Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]([C:14]([O:16]CC)=[O:15])[CH:12]3[CH2:19][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]([C:14]([OH:16])=[O:15])[CH:12]3[CH2:19][CH:9]2[CH2:10][CH2:11]3)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1C2CCC(C2)N1Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2C3CCC(C3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (340 mg, 1.18 mmol) in tetrahydrofuran (8 ml)-methanol (4 ml) was added 1N sodium hydroxide (8 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid and then concentrated. The resulting white solid was washed with chloroform and then filtrated. The filtrate was dried over magnesium sulfate and the solvent was evaporated, to give 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([C:31]([CH3:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32])[CH2:10][NH:11][C@H:12]([C:17]([N:19]([CH3:30])[C@@H:20]([CH:27]([CH3:29])[CH3:28])/[CH:21]=[C:22](\[CH3:26])/[C:23]([OH:25])=[O:24])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])=O)(C)(C)C.Cl>ClCCl>[CH3:26]/[C:22](=[CH:21]\[C@@H:20]([N:19]([CH3:30])[C:17](=[O:18])[C@H:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[NH:11][CH2:10][C@@H:9]([NH:8][CH3:6])[C:31]([CH3:32])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:39])[CH:27]([CH3:29])[CH3:28])/[C:23]([OH:25])=[O:24]
Reactant: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC[C@@H](N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: CN[C@H](CN[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Yield: 92.8 %

Procedure:
(2E,4S)-4-[(N-{(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutyl}-3-methyl-L-valyl)(methyl)amino]-2,5-dimethyl-2-hexenoic acid (40 mg, 0.068 mmol, from reference example 21) is dissolved in dichloromethane (3 ml) and treated with 4N hydrogen chloride (0.068 ml, 0.27 mmol) at room temperature for 30 minutes. The reaction mixture is then concentrated in vacuo and triturated with ether to give a white solid (29 mg, 87%). The crude material is purified by reverse phase HPLC. MS [M+H] 488.62
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[Br:10][C:11]1[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=1[F:18].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:11]1[CH:16]=[C:15]([C:9]#[C:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[CH:14]=[CH:13][C:12]=1[F:18]
Reactant: C#Cc1cncc(Cl)c1
Reactant: Fc1ccc(I)cc1Br
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (77 mg, 0.11 mmol), copper (I) iodide (42 mg, 0.22 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (300 mg, 2.2 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (0.78 g, 2.6 mmol) in triethylamine (3.3 mL, 33 mmol). Stir at room temperature for 24 h then concentrate. Purify by silica gel chromatography, eluting with 75:25 dichloromethane:hexanes to 100:0 dichloromethane:hexanes to 95:5 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 95:5 to 90:10 hexanes:ethyl acetate, to give the title compound as a white solid (560 mg, 82%).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]1[C:31](B(O)O)=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]1>C1(C)C=CC=CC=1.O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:27]1[C:31]([C:2]2[N:3]=[C:4]([O:9][C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:5]([CH3:8])=[CH:6][N:7]=2)=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Reactant: Cc1cnc(I)nc1Oc1cc(C(F)(F)F)nn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1cnc(-c2cc(C(F)(F)F)nn2C)nc1Oc1cc(C(F)(F)F)nn1C

Procedure:
To a solution of 4A (1 g) in toluene (10 ml) is added a 2 M solution of potassium carbonate in water (2.5 ml) under an inert gas atmosphere. A suspension of 4B (0.66 g) and tetrakis(triphenylphosphine)palladium (0.15 g) in methanol (3 ml) is added and the mixture is heated to for 36 h to reflux. After cooling, the organic phase is separated and the water phase is washed twice with ethyl acetate. The combined organic phases are dried, evaporated to dryness and the residue is purified by silica-gel flash chromatography and preparative HPLC. One obtains the title compound as colorless crystals of mp. 113° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4](N(C)C)=[O:5].CC1C=CC([N+]([O-])=O)=CC=1C(O)=O.S(Cl)([Cl:31])=O>>[CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([Cl:31])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)N(C)C
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl

