Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[C:36]([CH3:42])=[N:37][N:38]([CH3:41])[C:39]=2[CH3:40])O1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:35]2[C:36]([CH3:42])=[N:37][N:38]([CH3:41])[C:39]=2[CH3:40])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2c(C)nn(C)c2C)c1
Yield: 46 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,5-trimethyl-1H-pyrazole, the expected product is obtained in the form of a white solid with a yield of 46%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:17])[N:5]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:18]([NH:28][C@H:29]([C:34](O)=[O:35])[CH2:30][CH2:31][S:32][CH3:33])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:21]([O:20][C:18]([NH:28][C@@H:29]([CH2:30][CH2:31][S:32][CH3:33])[C:34]([NH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:17])[N:5]2[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:35])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H]2C[C@H]1C(=O)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Preparation A3, Step 2: A solution of (1R,2S,5R)-tert-butyl 2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.5 g) was dissolved in DMF (34 mL) and cooled to 0° C. prior to the addition of N-Cbz methionine (5.3 g), 4-methyl morpholine (3.7 g), and BOP (8.3 g). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford (1R,2S,5R)-tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (5.1 g). MS found: (M+H)+=506.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CO
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c(N)cc1OC

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.0 g, 99.2 mmol) in methanol (250 mL) was added thionyl chloride (7.2 mL, 99.2 mmol). The reaction was refluxed for 16 h then concentrated in vacuo. Purification by silica gel chromatography (0-90% ethyl acetate/hexanes) provided methyl 4-amino-5-chloro-2-methoxybenzoate (21.3 g, quantitative yield). LC/MS m/z 216.3 [M+H]+.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(CC)C1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)C1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 43b (1.1 g, 2.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 98%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:16])[NH:9][CH:10]=[N:11]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:16])[NH:9][CH:10]=[N:11]2)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CNCCOc1cccc2nc[nH]c(=O)c12
Solvent: c1ccncc1
Product: CC(=O)N(C)CCOc1cccc2nc[nH]c(=O)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
5-[2-(Methylamino)ethoxy]quinazolin-4(3H)-one (823 mg, 3.76 mmol) was dissolved in pyridine (25 ml), and the solution cooled to 0° C. Acetic anhydride (1.20 ml, 12.70 mmol) was added drop wise; the solution was warmed to ambient temperature and stirred for 90 minutes. The mixture was concentrated in vacuo, and the residue purified by chromatography, eluting with 4% to 7% (10:1 methanol/conc. NH3(aq)) in DCM. Evaporation of the appropriate fractions gave N-methyl-N-{2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]ethyl}acetamide as a white foam (970 mg, 99%); NMR Spectrum (DMSO-d6, 400 MHz, 373K) 2.05 (bs, 3H), 2.92 (s, 3H), 3.71 (bt, 2H), 4.20 (bt, 2H), 7.01 (d, 1H), 7.19 (d, 1H), 7.63 (dd, 1H), 7.89 (s, 1H); Mass spectrum M+NH4+284.0 (ES−) M−H+ 260.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([CH:20]([CH2:22][OH:23])[OH:21])([OH:19])[CH3:18])[CH3:13])[CH3:8])[CH3:3].[CH3:24][C:25]([CH3:27])=O>C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:24][C:25]1([CH3:27])[O:21][CH:20]([C:17]([OH:19])([CH2:16][CH2:15][CH2:14][CH:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:18])[CH2:22][O:23]1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C(O)CO
Reactant: CC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C1COC(C)(C)O1

Procedure:
One g of phytantriol (3.0 mmol, Sigma-Aldrich) was refluxed using deanstock apparatus for 15 hr in 25 ml of acetone solution with toluene sulfonic acid as catalyst. After the completion of the reaction, the acetone solvent was removed under reduced pressure and the resultant was extracted with chloroform solution. The extract was washed with saturated sodium bicarbonate solution and was again washed with saline to obtain 0.3 g of (2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-6,10,14-trimethyl-pentadecan-2-ol) of which 1- and 2-positions were protected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:17](Cl)Cl.OS(O)(=O)=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1CC(=O)N(c2ccc(F)cc2)C1

