Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[CH:11]2)=[N:6]1
Reactant: CN(C)CCn1cc2cc(N)ccc2n1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2cc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)ccc2n1
Reaction time: 6 h

Procedure:
A mixture of 2-(2-Dimethylamino-ethyl)-2H-indazol-5-ylamine (49.0 mg, 0.243 mmol), (4-phenoxy-phenyl)-acetic acid (60.0 mg, 0.248 mmol), EDCI (57.0 mg, 0.298 mmol), N-hydroxybenzotriazole (40.0 mg, 0.296 mmol), N-methyl morpholine (64.0 mg, 0.633 mmol) and 2 mL of N,N-dimethylformamide was shaken for 6 hours. The solvents were removed under vacuo and the residue dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol was purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.49(s, 6H) 3.34 (t, 2H, J=6.44), 3.37 (s, 2H), 4.50 (t, 2H, J=6.44), 6.69–6.74 (m, 4H), 6.85 (m, 1H), 7.03 (m, 1H), 7.08–7.13 (m, 4H), 7.32 (m, 1H), 7.90 (s, 1H), 8.10 (s, 1H), 9.26 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1.O>[CH3:13][O:14][C:15]1[C:20]([B:21]([OH:26])[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: COc1ccccn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COc1ncccc1B(O)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 32.7 %

Procedure:
To a solution of diisopropylamine (1.42 mL, 10 mmol) in THF (10 mL) at 0° C. was added nBuLi (2.5 M, 4.25 mL, 10.6 mmol) dropwise. After stirring at 0° C. for 45 min, a solution of 2-methoxypyridine (0.96 mL, 9.2 mmol) in THF (5 mL) was added, and the mixture was stirred for an additional 1 h before B(OiPr)3 (2.54 mL, 11 mmol) was added. 30 min later, H2O was added to quench the reaction, the THF was removed in vacuo and the aqueous layer was extracted with ether. The aqueous layer was separated, acidified with 48% HBr to pH=4, the resulting precipitates were collected by filtration to yield 2-methoxypyridine-3-ylboronic acid (0.46 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](/[CH:20]=[C:21]2\[O:22][C:23]3[C:30]([CH2:31][N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[C:29]([OH:45])[CH:28]=[CH:27][C:24]=3[C:25]\2=[O:26])=[CH:12]1)(=[O:10])=[O:9].FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](/[CH:20]=[C:21]2\[O:22][C:23]3[C:30]([CH2:31][N:32]4[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]4)=[C:29]([OH:45])[CH:28]=[CH:27][C:24]=3[C:25]\2=[O:26])=[CH:12]1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccccc4Cl)c4ccccc24)C3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1/C(=C/c2cn(S(=O)(=O)c3ccccc3Cl)c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 239.4 %

Procedure:
A solution of tert-butyl (Z)-4-[(2-{[1-(2-chlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0930 g, 0.143 mmol) in methylene chloride (4 mL) was added with trifluoroacetic acid (4 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (4 mL) was added with a 5% solution of hydrogen chloride in methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain (Z)-2-{[1-(2-chlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.0711 g, 79%).
Reaction SMILES: COC1C=CC(C[O:8][C@@H:9]([CH3:57])[C:10]([O:12][C@H:13]2[C@H:18]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]([C:24]3[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([NH:32][C:33]4[N:38]=[C:37]([N:39](CC)[CH2:40][C:41]5C=CC(OC)=CC=5)[C:36]5=[N:51][CH:52]=[C:53]([C:54]#[N:55])[N:35]5[N:34]=4)[C:25]=3[Cl:56])[CH2:14]2)=[O:11])=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[OH:8][C@@H:9]([CH3:57])[C:10]([O:12][C@H:13]1[C@H:18]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]([C:24]2[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([NH:32][C:33]3[N:38]=[C:37]([NH:39][CH2:40][CH3:41])[C:36]4=[N:51][CH:52]=[C:53]([C:54]#[N:55])[N:35]4[N:34]=3)[C:25]=2[Cl:56])[CH2:14]1)=[O:11]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@H](C)OCc4ccc(OC)cc4)C3)c2Cl)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@H](C)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
To a solution of (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((4-methoxybenzyl)oxy)propanoate (0.050 g, 0.061 mmol) in DCE (3 mL) was added anisole (0.027 ml, 0.243 mmol) followed by TFA (25% in DCE) (4.68 mL, 15.18 mmol) and stirred at 35° C. for overnight. The reaction mixture was concentrated at 30° C. and resultant residue was washed with diethyl ether to give solid and this was purified by reverse phase preparative HPLC and collected fractions were lyophilized to give (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-hydroxypropanoate (0.005 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:20]>>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([C:15]([OH:20])=[O:16])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: CC(C)=O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (93.4 g, 401 mmol) in 2.6 L of acetone was added 400 mL of Jone's reagent (2.45 M) at 0° C. The reaction was warmed to room temperature, and the mixture was stirred overnight. The solid was removed by filtration, and the filtrate was concentrated. The concentrated residue was poured into water. The resulting white solid was collected and washed with water and dried to obtain 5-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. 1H NMR δ (400 MHz, d6-DMSO): 8.34 (s, 1H), 7.42-7.33 (m, 5H), 6.91(s, 1H), 4.95 (s, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:20]2[CH:27]=[C:26]([F:28])[C:24](N)=[N:23][C:21]2=[O:22])[C@H:6]1[F:29])(=[O:3])[CH3:2].C(O)(=[O:32])C>>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:20]2[CH:27]=[C:26]([F:28])[C:24](=[O:32])[NH:23][C:21]2=[O:22])[C@H:6]1[F:29])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(F)c(N)nc2=O)O[C@@H]1COC(=O)c1ccccc1
Reactant: CC(=O)O
Product: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1