Procedure:
The preparation of 2,N,N-trimethyl-5-nitrobenzamide utilized the procedure described in U.S. Pat. No. 4,942,163. The reaction mixture of 2-methyl-5-nitrobenzoic acid (5 g, 27.6 mmol) and thionyl chloride (16.4 g, 138 mmol) was refluxed overnight. The excess thionyl chloride was removed by vacuum distillation to afford 2-methyl-5-nitro-benzoyl chloride as a solid residue. This material was dissolved in methylene chloride (30 mL) and added dropwise with stirring to a commercial 40% dimethylamine solution (30 g, 270 mmol) maintaining the temperature at 0 to 12° C. After complete addition, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried and concentrated. The residue was purified by column chromatography with n-hexane-ethyl acetate (3:1) to afford amide as a solid (5.46 g, 95%). The identity was verified by 1H NMR
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]([OH:5])=[O:4]>Cl>[CH3:1][C:2]([CH3:23])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(CCC/C=C(/c1ccccc1)c1cccnc1)C(=O)O
Agent: Cl
Product: CC(C)(CCC/C=C(\c1ccccc1)c1cccnc1)C(=O)O
Temperature: 100 °C
Yield: 46 %

Procedure:
(Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (0.1 g) was dissolved in 18% aqueous hydrochloric acid (1 ml) and the solution was heated at 100° C. for 21 hours. Extraction, separation and concentration in the conventional manner gave the crude product. High performance liquid chromatography of this crude product revealed that its E isomer/Z isomer ratio was E/Z=63:28. This crude product (85 mg) was subjected to preparative high performance chromatography to give (E)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (46 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:33])[C:11]([CH3:32])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:31])=[C:18]([CH:27]=[CH:28][C:29]=3[CH3:30])[O:19][CH2:20][C:21]([O:23]C(C)C)=[O:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:33])[C:11]([CH3:32])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:31])=[C:18]([CH:27]=[CH:28][C:29]=3[CH3:30])[O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)O)c2C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of isopropyl 2-[3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (80 mg, 0.17 mmol, 1.0 eq) in a mixture of THF (5 mL) and MeOH (5 mL) was added NaOH (2M aqueous solution, 3 mL, 6.0 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The organic solvent was removed in vacuo and the remaining aqueous solution diluted with water and acidified to pH 4-6 with diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (20 mg, 27%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:12])[C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+].ClCCl>O.CCOC(C)=O.CCCCCC.O1CCOCC1>[Br:12][C:5]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=2)[S:3][CH:4]=1
Reactant: CCCOc1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1c(Br)csc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCOc1ccc(-c2scc(Br)c2CC(=O)OC)cc1
Yield: 57.5 %

Procedure:
Into dioxane (3 mL) was dissolved methyl (2,4-dibromothien-3-yl)acetate (0.355 g, 1.13 mmol) and 4-propoxyphenylboronic acid (0.214 g, 1.19 mmol). K2CO3 (0.195 g, 1.41 mmol) was dissolved in H2O (0.4 mL) and added to the dioxane. The solution was degassed by bubbling argon through the mixture for five minutes. {1,1′-Bis(diphenylphosphino)-ferrocene}dichloropalladium(II) complex with dichloromethane (1:1) (0.027 g, 0.033 mmol) was added and the mixture heated under argon to 50° C. for 4 hours (followed by TLC 15:1 Hexane:EtOAc). The solvents were removed and the mixture partitioned between EtOAc and H2O. The EtOAc layer was dried (MgSO4) and absorbed onto silica gel. The product was purified by flash chromatography (25:1 hexane:EtOAc) to yield methyl [4-bromo-2-(4-propoxyphenyl)thien-3-yl]acetate (0.240 g) as a clear oil. 1H NMR (500 MHz, DMSO-d6) δ: 0.99 (t, 3H, J=7.32 Hz), 1.75 (m, 2H), 3.65 (s, 5H), 3.98 (t, 2H, J=6.6 Hz), 7.05 (d, 2H, J=8.2 Hz), 7.33 (d, 2H, J=8.2 Hz), 7.72 (s, 1H). MS (ES) m/z 369.0 ([M+H]+). MS (ES) m/z 386.0 ([M+NH4]+).
Reaction SMILES: C(OC([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:14][CH2:15][C:16]2([F:20])[F:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:25]([O:24][C:22]([NH:21][C@@:13]12[CH2:14][CH2:15][C:16]([F:20])([F:19])[C@@H:17]1[CH2:18][NH:11][CH2:12]2)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@]12CCC(F)(F)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@]12CCC(F)(F)[C@@H]1CNC2
Yield: 102.5 %