Procedure:
To 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid 51 was added 80 mL of CH2Cl2, 30 mL of MeOH, and 1.0 mL of concentrated H2SO4. After heating at reflux overnight, the mixture concentrated and triturated with water to give methyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate 52.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.CCO.N.[Li]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2CCN(C)CC2)cc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C[C@@H]2CCCN2)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a flame dried 3 neck 250 mL round bottom flask fitted with dry ice condenser, ammonia (50 mL) was condensed at −78° C. using an acetone bath. 1-Methyl-4-({(2S)-1-[(4-methylphenyl)sulfonyl]pyrrolidin-2-yl}methyl)piperazine (2.562 g, 7.790 mmol) dissolved in THF (40 mL), EtOH (2 mL) and NH3 (40 mL) was transferred via syringe into the reaction vessel. Lithium (0.500 g, 72.000 mmol) was added by small pieces into the stirred solution. Acetone bath was then removed and the reaction was allowed to reflux for 2 hours and then warmed up to rt. The reaction was quenched with H2O (50 mL) basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The aqueous layer was re-extracted with CH2Cl2/MeOH (90/10) and the combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound as a yellow oil (1.300 g, 93% ). NMR (400 Mz, DMSO-d6): consistent. Reference: (Tetrahedron, 43(14), 3289, 1987).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]([N:22]1[C:26]([CH:27]=O)=[CH:25][C:24]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[CH:25][C:24]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cc(C=O)n(C(C)(C)C)n1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(CC(C)C)nn3C(C)(C)C)CC2)cc1
Yield: 29.7 %

Procedure:
Compound 41 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 2-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [SH:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9]C(NCCN3CCOCC3)=O)[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[N:34]2[N:35]=[C:36]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:37]=[CH:38][C:33]2=[N:32][N:31]=1.C(=O)([O-])O>O.CS(C)=O>[CH3:44][N:42]1[CH:43]=[C:39]([C:36]2[CH:37]=[CH:38][C:33]3[N:34]([C:30]([S:1][C:2]4[CH:22]=[CH:21][C:5]5[N:6]=[C:7]([NH2:9])[S:8][C:4]=5[CH:3]=4)=[N:31][N:32]=3)[N:35]=2)[CH:40]=[N:41]1
Reactant: Cn1cc(-c2ccc3nnc(Cl)n3n2)cn1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5nc(N)sc5c4)n3n2)cn1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
280 mg of 1-(6-sulphanyl-benzothiazol-2-yl)-3-(2-morpholin-4-yl-ethyl)urea, 2 cm3 of dimethyl sulphoxide and 240 mg of potassium carbonate are introduced, at 20° C., in a microwave tube equipped with a magnetic stirrer. The suspension thus obtained is stirred for 5 minutes before the addition of 200 mg of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazine. The reaction mixture is then heated in a microwave oven for 10 minutes at 190° C., and then poured into 100 cm3 of water. The resulting mixture is stirred for 30 minutes under cold conditions. The solid is filtered off, washed with 3×100 cm3 of water and then spin-filter-dried. The brown powder thus obtained is purified by chromatography on silica gel (eluent: 95/5/0.5 dichloromethane/methanol/aqueous ammonia). A small amount of methanol and of hydrochloric acid in solution in dioxane is added to the fractions containing the expected product (to improve solubility). The fractions are combined and concentrated under reduced pressure. The oil thus obtained is taken up with 20 cm3 of a saturated aqueous solution of hydrogen carbonate (pH 8-9). The precipitate formed is filtered off and then washed with 3×20 cm3 of water and dried under vacuum. 120 mg of 6-{[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine are thus obtained in the form of a light brown solid.
Reaction SMILES: C[O:2][C:3]([CH:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][C:9]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].O[Li].O>CO.O>[CH2:17]([O:16][P:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:3]([OH:4])=[O:2])=[CH:7][CH:8]=1)([O:13][CH2:14][CH3:15])=[O:19])[CH3:18]
Reactant: CCOP(=O)(OCC)c1ccc(C(C(=O)OC)c2ccccc2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of Diethyl 4-((methoxycarbonyl)(phenyl)methyl)phenylphosphonate, 14-e, (1.7 g, 5.0 mmol) and LiOH.H2O (0.3 g, 7 mmol) in methanol (10 mL) and H2O (10 mL) was stirred overnight. The resulting mixture was concentrated and extracted by EA. The aqueous layers were added HCl (1 M) until pH 1˜2. The mixture was extracted by EA. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford the title compound, 14-f, as colorless oil (1.18 g, 72%). 1H NMR (300 MHz, CDCl3) δ1.22-1.31 (m, 6H), 4.03-4.14 (m, 4H), 5.05 (s, 1H), 7.25-7.31 (m, 5H), 7.38-7.42 (m, 2H), 7.68-7.75 (m, 2H); LC-MS: (M+H)+ 349.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[CH:28][N+:25]([O-:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)c1ccc(C=O)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)c1ccc(C=C[N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 100 mL of nitromethane were added 10.44 g of 2-benzyloxy-4-isopropylbenzaldehyde and 4.71 g of ammonium acetate. After being stirred at external 100° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the organic layer was washed successively with 1 mol/L hydrochloric acid, and saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 9.45 g of 2-benzyloxy-4-isopropyl-1-(2-nitrovinyl)benzene.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:27])[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[CH3:27][C:11]1([NH2:10])[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2nccc(C(F)(F)F)n2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1(N)CCN(c2nccc(C(F)(F)F)n2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamic acid benzyl ester (0.060 g, 0.17 mmol) in acetonitrile (1.0 mL) at room temperature was added iodotrimethysilane (0.04 mL, 0.25 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, concentrated under reduced pressure and purified by flash chromatography with 3% methanol in dichloromethane to provide the titled compound. MS (CI) m/z 261 (M+1)+; 1H NMR (300 MHz, methanol-d4) δ ppm 8.61 (d, 1H), 6.92 (d, 1H), 4.83 (m, 2H), 4.50 (m, 2H), 3.51 (m, 2H), 1.90-1.74 (m, 4H), 1.51 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[NH:8]([C:15]([C:18]1[N:19]([CH3:30])[C:20]([C:23]2[CH:28]=CC(O)=[CH:25][CH:24]=2)=[N:21][N:22]=1)([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([O:4][C:1]1[CH:25]=[CH:24][C:23]([C:20]2[N:19]([CH3:30])[C:18]([C:15]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:17])[CH3:16])=[N:22][N:21]=2)=[CH:28][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(-c2ccc(O)cc2)nnc1C(C)(C)Nc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2nnc(C(C)(C)Nc3ccccc3)n2C)cc1
Reaction time: 3 h

