Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([CH:17]=[O:18])[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.[CH2:19]=[CH:20][CH2:21][Si]1(Cl)N(CC2C=CC(Br)=CC=2)[C@@H]2[C@H](CCCC2)N1CC1C=CC(Br)=CC=1>>[OH:18][C@@H:17]([C@H:13]1[CH2:12][N:11]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:10])[C:15](=[O:16])[CH2:14]1)[CH2:21][CH:20]=[CH2:19]
Reactant: C=CC[Si]1(Cl)N(Cc2ccc(Br)cc2)[C@H]2CCCC[C@@H]2N1Cc1ccc(Br)cc1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Product: C=CC[C@@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde 1.07 (0.93 g, 3.76 mmol) at rt was added (S,S)-2-allyl-1,3-bis-(4-bromobenzyl)-2-chlorooctahydro-2-1H-1,3,2-benzodiazasilole (3.338 g, 6.02 mmol) followed by Sc(III) triflate (0.093 g, 0.188 mmol). The reaction was stirred at rt for 1.5 hr and the solvent was removed. To the residue was added Et2O (80 mL) and 1M HCl (20 mL). The suspension was stirred for 1 hr and the solids were removed by filtration. The filter cake was washed with ether. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with Et2O (3×40 mL). The combined organics were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography to afford (R)-4-((R)-1-hydroxybut-3-enyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.08.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[S:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH:13]=2)[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]=1[CH3:33])C.CO.[OH-].[Na+]>O1CCCC1>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH2:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH3:33])=[C:6]2[CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(OCc3nc4ccccc4s3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution containing the compound of Example 50, (2.5 g, 5.31 mmol), methanol (200 mL), tetrahydrofuran (200 mL) and 1N sodium hydroxide (9.5 mL) is refluxed for 3 hours. Upon cooling, the mixture is concentrated under reduced pressure, diluted with water (200 mL) and acidified with 2 N HCl. After stirring for 30 minutes, the product is filtered and recrystallized from acetonitrile to give the title compound as a white solid in 85% yield, m.p. 186°-188° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1)#[N:2]
Reactant: COC(=O)CC#N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CCCC1
Temperature: 75 °C
Yield: 77094.2 %

Procedure:
To a 22 L flask equipped with a mechanical stirrer, thermometer and condenser containing a nitrogen inlet was added dry DMF (8 L) and methyl cyanoacetate (800 g, 8.07 mol). Stirring was started and K2CO3 (2.67 kg, 19.3 mol) and then 1,4-dibromobutane (1.74 kg, 8.07 mmol) were added. The exothermic reaction mixture (temperature increased to 75° C.) was stirred at room temperature for 16 h followed by heating at 60-75° C. for 3 h. Approximately 2.5 L of solvent were removed under reduced pressure and the residue was diluted with water (8 L). The resultant mixture was extracted with Et2O (2×2 L) and the combined organic phases were washed with 1 N aqueous HCl and brine. Drying (MgSO4), filtering and concentrating afforded an orange liquid. This material was distilled (fraction boiling at 80° C., 0.7 mm Hg collected) to provide methyl 1-cyanocyclopentanecarboxylate as a clear colorless liquid (953 g, 77% yield). 1H-NMR (400 MHz, CDCl3) δ 3.80 (s, 3 H), 2.29-2.22 (m, 4 H), 1.90-1.84 (m, 4 H); 13C NMR (100.6 MHz, CDCl3) δ 169.2, 119.9, 52.6, 46.6, 36.9, 24.3; EI-MS exact mass calcd for C8H11NO2 : 153.0790; found: 153.0785.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)[CH2:4][OH:5].[C:19]([OH:36])(=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[C:19]([O:1][CH2:2][CH:3]([O:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]1=2)[CH2:4][O:5][C:19](=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 50 °C
Reaction time: 50 h
Yield: 97.6 %