Procedure:
[(1S,5R)-1-tert-Butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3,3,0]octan-3-yl]carboxylic acid benzyl ester (65.0 mg, 0.16 mmol) was dissolved in methanol (10 mL). 10% palladium-carbon (50% wet) (20 mg) was added, and the mixture was stirred in a hydrogen atmosphere for one hour. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure to give 43 mg of the title compound as a colorless solid.
Reaction SMILES: NC1SC=C(CCCCC)N=1.[NH2:12][C:13]1[S:14][C:15]([CH2:21]C)=[C:16]([CH2:18][CH2:19]C)[N:17]=1.NC1SC(C(C)C)=C(C(C)C)N=1.NC1SC(CCC)=CN=1.NC1SC(C(C)C)=CN=1.NC1SC(CCCCC)=CN=1.[C:64]([C:69]([C:77]([O:79][CH2:80][CH3:81])=[O:78])=[CH:70]NC1SC=CN=1)([O:66][CH2:67][CH3:68])=[O:65]>>[C:77]([C:69]([C:64]([O:66][CH2:67][CH3:68])=[O:65])=[CH:70][NH:12][C:13]1[S:14][C:15]([CH3:21])=[C:16]([CH2:18][CH3:19])[N:17]=1)([O:79][CH2:80][CH3:81])=[O:78]
Reactant: CCCc1nc(N)sc1CC
Reactant: CCOC(=O)C(=CNc1nccs1)C(=O)OCC
Agent: CC(C)c1cnc(N)s1
Agent: CC(C)c1nc(N)sc1C(C)C
Agent: CCCCCc1cnc(N)s1
Product: CCOC(=O)C(=CNc1nc(CC)c(C)s1)C(=O)OCC

Procedure:
By the same method, 2-amino-4-pentylthiazole, 2-amino-4-propyl-5-ethylthiazole, 2-amino-4,5-diisopropylthiazole, 2-amino-5-propylthiazole, 2-amino-5-isopropylthiazole, 2-amino-5-pentylthiazole, 2-amino-6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,6,6-trimethylcyclopentenothiazole, and 2-amino-7-methylcyclooctenothiazole are converted to the corresponding 2-(2,2-dicarbethoxyethenylamino) thiazole derivatives.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:22])=[CH:10][C:11](=[O:21])[N:12]3[CH2:15][CH:16]3OCC[O:17]3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[OH-].[Na+]>O.C(OCC)(=O)C>[CH:1]1([O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:22])=[CH:10][C:11](=[O:21])[N:12]3[CH2:15][CH:16]=[O:17])=[CH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(OC3CC3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n(CC=O)c2cc(OC3CC3)ccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 95 mg of 7-(cyclopropoxy)-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one, 1.5 mL of an 80% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 6 hours, and then stood still at room temperature for 14 hours. Thereto were added ethyl acetate and water, and the mixture was neutralized with an aqueous saturated sodium hydrogen carbonate solution and an aqueous sodium hydroxide solution. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 84 mg of a yellow oily substance, (7-(cyclopropoxy)-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH3-]C#N.[Na+]>CO>[CH2:19]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:17][CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(Oc2ccc(CCN)cc2)nc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 6-[4-(2-aminoethyl)phenoxy]nicotinonitrile (2.09 g, 8.75 mmol) in methanol. Add 3 Å molecular sieves and benzaldehyde (0.89 mL, 8.75 mmol). Stir at room temperature for 18 hours. Add NaBH3CN (1.10 g). After the bubbling subsides, filter. Purify by flash chromatography, eluting with 3% (2.0 M NH3 in methanol) in dichloromethane to give the title compound: HRMS calcd for C22H20N3O 330.1620 (M+H)+, found 330.1620, time 0.39 min, MS TOF ES+ 330.2 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=2.4 min, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28][CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:51])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:51])[CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCS(=O)C1

Procedure:
97 mg (0.19 mmol) of the compound of Example 30 is reacted overnight analogously to the synthesis of the compound of Example 6 with 48 mg (0.19 mmol, 70%) of meta-chloroperbenzoic acid. After the crude product is filtered by a Millipore spray filter and the residue is subsequently purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 82 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:45]([NH:47][NH2:48])=O.P(Cl)(Cl)(Cl)=O>C1COCC1.C(#N)C>[CH2:31]([O:30][C:24]1[CH:23]=[C:22]([CH:17]([N:13]2[C:14](=[O:16])[C:15]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12]2)[CH2:18][C:19]2[O:21][CH:45]=[N:47][N:48]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH3:32]
Reactant: NNC=O
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(Cc2nnco2)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC

