Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=N[C:4]2[C:5]3N=CC=C[C:6]=3[CH:11]=[CH:12][C:3]=2C=1.[OH2:15].[C:16]([O:28][CH3:29])(=[O:27])[C:17]1[C:18](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH3:22])=[O:20]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:25]1([C:3]2[CH:12]=[CH:11][CH:6]=[CH:5][CH:4]=2)[CH:26]=[C:17]([C:16]([O:28][CH3:29])=[O:27])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:23]([C:16]([O:28][CH3:29])=[O:15])[C:24]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O
Reactant: COC(=O)c1ccccc1C(=O)OC
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1cc(-c2ccccc2)c(C(=O)OC)c(C(=O)OC)c1C(=O)OC

Procedure:
Into a 300 ml-round bottom flask equipped with a refluxed condenser, a thermometer, a stirrer and a gas-blowing tube were charged 100 ml (119 g.) of dimethyl phthalate, 180 mg. of palladium acetate, 48 mg. of copper acetate monohydrate and 159 mg. of o-phenanthroline monohydrate, and they were heated at 220° C. in an oil bath for 8 hours, while bubbling air at a rate of 300 ml/min under stirring at approx. 500 rpm, to perform dimerization of dimethyl phthalate so as to produce tetramethyl biphenyltetracarboxylate. The liquid reaction mixture contained 85.1 mg. of palladium and 15.2 mg. of copper.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.[OH-].[Li+]>O1CCOCC1.O.CO>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(C)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (5.00 g, 31.6 mmol) in 1:1:1 dioxane/water/MeOH (60 mL) was treated with lithium hydroxide hydrate (5.31 g, 126 mmol) and stirred at RT overnight. The mixture was partially concentrated, diluted with water and EtOAc and acidified to pH=1 with 6M HCl. The layers were separated, the aqueous layer extracted with additional EtOAc (50 mL) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 4-methyltetrahydro-2H-pyran-4-carboxylic acid (4.61 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 3.65 (dt, J=11.8, 4.3 Hz, 2H), 3.33-3.32 (m, 2H), 1.87-1.86 (m, 2H), 1.35 (ddd, J=13.5, 9.9, 4.1 Hz, 2H), 1.13 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:10]([O:13]O)(=[O:12])[CH3:11]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:12])=[CH:6][CH:5]=1)[CH3:2].[CH2:1]([O:3][C:4]1[C:10](=[CH:11][CH:7]=[CH:6][CH:5]=1)[OH:13])[CH3:2]
Reactant: CC(=O)OO
Reactant: CCOc1ccccc1
Product: CCOc1ccc(O)cc1
Product: CCOc1ccccc1O
Reaction time: 2 h

Procedure:
The procedure of Example 18 was followed, except the reaction was carried out for two hours at 60°C using phenyl ethyl ether in place of 4-metyl anisole. Consequently, the conversion of peracetic acid was 65.1%, the conversion of phenyl ethyl ether was 5.97% and there were produced 3.51g of hydroquinone ethyl ether and 1.49g of pyrocatechol monoethyl ether.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH:10]([O-])([O-])OC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][CH:7]1[CH2:6][CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:8]1
Reactant: O=C1CCCNC(=O)C1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1CCCNC(=O)C1
Yield: 63 %