Procedure:
A mixture of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluorocytosine (650 mg) in 80% acetic acid (50 ml) is heated under reflux for 48 hours. After removal of the solvent in vacuo the residue is chromatographed over a column of silica gel G60 (22×2 cm) using CHCl3 :MeOH (30:1 v/v) as the eluent. Each fraction is checked by tlc and the appropriate fractions are collected and evaporated in vacuo, and the residue is crystallized from ethanol to give pure 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluorouracil, 300 mg, m.p. 177°-179°.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([O:18]CC)=O)[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C(N(CC)C(C)C)(C)C>CO>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][CH:6]2[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:16]2=[O:18])[CH:13]=[CH:12][N:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CN
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CC2NC(=O)CNC2=O)ccn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-(2-methoxy-4-pyridinyl)alaninate (1.70 g, 6.03 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.03 mmol) in MeOH (20 mL). The reaction mixture was stirred at 70° C. for 18 h and allowed to cool to room temperature. The solid formed was filtered and washed with MeOH to give 3-((2-methoxy-4-pyridinyl)methyl)-2,5-piperazinedione (1.32 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.[F:21][C:22]([F:26])([F:25])[CH:23]=[O:24]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([CH:23]([C:22]([F:26])([F:25])[F:21])[OH:24])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: O=CC(F)(F)F
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)F
Yield: 53.8 %

Procedure:
A mixture of 2.55 g (0.01 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 1.3 g (0.011 mole) of trifluoroacetaldehyde hydrate in 75 ml toluene was heated at reflux for 3.5 hours. The mixture was concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel to give 1.9 g of product, m.p. 121°-122°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:17])[C:5]([CH3:16])=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([I:17])[C:5]([CH3:16])=[C:6]([CH:7]=1)[NH2:8]
Reactant: Cc1c(I)cc(Cl)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N)cc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 1,1-dimethylethyl (5-chloro-3-iodo-2-methylphenyl)carbamate (5 g, 13.6 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (10 mL). The solution was stirred at ambient temperature for 2 hours, then concentrated in-vacuo. The resultant residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford an orange residue which was purified by column chromatography (silica gel, 5% ethyl acetate in hexane). The product was isolated to afford 3.05 g, 11.4 mmol (84%) of 5-chloro-3-iodo-2-methylaniline as a yellow solid. 1H NMR (400 MHz, CDCl3): 7.26 (d, 1H), 6.64 (d, 1H), 3.78 (br s, 2H), 2.28 (s, 3H); MS (EI) for C7H7Cl1N: 268 (MH+).
Reaction SMILES: [C:1](=[O:4])([O-:3])N.CCCC[N+:9]([CH2:18][CH2:19][CH2:20][CH3:21])(CCCC)CCCC.[F-].[CH2:23]1COCC1>CCOC(C)=O>[NH2:9][C@@:18]1([C:1]([OH:3])=[O:4])[CH2:19][C@@H:20]1[CH2:21][CH3:23]
Reactant: NC(=O)[O-]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC[C@H]1C[C@@]1(N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To carbamate 14c (267 mg, 0.810 mmol) was added a 1.0 M TBAF solution in THF (1.62 mL, 1.62 mmol, 2.0 eq.). The reaction mixture was stirred overnight at RT, refluxed for 30 min and then diluted with AcOEt. The solution was successively washed with water (2×) and brine. After the usual treatment (MgSO4, filtration and concentration) the desired amine 14d was isolated (122 mg, 0.721 mmol, 89% yield) as a pale yellow liquid. 1H NMR (CDCl3) δ5.94-5.86 (m,1H), 5.31-5.22 (m, 2H), 4.58 (d, J=5.7 Hz, 2H), 1.75 (bs, 2H), 1.61-1.53 (m, 2H), 1.51-1.42 (m, 2H), 1.00 (t, J=7.3 Hz, 3H), 0.70-0.62 (m, 1H).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:24])[C:6]1[C:17]([I:18])=[C:16]([N:19]=[C:20]=[O:21])[C:15]([I:22])=[C:8]([C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C:7]=1[I:23])[CH:2]=[CH2:3].[CH2:25]([OH:28])[CH2:26][OH:27]>ClCCl>[CH2:12]([N:11]([CH2:14][CH:13]=[CH2:12])[C:9]([C:8]1[C:15]([I:22])=[C:16]([NH:19][C:20]([O:27][CH2:26][CH2:25][O:28][C:20](=[O:21])[NH:19][C:16]2[C:17]([I:18])=[C:6]([C:5](=[O:24])[N:4]([CH2:15][CH:8]=[CH2:9])[CH2:1][CH:2]=[CH2:3])[C:7]([I:23])=[C:8]([C:9](=[O:10])[N:11]([CH2:3][CH:2]=[CH2:1])[CH2:12][CH:13]=[CH2:14])[C:15]=2[I:22])=[O:21])[C:17]([I:18])=[C:6]([C:5](=[O:24])[N:4]([CH2:7][CH:6]=[CH2:5])[CH2:1][CH:2]=[CH2:3])[C:7]=1[I:23])=[O:10])[CH:13]=[CH2:14]
Reactant: OCCO
Reactant: C=CCNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC=C)c1I
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)c1c(I)c(NC(=O)OCCOC(=O)Nc2c(I)c(C(=O)N(CC=C)CC=C)c(I)c(C(=O)N(CC=C)CC=C)c2I)c(I)c(C(=O)N(CC=C)CC=C)c1I
Reaction time: 18 h