Procedure:
To 50 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in 5 ml of N,N-dimethylformamide were added 290 mg dicyclohexycarbodiimide and 300 mg of n-hexadecanoic acid and the solution was stirred at 50° C. for 50 hours. The compound was then precipitated in ice water. The water was extracted with methylene chloride (3×). The combined methylene chloride extracts were concentrated, then purified on preparative silica gel plates developed in 1:9 methanol:methylene chloride to yield 140 mg 9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine, m.p. 150°-154° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH2:21](OC(OCC)OCC)[CH3:22].[Al+3].[Cl-].[Cl-].[Cl-]>C(O)C>[CH3:21][CH2:22][O:19][C@H:7]1[O:8][C@@H:9]2[O:15][C:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:11]4[CH2:12][CH2:13]3)[C@H:6]1[CH3:20]
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reactant: CCOC(OCC)OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
Dihydroartemisinin (50 mg) was dissolved in dry ethanol (3 ml). Add 2 ml of triethylorthoformate and anhydrous AlCl3 (33 mg) was added in the reaction vessel. The reaction mixture was refluxed at 40° C. for 45 min over oil bath with constant stirring. After 45 mins of stirring the reaction product was worked up as mention in the example-3. The pure arteether yielded (45 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14](=[CH:15][C@@H:16]([OH:28])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:29][Si:30]([CH3:33])([CH3:32])Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14](=[CH:15][C@@H:16]([O:28][Si:30]([CH3:33])([CH3:32])[CH3:29])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@]12CC[C@H](O[Si](C)(C)C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
A solution of 4-androstene-3β,17β,19-triol 17,19-diacetate, trimethylchlorosilane and pyridine in toluene is refluxed for 24 hours. The solid is removed by filtration and the filtrate reduced to dryness under vacuum. The oil is crystallized from hexane to yield 3β-trimethylsiloxy-4-androstene-17β,19-diol 17,19-diacetate. This produce is refluxed one hour with 1 equivalent of sodium bicarbonate in 10% aqueous methanol. The solution is poured onto water. The solid which forms is filtered, dried, and crystallized from ether-hexane to yield 3β-trimethylsiloxy-4-androstene-17β,19-diol 17-acetate.
Reaction SMILES: C(N=[C:10]=[S:11])(=O)C1C=CC=CC=1.[CH3:12][C:13]1[C:17]([CH2:18][NH:19][C:20]2[N:21]=[CH:22][NH:23][C:24]=2[C:25]([NH2:27])=[O:26])=[C:16]([CH3:28])[O:15][N:14]=1>CC(C)=O>[CH3:12][C:13]1[C:17]([CH2:18][N:19]2[C:20]3[N:21]=[CH:22][NH:23][C:24]=3[C:25](=[O:26])[NH:27][C:10]2=[S:11])=[C:16]([CH3:28])[O:15][N:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1noc(C)c1CNc1nc[nH]c1C(N)=O
Solvent: CC(C)=O
Product: Cc1noc(C)c1Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Yield: 9.3 %

Procedure:
Benzoyl isothiocyanate (0.62 mL, 4.64 mmol) was added, dropwise, to a solution of 4-{[(3,5-dimethylisoxazol-4-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.91 g, 3.86 mmol, obtained from Example 21(a)) in acetone (20 mL). After stirring o.n., the solvent was evaporated in vacuo and the residue triturated with dichloromethane. The solid was removed by filtration and the filtrate was concentrated in vacuo. A solution of ammonia in methanol (7 N, 20 mL) was added to the resulting residue and this solution was transferred to a sealable tube. The vessel was sealed and placed in an 80° C. oil bath for 3 h. After cooling to r.t., the solution was concentrated in vacuo. The product was purified by recrystallization from DMSO/water, filtered and triturated sequentially with water, methanol and dichloromethane, providing the title compound (0.10 g, 10% yield) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[CH3:14][O:15][C:16]1[C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:17]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:23]([CH2:22][C:21]3[C:16]([O:15][CH3:14])=[N:17][C:18]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:19][CH:20]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: COc1nc(OCC(F)(F)F)ccc1CN
Product: COc1nc(OCC(F)(F)F)ccc1CN1Cc2c(ccnc2Cl)C1=O
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (155 mg, 0.57 mmol, Amine-13) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CSC(=S)NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CSC(=S)NCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (7.5 g) in pyridine (40 ml) is added triphenylmethyl chloride (15 g), and the mixture is left to stand overnight at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with diluted hydrochloric acid and water, dried and concentrated to remove the solvent. The residue is crystallized from a mixture of dichloromethane and ether to give N-(2-triphenylmethoxyethyl)dithiocarbamic acid methyl ester (14.73 g).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3].Cl[CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:15][CH2:14][CH2:13][C:12]#[CH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:1]
Reactant: CC(C)N1CCNCC1
Reactant: C#CCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCN1CCN(C(C)C)CC1
Temperature: 80 °C
Yield: 35.4 %