Procedure:
Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-[1,3,4]oxadiazol-2-yl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by reacting 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (400 mg, 0.9 mmol), CDI (160 mg, 1.0 mmol) and formic hydrazide (0.09 g, 1.5 mmol) in THF (5 mL). The crude was then reacted with phosphorus oxychloride (0.18 mL, 1.9 mmol) in acetonitrile (15 mL). The product was obtained as a white solid (60 mg, 15% yield): mp 181-183° C.; 1H NMR (CDCl3) δ 0.86-0.92 (m, 2H, cyclopropyl CH2), 1.06-1.11 (m, 2H, cyclopropyl CH2), 1.45 (t, J=7.5 Hz, 3H, CH3), 1.58-1.68 (m, 1H, cyclopropyl CH), 3.66 (dd, J=5, 15 Hz, 1H, CHH), 3.85 (dd, J=10, 15 Hz, 1H, CHH), 3.87 (s, 3H, CH3), 4.03-4.11 (m, 3H, OCH2CH3+CHH), 4.43 (d, J=17 Hz, 1H, CHH), 5.86-5.91 (m, 1H, NCH), 6.85-6.90 (m, 2H, Ar), 6.96-7.01 (m, 2H, Ar), 7.43 (t, J=7.5 Hz, 1H, Ar), 8.35 (s, 1H, Ar), 8.41 (d, J=7.5 Hz, 1H, Ar), 10.41 (s, 1H, NH); 13C NMR (CDCl3) , 8.27, 8.29, 14.73, 16.16, 28.04, 46.36, 52.26, 55.98, 64.64, 111.53, 112.36, 116.80, 116.96, 117.80, 119.16, 129.54, 133.43, 138.06, 141.25, 148.84, 149.64, 153.34, 163.79, 169.50, 172.66. Analy. calculated for C25H25N4O5+0.1H2O: C, 64.47; H, 5.69; N, 12.07. Found: C, 64.50; H, 5.70; N, 11.69.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:47][O:48][C:49]([C:51]1([NH2:57])[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1)=[O:50].Cl>O.CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1([NH:57][C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[OH:1])=[O:14])[CH2:52][CH2:53][S:54][CH2:55][CH2:56]1)=[O:50]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)C1(N)CCSCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2O)CCSCC1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of 0.50 g 1-hydroxy-2-naphthoic acid in 5 ml abs. DMF under inert atmosphere 0.18 g 1-hydroxybenzotriazole, 0.71 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.7 ml N,N-diisopropylethylamine were added. After 15 minutes 0.62 g 4-amino-tetrahydro-thiopyran-4-carboxylic acid methyl ester hydrochloride, followed by 0.55 ml N,N-diisopropylethylamine were added. After 16 h at room temperature and 5 h at 60° C. the reaction was poured unto water, adjusted to pH2 with 2 M HCl and extracted with ethyl acetate twice. The combined organic layers were washed with 2M HCl, 2M aqueous sodium carbonate solution and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 0.92 g of 4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-tetrahydro-thiopyran-4-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]([C@H:13]2[C@H:18]([C:19]([CH3:21])=[CH2:20])[CH2:17][CH2:16][C:15]([CH3:22])=[CH:14]2)=[C:10]([OH:12])[CH:11]=1.[Si:24]([O:31][CH2:32][C:33]([OH:35])=[O:34])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]([C@H:13]2[C@H:18]([C:19]([CH3:21])=[CH2:20])[CH2:17][CH2:16][C:15]([CH3:22])=[CH:14]2)=[C:8]([OH:23])[CH:7]=1.[Si:24]([O:31][CH2:32][C:33]([O-:35])=[O:34])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=C(C)[C@@H]1CCC(C)=C[C@H]1c1c(O)cc(CCCCC)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cannabidiol (125.8 mg, 0.4 mmol) and (t-butyldimethylsilyloxy)acetic acid (112.9 mg, 0.51 mmol) in dry dichloromethane (1 mL) was added of 4-dimethylaminopyridine (6.2 mg, 0.03 mmol) followed by N,N′-dicyclohexylcarbodiimide (123.8 mg, 0.6 mmol). The mixture was stirred at ambient temperature for 1 h. Additional amounts of the acid (26.6 mg) and N,N′-dicyclohexylcarbodiimide (31 mg) were added and stirring was continued for 1 h. Mixture was diluted with hexane (2 mL), filtered, and concentrated. The crude product was purified by preparative reverse phase HPLC (C8 column) with acetonitrile-water to afford cannabidiol (t-butyldimethylsilyloxy)acetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.[CH3:25][O:26]C1C=C(C=CC=1)C(CC#N)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:26][CH3:25])[CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: COc1cccc(C(=O)CC#N)c1
Product: COc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
Compound 17 was synthesised following similar procedures outlined in Example 1 (Compound 37), using 3-methoxybenzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile in Step 1.