Procedure:
To a solution of N,N′-Diallyl-2,4,6-triiodo-5-isocyanatoisophthalamide in dichloromethane was added ethylene glycol (0.5 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give (3,5-Bis-diallylcarbamoyl-2,4,6-triiodo-phenyl)-carbamic acid 2-(3,5-bis-diallylcarbamoyl-2,4,6-triiodo-phenylcarbamoyloxy)-ethyl ester. A cis-dihydroxylation using OsO4 and NMMO was performed and the crude mixture was purified by preparative HPLC to give 1,3-bis-(N,N,N′,N′-tetrakis-(2,3-dihydroxypropyl))-2,4,6-triiodo-5-ureido-isophthalamide]-2-hydroxypropane as a white powder after freeze drying.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].O.O.O.C([O-])(=O)C.[Na+].C(O)(=O)C>CO.O>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:2]([F:1])[C:7]=1[OH:8]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(O)c1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc(N)c(O)c1F
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Methyl 2-fluoro-3-hydroxy-4-nitrophenylacetate (5.22 g, 14.9 mmol), reduced iron powder (2.66 g, 47.7 mmol), sodium acetate-trihydrate (2.03 g, 14.9 mmol) and acetic acid (5.54 ml) were heated and refluxed at 110° C. for 4 hours in methanol:water (1:4, 300 ml). After cooling to room temperature, the reaction mixture was filtered through Celite under reduced pressure to remove the insoluble matter. The filtrate was then concentrated, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from hexane/ethyl acetate (2/1) eluate fractions, the title compound (1.29 g, 44%) was obtained as a brown oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@H:6]1[O:7][C:8]1[C:13]([CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@H:6]1[O:7][C:8]1[C:13]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2].[C:1]([O:4][C@@H:5]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@H:6]1[O:7][C:8]1[C:13]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ncccc2C2CCCN2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ncccc2[C@@H]2CCCN2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ncccc2[C@H]2CCCN2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The diastereomer mixture (5a) was resolved by means of silica gel column chromatography using ethyl acetate as an eluent. As a result, (S)-(-)-3-(1-methyl-2-pyrrolidinyl)-2-pyridyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (6a) and (R)-(+)-3-(1-methyl-2-pyrrolidinyl)-2-pyridyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7a) were obtained in white-solid form and in yields of 1.8 g and 1.7 g, respectively. Further, (S)-(-)-3-(1-methyl-2-pyrrolidinyl)-2-pyridyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (6a) and (R)-(+)-3-(1-methyl-2-pyrrolidinyl)-2-pyridyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7a) were each recrystallized from ethyl acetate-hexane. As a result, highly purified (S)-(-)-3-(1-methyl-2-pyrrolidinyl)-2-pyridyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (6a) and (R)-(+)-3-(1-methyl-2-pyrrolidinyl)-2-pyridyl 2,3,4,6tetra-O-acetyl-β-D-glucopyranoside (7a) were obtained in yields of 1.7 g (30%) and 1.6 g (28%), respectively.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][C:13]([CH3:21])=[N:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([CH3:21])=[N:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc2onc(N)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)n(-c2ccc3onc(N)c3c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of ethyl 1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylate (0.14 g) in THF (5 mL) was added NaOH (10% in water, 5 mL). The reaction was stirred at 60° C. for 2 h, THF was evaporated, HCl (10% in water) was added dropwisely until the pH was between 4–5, partitioned between ethylacetate and water, washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(3-aminobenzisoxazole-5-yl)-3-methyl-5-pyrazole carboxylic acid (0.11 g). ESI mass spectrum z (rel. intensity) 259 (M+H, 100).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.C([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([F:21])[C:13]=1[OH:22])C=C.[CH3:23][C:24]([CH3:26])=[O:25].O>O=[Os](=O)(=O)=O>[F:21][C:14]1[C:13]([OH:22])=[C:12]([CH2:23][CH:24]([OH:25])[CH2:26][OH:5])[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cc([N+](=O)[O-])cc(F)c1O
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(O)c(CC(O)CO)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.2 %