Procedure:
A mixture of 1-(1-methylethyl)piperazine (6 g, 46.8 mmol), 5-chloro-1-pentyne (4.91 mL, 46.8 mmol) and sodium bicarbonate (3.93 g, 46.8 mmol) in N,N-dimethylformamide (75 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature then partitioned between ether (100 mL) and water (100 mL). The organic phase was washed with brine (25 mL) then dried using a hydrophobic frit and evaporated. The crude material was purified on a 50 g SCX cartridge (preconditioned with MeOH) eluted with MeOH and flushed with 2M NH3/MeOH. The appropriate fractions were concentrated and dried under vacuum to obtain the title compound as a light brown oil (3.22 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
70 (171 mg, 0.81 mmol), methyl 3-(bromomethyl)benzoate (0.01 mL, 0.97 mmol), and Cs2CO3 (791 mg, 2.43 mmol) were suspended in DMF (3 mL), and stirred overnight at ambient temperature. The reaction solution was purified directly via flash chromatography on silica gel to provide 458 (130 mg, 44% yield) as a white powder. LC-MS (M+H=360, obsd.=360). 1H NMR (400 MHz, DMSO-D6) δ 8.53 (dd, J=6.3, 11.9, 2H), 8.06 (d, J=8.7, 1H), 7.86 (s, 1H), 7.80 (d, J=8.0, 1H), 7.56 (d, J=7.6, 1H), 7.44 (d, J=8.5, 2H), 7.31 (m, 1H), 6.91 (d, J=9.0, 1H), 6.22 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C1COCC1>[CH2:1]([C:4]1[C:5]([O:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:20](=[O:21])[NH:19][CH2:17][CH3:18])[N:10]=[CH:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC(C)=O)ccc2cn[nH]c12
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: C=CCc1c(OC(C)=O)ccc2cnn(C(=O)NCC)c12
Temperature: 70 °C
Yield: 81 %

Procedure:
To a solution of the product from Step C (2.5 g, 11.6 mmol) in THF (10 mL) was added ethylisocyanate (1.01 ml, 13 mmol) and the mixture heated at 70° C. for 18 h. The reaction mixture was evaporated to a residue which was purified by chromatography (silica, 10% to 50% EtOAc/hexane) to give a colorless oil (2.70 g, 81%): LC/MS (+APCI) m/z 288 (M+H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C(O)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:13]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:15][CH:16]=1)(=[O:22])[CH3:21]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CC(=O)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 104.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 1-(4-aminophenyl) ethanone (1.19 g, 1.19 mmol) in ethanol (3 mL). 1-(4-acetylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.307 g (42%) was obtained as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Cl)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-chlorobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-chlorophenyl ketone as a colorless powder. APCI-Mass m/Z 620/622 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (br-d, J=4.2 Hz, 2H), 4.30 (m, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.53 (t, J=9.6 Hz, 1H), 5.73 (t, J=9.4 Hz, 1H), 6.34 (d, J=9.2 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.80 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 8.18 (s, 1H).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.Cl.C(N=C=NCCCN(C)C)C.[CH2:28]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([OH:43])[C@H:40]([C:44](O)=[O:45])[CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH:12]1([NH:15][C:44]([C@H:40]2[C@H:41]([OH:43])[CH2:42][N:38]([C:36]([O:35][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:39]2)=[O:45])[CH2:14][CH2:13]1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CC1)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Yield: 48.9 %