Procedure:
2,4-Dioxohexahydroazepine (4.57 g), methyl orthoformate (8.15 g) and p-toluenesulfonic acid (215 mg) are treated in the same manner as described in Example 1-(1) to give 4-methoxy-2,4,6,7-tetrahydroazepine-2-one (3.24 g, 63.8%) as colorless prisms. m.p. 70°-73° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[CH2:26][O:27][CH2:28][CH2:29][OH:30]>C(#N)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][CH2:28][CH2:29][OH:30])=[C:20]([F:19])[CH:21]=2)=[O:33])[N:7]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(COCCO)c(F)c1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)cc2)n1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(COCCO)c(F)c2)n(-c2ccc(F)cc2)n1
Yield: 73.3 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.247 mmol, 1.0 eq) in acetonitrile (6 mL) was added TEA (0.136 mL, 99 mg, 0.986 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-((2-hydroxyethoxy)methyl)-phenylcarbamate (76 mg, 0.252 mmol, 1.02 eq.) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:2)) to get 1-((3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)urea (83 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]([OH:17])=O)[CH:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:18][C:19]1(C)OC(=O)CC(=O)[O:20]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19](=[O:20])[CH:18]=[C:15]([OH:17])[CH:11]2[CH:12]([CH3:13])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)valine (5.66 g), Meldrum's acid (3.39 g) and 4-(N,N-dimethylamino)pyridine (4.11 g) in tetrahydrofuran (70 mL) was added N,N′-carbonyldiimidazole (4.36 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (70 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-isopropyl ether to give the title compound as colorless crystals (yield: 653 mg, 11%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.Cl.CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)=[CH:38][N:37]=2)=[CH:30][CH:29]=1)(=O)=O>CN(C=O)C>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:35]#[C:34][C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:14]4[CH2:15][CH2:16][CH2:17][CH:13]4[C:12]([O:11][CH3:10])=[O:18])=[CH:33][CH:32]=3)=[N:37][CH:38]=2)=[CH:43][CH:44]=1
Reactant: CS(=O)(=O)OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.15 mL ethyldiisopropylamine and 73 mg (0.44 mmol) proline-methyl ester (used as the hydrochloride) are added to a solution of 171 mg (0.4 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl methanesulphonate in 2 mL DMF and the reaction mixture is stirred for 18 h at RT. The mixture is evaporated down i. vac. and the residue is purified by HPLC.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:29]=[O:30].[Cl-].[NH4+]>C(#N)C.O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:29]=[O:30])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Yield: 15.1 %

Procedure:
To a solution of 1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ol (297 mg, 1.24 mmol) from step 2 in anhydrous acetonitrile (6 mL) was added magnesium chloride (177 mg, 1.86 mmol), triethylamine (650 μl, 4.65 mmol) and paraformaldehyde (251 mg, 8.38 mmol). The reaction mixture was reflux for a half hour. Added some water and saturated aqueous ammonium chloride until pH=7. Extracted it with ether several times. The organic layer was combined, dried over magnesium sulfate, and filtrated. The solution was evaporated under vacuum. The crude residue was purified by prep TLC eluting with 25% ethyl acetate-hexane and providing 50 mg (15%) of the title compound. 1H-NMR (CDCl3) δ 11.4 (s, 1H), 9.38 (s, 1H), 7.30-7.20 (m, 3H), 7.14-7.10 (m, 2H), 6.94 (s, 1H), 5.93 (s, 1H), 4.48 (s, 2H), 3.36 (t, J=5.5 Hz, 2H), 2.68 (t, J=6.2 Hz, 2H); MS LC-MS (MH+=268.5), LC MS RT: 3.24 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH3:11][I:12]>CC(C)=O>[IH:12].[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([S:7][CH3:11])=[NH:8])=[CH:4][CH:3]=1
Reactant: CI
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: CC(C)=O
Product: CSC(=N)c1ccc(Cl)cc1
Product: I
Reaction time: 2 h