Procedure:
N-methylmorpholine N-oxide (2.7 g, 23 mmol) was added to a suspension of Compound 3 (4.55 g, 23 mmol) in 50 mL of acetone/water (10:1) at 0° C. After 7 min OsO4 (1.048 mL, 0.092 mmol) was added slowly. The solution was stirred 36 h at room temperature, and then the solvent was evaporated in vacuo. It was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The filtrate was concentrated to yield the corresponding compound 4 (5.1 g, yield 85.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.N(C(C)(C)[C:26]#[N:27])=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:10][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[CH:7][N:6]=1)[CH3:9]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccc(C#N)cn1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-ethylpyridine (500 mg, 2.69 mmol), N-bromosuccinimide (484 mg, 2.69 mmol) and 2,2′-azo-bis(isobutyronitrile) (5 mg, 0.03 mmol) in chloroform is heated at reflux for 2 h. After stirring over night at room temperature, the reaction mixture is filtered, evaporated under reduced pressure and purified by preparative reversed-phase HPLC (Gilson, XBridge, gradient of acetonitrile in water, 0.1% HCOOH). Yield: 37 mg (5% of theory); Retention time HPLC: 0.89 min (Z011_S03).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1.C(OCC)C>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:28])([CH3:29])[CH2:27][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(OCCO)c(C)c2)c2c1CC(C)(C)CC2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCc1sc(C(=O)CCc2cc(C)c(OCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-propan-1-one (255 mg, 0.615 mmol) in THF (10 mL) and DIPEA (0.29 mL, 1.70 mmol) is added methane sulfonylchloride (0.09 mL, 1.15 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with diethyl ether, washed with sat. aq. NaHCO3 solution followed by 10% aq. citric acid solution, dried over Na2SO4 and evaporated to give methanesulfonic acid 2-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-ethyl ester (300 mg) as a brown resin; LC-MS: tR=1.18 min, [M+1]+=493.36.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[N:21]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[N:21]=3)[CH3:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C2CCCN2CCNCc2ccc3c(c2)OCCO3)nc(-n2ccnc2)n1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C2CCCN2CCN(C)Cc2ccc3c(c2)OCCO3)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine (65 mg, 156 μmol), formalin (63 μL, 780 μmol), and acetic acid (170 μL, 2.83 mmol) in MeOH (1 mL) was stirred at r.t. for 5 min. Sodium triacetoxyborohydride (99 mg, 470 μmol) was then added. The reaction mixture was stirred at r.t. for 20 min and then concentrated to residue. EtOAc (5 mL) and 1N NaOH (5 mL) were added. The organic layer was isolated, dried (MgSO4), filtered, and concentrated. Silica gel chromatography (0% to 10% MeOH/DCM) afforded 60 mg (89%) of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-methyl-amine. [M+H]+ 435.32; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.88 (s, 1H), 7.33 (s, 1H), 7.12 (s, 1H), 6.65-6.79 (m, 3H), 4.21 (s, 4H), 3.54 (t, 1H), 3.24-3.42 (m, 3H), 2.76 (m, 1H), 2.11-2.55 (m, 8H), 2.15 (s, 3H), 1.84 (m, 2H), 1.70 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([NH2:9])=[O:8].C(O)C.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:15][OH:16])[C:7]([NH2:9])=[O:8]
Reactant: NO
Reactant: NC(=O)C(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)C(=NO)c1cccs1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A mixture of 15.5 g of 2-thienylglyoxylamide, 75 ml of water, 75 ml of ethanol, 10.4 g of hydroxylamine hydrochloride and 24.6 g of sodium acetate is stirred at 40° C. for 5 h, the volatile fractions are stripped off in vacuo, and the residue is taken up in water. The product is extracted with ethyl acetate, and the organic phase is dried and concentrated. The residue is recrystallized from a little ethyl acetate.