Procedure:
17.9 g of 1-hydroxybenzotriazole hydrate (117 mmol), 16.9 mL of cyclopropylamine (244 mmol) and 22.4 g of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (117 mmol) were successively added to a solution of (3R,4S)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-3-carboxylic acid (25.9 g, 97.5 mmol) in 259 mL of dehydrated tetrahydrofuran under stirring at room temperature. The mixture was further stirred at room temperature for 5 hours. Subsequently, the reaction mixture was concentrated under reduced pressure, followed by addition of 130 mL of ethyl acetate and 260 mL of 1 mol/L hydrochloric acid and subsequent stirring for 30 minutes. The resulting crystals were collected by filtration and washed with 26 mL of ethyl acetate. The organic layer was collected and washed with 130 mL of a 10% aqueous sodium bicarbonate solution and 130 mL of 28% brine. To this layer, 39.0 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The insoluble material was separated by filtration and washed with 52 mL of ethyl acetate. The filtrate was concentrated under reduced pressure. To the resulting residue, 156 mL of diisopropyl ether was added and the product was tritulated. The precipitated powder was collected by filtration and washed with 39 mL of diisopropyl ether. The washed product was dried by air-blowing at room temperature for 30 minutes. 25.6 g of the resulting crystals were added to 308 mL of ethylacetate. The mixture was heated at an external temperature of 80° C. for 25 minutes under stirring, then allowed to cool in the air for 40 minutes under stirring, then cooled in a water bath for 5 minutes under stirring at an internal temperature of 40° C., and then stirred at room temperature for 5 minutes at an internal temperature of 25° C. The precipitated powder was collected by filtration and washed with 52 mL of diisopropyl ether. The washed product was dried for 1 hour by air-blowing. Further drying the product by air-blowing at 60° C. for 16 hours gave 14.5 g of the title compound as fluffy colorless crystals (43% yield in the 3 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)cc2)c1=O
Yield: 86.6 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 86.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:10]([CH3:24])[NH:9]2)=[CH:4][CH:3]=1.F[C:26](F)(F)S(OC)(=O)=O>ClCCl>[CH2:17]([O:16][C:14]([C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]([CH3:26])[C:10]=1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Cc1[nH]n(-c2ccc(F)cc2)c(=O)c1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccc(F)cc2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
To a solution of benzyl 2-(4-fluorophenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (8.0 g, 0.024 mol) in dichloromethane (80 mL), methyl trifluoromethanesulfonate (4.8 g, 0.029 mol) was added and stirred at room temperature for 24 hours. The resulting mixture was extracted with dichloromethane and saturated baryta water. After phase separation, the aqueous layer was extracted again with dichloromethane. All the organic layers were collected, dried with Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=4:1) to give the target compound (2.69 g, 32% yield).
Reaction SMILES: [Br:1][C:2]1N=C[C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.BrC1[CH:21]=[N:22]C(C=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:22][CH:21]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: COc1ccc2nc(-c3ccc(Br)nc3)oc2c1
Product: COc1ccc2nc(-c3ccc(Br)cn3)oc2c1

Procedure:
The title compound was synthesized according to a procedure similar to that as described for 2-(6-bromopyridin-3-yl)-6-methoxy-1,3-benzoxazole starting from 3-bromo-6-formylpyridine to give 578.1 mg as an off white solid: 1H NMR δ ppm 8.91 (dd, 1H) 8.26-8.32 (m, 1H) 8.20 (dd, 1H) 7.75 (d, 1H) 7.46 (d, 1H) 7.06 (dd, 1H) 3.86 (s, 3 H); MS m/z 305, 307 (M+H, Bromo isotopes).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2[C:17]([CH:18]=[O:19])=[CH:16][O:15][C:14]=2[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:7]1([C:13]2[C:17]([CH2:18][OH:19])=[CH:16][O:15][C:14]=2[Si:20]([CH2:23][CH3:24])([CH2:25][CH3:26])[CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC[Si](CC)(CC)c1occ(C=O)c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1occ(CO)c1-c1ccccc1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0M solution in hexane, 1.48 ml, 1.48 mmol) was added dropwise to a solution of 3-phenyl-2-triethylsilyl-4-furaldehyde (422 mg, 1.48 mmol) in tetrahydrofuran (10 ml) at 0 degrees under argon. This mixture was warmed to room temperature, quenched with ice-cold 5% (V/V) hydrochloric acid and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, H2O and brine. The dried extracts (magnesium sulfate) were concentrated to an oil which was purified by flash chromatography on silica using 20% ethyl acetate/hexanes to give the title compound. IR (neat): 3300 (broad); 2953 cm-1.