC=2)C2OC2)[CH:21]2[O:23][CH2:22]2)=CC=1)#N.[OH-].[CH2:38]([N+:45](C)(C)C)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(OCCO)C>[C:2]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:11])[O:10][CH2:22][CH:21]([OH:23])[CH2:20][O:24][C:42]1[CH:43]=[CH:44][C:39]([C:38]#[N:45])=[CH:40][CH:41]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: N#Cc1ccc(C(OC(c2ccc(C#N)cc2)C2CO2)C2CO2)cc1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1cc(OCC(O)COc2ccc(C#N)cc2)ccc1O

Procedure:
A solution of 2,5 -dihydroxyacetophenone (30.4 g), p-cyanophenylglycidyl ether (35.0 g) and benzyltrimethylammonium hydroxide (10 drops of a 40% solution) in 2-ethoxyethanol (150 ml) was heated under reflux for 72 hours. The solvent was then removed under reduced pressure to give a dark viscous oil which rapidly solidified. This solid was extracted with ether in a Soxhlet thimble and the ether then removed to give a yellow solid residue. This was triturated with a little ethanol, filtered off, washed with a little more ethanol and dried. Some further material was obtained by grinding the residue from the Soxhlet thimble and extracting it with boiling ether. Recrystallization from aqueous ethanol gave 1-(3-acetyl-4-hydroxyphenoxy)-2 -hydroxy-3-(p-cyano-phenoxy) propane as lemon-yellow needles m.p. 118°-120° C.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([Cl:10])=[N:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:5]1[CH:6]=[C:7]([C:2]([C:19]#[C:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:3][N:4]=1)[CH:8]=[O:9]
Reactant: C#Cc1ccccc1Cl
Reactant: O=Cc1cc(Cl)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Temperature: 50 °C
Yield: 88.5 %

Procedure:
A mixture of 5-bromo-2-chloroisonicotinaldehyde (1.0 g, 4.5 mmol), 1-chloro-2-ethynylbenzene (650 mg, 4.7 mmol), N,N-diisopropylethylamine (1.6 mL, 9.1 mmol), copper(I) iodide (43 mg, 0.23 mmol), and bis(triphenylphosphine)palladium(II) chloride (159 mg, 0.23 mmol) in 1,4-dioxane (21 mL) was heated at 50° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-30% ethyl acetate in heptane) to afford the title compound as an off-white solid (1.1 g, 88%). 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 8.77 (s, 1H), 7.77 (s, 1H), 7.62 (dd, J=7.5, 1.7 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.38 (td, J=7.8, 1.8 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz, 1H).
Reaction SMILES: CON(C)[C:4](=[O:16])[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:7])[CH3:6].[CH3:18][Li].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[CH3:7][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])([C:4](=[O:16])[CH3:18])[CH3:6]
Reactant: [Li]C
Reactant: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 1-(methoxy(methyl)amino)-2-methyl-1-oxopropan-2-ylcarbamate (4.26 g, 17.30 mmol) in THF (100 mL) at −70° C. was added drop wise methyl lithium (32.4 mL, 51.9 mmol). Cold bath was replaced with −40° C. bath and the reaction was stirred for 4 hours. Saturated NH4Cl solution (10 mL) was then added cautiously to quench the reaction. The reaction mixture was then allowed to warm to room temperature, and diluted with EtOAc (100 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (2.36 g). LCMS m/z 224.2 (M+Na)+, Rt 0.7 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]([O-])(=O)C.[K+].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.C(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[N:1]1([CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: NCC(=O)O
Reactant: CC(=O)[O-]
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cn1cccc1
Reaction time: 4 h
Yield: 37.7 %