Procedure:
A 17.16 g portion of 4-chlorothiobenzamide was dissolved in 80 ml of acetone and 15.14 g of methyl iodide was added. The mixture was stirred for 2 hours and then the solid was collected, washed with acetone and dried, giving 21.3 g of 4-chlorobenzenecarboximidothioic acid, methyl ester, hydroiodide.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:24])C=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[OH:24][CH2:3][CH:2]1[CH2:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[CH:13][C:14]=2[O:15]1
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of ethyl 3-allyl-4-hydroxybenzoate (6.74 g, 32.7 mmol) in chloroform (105 ml) was added with meta-chloroperbenzoic acid (11.40 g, 66.1 mmol) and the mixture was refluxed under stirring for 4 h. Afterwards, the solvent was evaporated, the crude was redissolved in ethyl acetate and washed with a 1M NaOH solution. After drying and removing the solvent, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 90:10, to recover 5.95 g of the title compound (82% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=2)=[C:7]([O:19][CH3:20])[CH:6]=1.[Na+].[I-].C(N(C(C)C)CC)(C)C.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1>C1COCC1.CN(C=O)C>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([CH2:4][CH2:3][CH2:2][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)=[CH:6][C:7]=2[O:19][CH3:20])[N:11]=1
Reactant: c1nc[nH]n1
Reactant: COc1cc(CCCCl)ccc1Oc1cccc(F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(CCCn2cncn2)ccc1Oc1cccc(F)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of 2-[4-(3-chloropropyl)-2-methoxyphenoxy]-6-fluoropyridine (0.14 mmol) in a THF/DMF mixture (340 μL/170 μL), under argon, was added NaI (0.14 mmol; 21 mg). The mixture was stirred 30 minutes at 50° C., before addition of diisopropylethylamine (0.28 mmol, 36 mg) and 1,2,4-triazol (0.28 mmol; 19 mg). The reaction mixture was allowed to stir overnight at 50° C. After concentration, the reaction was hydrolysed with saturated NH4Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (15 mg; 33%) was obtained as a yellow oil after purification on preparative TLC (dichloromethane/methanol: 9/1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([N:10]4[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:28]=2)[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: C[C@@H](COC1CCN(c2nc3cc(O)ccc3o2)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3cc(OCC4CC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(5-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (345 mg) in DMF (5 mL) were added potassium carbonate (366 mg) and (bromomethyl)cyclopropane (0.171 mL), and the mixture was stirred with heating at 60° C. for 1.5 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (375 mg).
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH:20]([N-]C(C)C)(C)C.[Li+].CI.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:20][CH:6]1[C:5](=[O:9])[N:4]2[CH:7]1[CH2:8][C:2]([Cl:1])=[C:3]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12

Procedure:
A solution of benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (56 mg) in anhydrous THF (0.5 ml) is added dropwise over a few minutes to a stirring solution of lithium diisopropylamide (from 31 μl diisopropylamine and 140 μl 1.6N BuLi) in anhydrous THF (3 ml) at -78°. After 15 more mins at -78°, the solution is treated with methyliodide (125 μl) and then allowed to warm to -20° over a period of 30 mins. Saturated aqueous NH4Cl (3 ml) is added and the mixture is allowed to come to room temperature. The mixture is diluted with EtOAc (50 ml), washed with pH 3 phosphate buffer, water, 5% NaHCO3, and brine, dried with magnesium sulfate, and evaporated in vacuo to give benzyl 6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(S(C1C=C(C2C=C(CN(C)C)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN3CCOCC3)cc3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 133 and morpholine according to the procedure outline for the preparation of Compound 134. 1H NMR (400 MHz, CD3OD) δ 8.42 (br s, 1H), 8.24 (s, 1H), 8.14 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6 Hz), 7.97 (s, 1H), 7.90 (t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.48 (s, 1H), 4.62 (s, 2H), 4.00-4.09 (m, 2H), 3.71-3.80 (m, 2H), 3.41-3.50 (m, 2H), 3.27-3.32 (m, 4H), 2.39 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C25H27N3O3S, 450; found 450.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]([C:20]([O:22]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)[CH:2]=1.[C:28]1([C:34]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[S:36][N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:28]1([C:34]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][N:42]([C:20]([NH:11][C:3]4[CH:2]=[N:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:22])[CH2:41][CH2:40]3)[S:36][N:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1cnc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cnc2ccccc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixed solution of bis(2,2,2-trichloroethyl) quinolin-3-ylimidodicarbonate (301.4 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.106 ml, 0.610 mmol) in dimethyl sulfoxide (2 ml) was stirred at 70° C. for 5 hours and then stirred at 80° C. for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was poured to the residue, and 110 mg (43.2%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C>O1CCCC1>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Clc1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccnc1Br
Temperature: -70 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2-bromo-4-chloropyridine (1.6 g, 8.0 mmol) in anhydrous tetrahydrofuran (40 mL) cooled at −70° C. was added the solution of lithium diisopropyl-amide (5.0 mL, 10.0 mmol, 2.0 M) over a period of 5 minutes and stirred at −70° C. for another 1 h. Anhydrous DMF (1.3 g) was introduced over a period of 3 minutes and the mixture was stirred for another 30 minutes. It was then quenched with saturated NH4Cl (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (20:1) to afford 103a as a yellow solid (900 mg, 48%). 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 7.79 (d, J=5.0 Hz, 1H).
Reaction SMILES: [Cl:1][CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[CH3:14][C:15]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>[I-].[K+].C(O)(C)C>[ClH:1].[ClH:1].[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[NH:4][CH2:3][CH:2]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:15]=1[CH3:14])[CH3:13]
Reactant: Cc1cccc(N)c1C
Reactant: Cc1cccc(C)c1NCC(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc(NC(C)CNc2c(C)cccc2C)c1C
Product: Cl
Reaction time: 3 h
Yield: 113.3 %