Procedure:
Acetic anhydride (37 μl) was added to a pyridine solution (1 ml) of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenol (60 mg), followed by stirring for 3 hours. After most of acetic anhydride and pyridine was removed by evaporation under reduced pressure, the residue was purified by thin layer chromatography (chloroform:methanol=9:1) to obtain 40 mg of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenyl acetate (white crystals).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2>ClCCl.Cl>[Si:22]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[N:7][NH:8]2)=[CH:4][CH:3]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(O)ccc12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(N3C(=O)c4ccccc4C3=O)n[nH]c2c1
Temperature: 50 °C
Yield: 71 %

Procedure:
To a suspension of 15.03 g (53.82 mmol) of 2-({6-hydroxy}-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione in 150 ml of dichloromethane, a solution of 20.19 g (0.134 mol) of TBDMS chloride in 75 ml of dichloromethane was added. The resulting mixture was treated dropwise with 12.06 ml (80.73 mmol) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature, obtaining a clear solution. After 3 hours the reaction mixture was poured in 250 ml of 0.5 N HCl. The aqueous layer was separated and extracted with 120 ml of dichloromethane. Organic extracts were dried over sodium sulfate and the solvent evaporated under vacuum. The moist raw product was stirred in 50 ml of ethyl acetate at 50° C. Then, about one half of the solvent was evaporated under vacuum and the mixture was treated dropwise with 100 ml of cyclohexane. The product was isolated by suction as light yellow solid (15.04 g). Yield=71.0%. mp=207-209° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:25]2[CH2:24][CH:23]3[CH:27]([C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21][C:22]3=[O:28])[CH2:26]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: Cc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(CC(=O)N2CC3C(=O)CCC(c4ccccc4)(c4ccccc4)C3C2)c1
Reaction time: 0.58 h
Yield: 46.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(3-methylphenyl)acetic acid (1.05 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 35 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized by dissolving in boiling ethyl acetate (10 cc). The crystals are drained, dried and recrystallized from a mixture of acetonitrile (8 cc) and isopropyl ether (7.5 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(3-methylphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1.37 g) melting at 184° C. is obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([CH3:25])[C:22]([OH:24])=O.Cl.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][NH:36][CH2:37]3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.C(N(CC)CC)C>[C:43]1([C:33]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][N:36]([C:22](=[O:24])[C@H:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH3:25])[CH2:37]3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
0.32 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.36 g of (S)-2-(2-methoxyphenyl)propionic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR, 7R,7aR)-4,4-diphenyl- 7-fluoroperhydroisoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine is added. The reaction mixture is stirred at room temperature for 20 hours, diluted with 200 cm3 of dichloromethane and then washed with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 20 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (60/40 by volume) and collecting fractions of 20 cm3. Fractions 10 to 15 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 0.6 cm3 of isopropyl oxide. The crystals obtained are drained, washed with isopropyl oxide, and then dried. 0.19 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoro-2-[ (S)-2-(2methoxyphenyl)propionyl]perhydroisoindole is obtained in the form of white crystals; melting point 195° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33](=[O:42])[CH2:34][C:35](=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44]O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:33]1[O:42][N:44]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Yield: 80.4 %

Procedure:
A stirred solution of ethyl 4-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-2,4-dioxobutanoate (5 g, 9 mmol) and hydroxylamine hydrochloride (0.74 g, 15 mmol, 1.2 eq) in ethanol (mL 50) was refluxed for 2 hours. The solution was concentrated to a small volume and diluted with ethyl acetate. After washing with brine and drying, the solvent was removed and the residue was carefully chromatographed on silica gel eluting with hexane/ethyl acetate 6/1, to provide the title compound (4.1 g, 82% yield).