Procedure:
A solution of the hydrochloride salt of the methyl ester of glycine (6.30 g) and potassium acetate (8.00 g) in water (10 ml) was added to glacial acetic acid (50 ml). The resulting mixture was heated to reflux, 2,5-dimethoxytetrahydrofuran (6.60 g) was added in one portion, and heating under reflux was continued for 4 hours. After cooling, the reaction mixture was neutralised with sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried, concentrated under reduced pressure, and distilled at 125° C. and ca. 15 torr using a short-path distillation apparatus to give methyl pyrrol-1-ylacetate (2.62 g, 38% yield) as a colourless
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:8][C@H:5]1SC)=[N+:2]=[N-:3].[CH2:56]1[O:66][C:65]2[CH:64]=[CH:63][C:60]([CH2:61][OH:62])=[CH:59][C:58]=2[O:57]1.COS(C(F)(F)F)(=O)=O>ClCCCl>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:8][CH:5]1[O:62][CH2:61][C:60]1[CH:63]=[CH:64][C:65]2[O:66][CH2:56][O:57][C:58]=2[CH:59]=1)=[N+:2]=[N-:3]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc(CO[C@H]2[C@H](OC(=O)c3ccccc3-c3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OC(OCc3ccc4c(c3)OCO4)[C@@H]2N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A mixture of methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (11) (200 mg, 0.26 mmol), 3,4-methylenedioxybenzyl alcohol 59 mg, 0.39 mmol), molecular sieves 4A (1 g) and methyltriflate (106 mg, 0.65 mmol) in 1,2-dichloroethane (10 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with TEA (0.5 mL) and evaporated. The residue was purified by chromatography using EtOAc—hexane 15:85 as the mobile phase to give 3,4-methylenedioxybenzyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-α,β-D-glucopyranoside (43) (173 mg, 76%).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:33])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]1=[O:32])([CH3:10])([CH3:9])[CH3:8].[NH:34]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:35]([C:45](O)=[O:46])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>>[C:7]([O:11][C:12](=[O:33])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:45](=[O:46])[C@@H:35]([NH:34][C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C@@H:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]1=[O:32])([CH3:10])([CH3:8])[CH3:9]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CN1CCN[C@@H](CCCCNC(=O)OC(C)(C)C)C1=O
Agent: O=C(O)C(=O)O
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)OC(C)(C)C)C(=O)[C@@H]2CCCCNC(=O)OC(C)(C)C)cc1

Procedure:
In substantially the same manner as in Reference Example 2, the title compound was synthesized using (S)-3-(4-t-butoxycarbonylaminobutyl)-2-oxopiperazine-1-acetic acid t-butyl ester oxalate and N-Z-Tyr(OMe)-OH.
Reaction SMILES: [C:1]([OH:4])(=O)C.Cl[C:6]1[N:11]=C(Cl)[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[N:7]=1.C([O-])(=[O:28])C.[Na+]>O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[NH:7][C:6](=[O:28])[NH:11][C:1](=[O:4])[N:9]=3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(N2CCN(c3nc(Cl)nc(Cl)n3)CC2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
An acetic acid solution of 2,4-dichloro-6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine (2.40 g, 7.31 mmol) synthesized in Reference Synthesis Example 1 and sodium acetate (1.80 g) was stirred at 80° C. for 8 hours. After completion of the reaction, the reaction solution was poured into water and the obtained solid was collected by filtration. Extraction with ethyl acetate was performed from the filtrate and the resultant ethyl acetate phase was concentrated under reduced pressure. The residue and the solid collected by filtration were combined and the combination was suspended into ethyl acetate, collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (1.82 g, yield 86%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.BrC1CC1>CS(C)=O.CCOCC>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH:5]2[CH2:2][CH2:1]2)=[CH:10][CH:9]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: Brc1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a degassed solution of potassium tert-butoxide (2.08 g, 18.51 mmol) in dry dimethylsulphoxide (6 mL), 4-bromo-benzenethiol (3.5 g, 18.5 mmol) was added and the mixture was stirred for 15 min at ambient temperature under nitrogen. Bromocyclopropane (4.4 mL, 55.5 mmol) was added afterwards and the reaction mixture was heated at 80° C. for 24 h in a sealed vessel. The mixture was cooled, diluted with ether (150 mL) and washed with water (100 mL). The aqueous layer was extracted with ether (3×50 mL). Combined organic extracts were finally dried with anhydrous magnesium sulfate. 1-Bromo-4-cyclopropylsulfanyl-benzene was obtained after evaporation of the solvent as yellow liquid.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1.[P:13]([O-:20])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:11][C:9]1[CH:10]=[C:5]([PH:13](=[O:20])[C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=2)[CH:6]=[C:7]([CH3:12])[CH:8]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc([PH](=O)c2cc(C)cc(C)c2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Under an argon atmosphere, a solution of magnesium (25 g, 0.95 equivalent) and a small amount of iodine in THF (250 mL) was stirred at room temperature for 1 hr. 5-Bromo-m-xylene (200 g, 1.08 moL) was added at 48° C., and the mixture was stirred at 5° C. for 1 hr. Diethyl phosphite (78.3 g, 0.52 equivalent) was added at 5° C., and the mixture was stirred at 5° C. for 2 hrs. Water (200 mL) was added at 3° C., and toluene (200 mL) and 6M-HCl (160 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water (100 mL), 5% aqueous NaHCO3 solution (100 mL) and 5% aqueous NaCl solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered by gravity. The filtrate was concentrated under reduced pressure and the residue was recrystallized from diisopropyl ether-heptane to give the title compound (43.3 g, white crystals). yield 33.3%.