Procedure:
A mixture of 29.5 g (0.15 moles) of N-(β-chloropropyl)-2,6-dimethyl-aniline, prepared as described in Example 3, Method (b), point (a), 37.2 ml (36.3 g, 0.3 moles) of 2,3-dimethylaniline and 0.5 g (3 mmoles) of potassium iodide is stirred at 100° to 105° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool, admixed with 30 ml of isopropanol, the separated precipitate is filtered off, washed with cold isopropanol and dried. In this way 14.25 g (30.2%) of 2,3-dimethylaniline hydrochloride are separated. The filtrate is admixed with 200 ml of water, the mixture is acidified with 20% aqueous hydrochloric acid, the separated precipitate is filtered off, washed with water and dried. 30.2 g (56.7%) of 1-(2',6'-dimethylphenyl-amino)-2-(2',3'-dimethylphenyl-amino)-propane dihydrochloride are obtained. This salt is treated as described in Example 3, Method (b) point (c) to obtain the free base. The base is isolated by extracting the mixture with chloroform. The resulting substance is an oil at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][N:27]2[CH2:32][CH2:31][S:30][CH2:29][CH2:28]2)[CH:6]=[CH:5][C:4]=1[C:33]1[NH:37][C:36](=[O:38])[O:35][N:34]=1.Cl.C[OH:41]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:41])[CH2:29][CH2:28]2)[CH:6]=[CH:5][C:4]=1[C:33]1[NH:37][C:36](=[O:38])[O:35][N:34]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCSCC2)ccc1-c1noc(=O)[nH]1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCS(=O)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 80 mg of 3-{2-methoxy-4-[4-thiomorpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1 mL of methanol was added 2 mL of a 2N solution of hydrochloric acid in diethylether. The resulting mixture was concentrated under reduced pressure. To a solution of the residue in 1 mL of acetonitrile were added 1 mL of water and 88 mg of Oxone®. The resulting mixture was stirred at room temperature for 1 h, then poured into water and extracted with dichloromethane. The organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of methanol in dichloromethane) to give 10.5 mg of 3-{2-methoxy-4-[4-(1-oxo-1λ4-thiomorpholin-4-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one as white solid.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[O:21]([C:28]1[CH:36]=[CH:35][C:31](C(Cl)=O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:37]([N:39]1[C:51]2[CH:50]=[CH:49][C:48]([NH2:52])=[CH:47][C:46]=2[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:38]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[C:31]2[CH:30]=[CH:29][C:28]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:36][CH:35]=2)[C@H:8]([C:18]([NH:52][C:48]2[CH:49]=[CH:50][C:51]3[N:39]([CH2:37][CH3:38])[C:40]4[C:45]([C:46]=3[CH:47]=2)=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(Oc3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=573.4.