Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[NH2:24].C1(C)C=CC=CC=1>O>[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[N:24]=[CH:10][C:7]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1cccs1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ncc(C=N[C@@H](Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 8 h

Procedure:
A solution of 2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-carboxaldehyde (0.6 g, 2.12 mmol), β-(2-thienyl)alanine methyl ester (0.4 g, 2.16 mmol) and toluene (25 ml) was refluxed under argon with a Dean-Stark water separator for 8 hours. The solvent was evaporated to an orange-red oil (1.1 g) of the title imine whose NMR was consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14]O)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:40])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][F:40])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCO)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCF)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
50 mg (0.10 mmol) of 2-[3-(4-chlorophenyl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 396 are dissolved in 1.5 ml of dichloromethane and treated at −10° C. with 20.5 μl (0.155 mmol) of diethylaminosulphur trifluoride. This is warmed to RT within 1 hr. Next, the reaction solution is treated with 5 ml of water and extracted twice with 5 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 37 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH3:35][C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1>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>[CH3:35][C:36]1[CH:41]=[C:40]([C:2]2[NH:3][N:4]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]3[C:10]=2[CH2:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=3)[CH:39]=[CH:38][N:37]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CCOC(=O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=CC=C2C(=C(c3ccnc(C)c3)NN2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 85 %

Procedure:
ethyl 3-bromo-1-trityl-1H-indazole-5-carboxylate (510 mg, 1.0 mol) was added to a vial containing 2-methylpyridin-4-ylboronic acid (128 mg, 1.04 mol) and tetrakis(triphenylphosphine)palladium (140 mg, 0.104 mol). After purging the vial with nitrogen gas, dioxane (5 mL) and 2M sodium carbonate (5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for overnight. Upon completion, the mixture was concentrated under vacuo. The mixture was extracted using ethyl acetate (3×100 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting mixture was purified using flash chromatography to give the desired compound in 85% yield.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7](Br)[CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4].C([O-])(=O)C.[Na+]>C(O)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4]
Reactant: Cc1cc(Br)c(Cl)c(Cl)c1N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(Cl)c(Cl)c1N
Yield: 89.1 %

Procedure:
A slurry of 6.50 g (25.5 mmol) of 2,3-dichloro-4-bromo-6-methylaniline and 8.37 g (102 mmol) of sodium acetate in 120 ml of acetic acid-ethanol (1:1, v/v) was treated with 0.55 g of 5% palladium on carbon. The mixture was hydrogenated in a Parr hydrogenation apparatus at an initial pressure of 50 psi for 10 minutes. The reaction mixture was filtered, and the filtrate was concentrated by evaporation at reduced pressure. The residue was partitioned between ether and water, and the organic layer was washed with 5% aqueous sodium hydroxide, dried and evaporated at reduced pressure. The residue was purified by Kugelrohr distillation to afford 4.00 g (89%) of the desired product as a colorless oil, b.p. 60°-70° C. (0.15 mm). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: OO.C(O)C.[CH2:6]([O:8][C:9](=[O:27])/[CH:10]=[C:11](\[CH3:26])/[CH2:12][CH2:13][S:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17][N:16]=1)C>C(OCC)(=O)C>[CH3:6][O:8][C:9](=[O:27])/[CH:10]=[C:11](\[CH3:26])/[CH2:12][CH2:13][S:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17][N:16]=1
Reactant: CCOC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Reaction time: 12 h
Yield: 99.4 %

Procedure:
About 30% hydrogen peroxide solution (47.4 ml, 418.0 mmol) solution of hexaammonium heptamolybdate tetrahydrate (542 mg, 0.44 mmol) was added to an ethanol (200 ml) solution of ethyl-(2E)-3-methyl-5-[(1-phenyl-1-H-tetrazol-5-yl)thio]pent-2-enoate (13.31 g, 41.80 mmol) at room temperature. After stirred for at the same temperature for 12 hours, the reaction solution was diluted with ethyl acetate and washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=4:1) to obtain the title compound (12.65 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=3[CH:7]=[N:8]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (2.0 g, 7.4 mmol) in water (20 mL) and methanol (20 mL) was added a solution of 2 N sodium hydroxide (10 mL). The solution was warmed at reflux for 1 hour. The solution was cooled to room temperature and acidified with 1 N aqueous HCl (pH=3-4). The white solid was obtained by filtration, washed with MeOH (30 mL) and dried to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][C:34]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6](=[O:7])[N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCCCN(CCCC)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CCCCN(CCCC)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
In a manner analogous to that described in Example 1, from 3-dibutylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and cyclohexylisocyanate, there is obtained 1-cyclohexyl-3-[(3-dibutylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 118°-120° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with dibutylcarbamoyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](O)=O)=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:18]1[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][N:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 155 °C
Yield: 45.8 %

Procedure:
A mixture of 1,2-diaminobenzene (108 mg), indazole-3-carboxylic acid (118 mg) and polyphosphoric acid (1 mL) was heated at 150-160° C. for 24 hours. The mixture was cooled, then diluted with ice water (10 mL) and then treated with ethyl acetate (10 mL). The aqueous layer was basified by addition of solid potassium carbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phases were dried and then evaporated. The residue was subjected to chromatography on silica eluting with a mixture of heptane and ethyl acetate to give 3-(1H-benzoimidazol-2-yl)-1H-indazole (78 mg). LC-MS (METHOD A): RT=1.28 minutes; 235 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[N+:52]([O-:55])([OH:54])=[O:53]>C(Cl)(Cl)Cl.C(#N)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[N+:52]([O-:55])([O-:54])=[O:53]
Reactant: O=[N+]([O-])O
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared starting from an erythromycin solution (2 g, 2.72 mmoles) dissolved in a mixture of chloroform (30 ml)/acetonitrile (20 ml), by adding a 65% nitric acid solution (0.200 ml) in acetonitrile (5 ml), following then the procedure described in Example 5. Erythromycin nitrate as amorphous solid is obtained. Yield 83%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(Br)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 37.6 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.15 mmol), 3-tributylstannanyl-pyridine (0.072 mL, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 30 mg of the title compound. MS: (+) m/z 532.37 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)cc(C(F)(F)F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-fluoro-5-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl.[Pd](Cl)Cl.CN(C=O)C>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=1
Reactant: O=C(O)c1ccc(Cl)c(Br)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
Under nitrogen atmosphere, 6-bromo-5-chloro-pyridine-2-carboxylic acid (0.38 g, 1.6 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.33 g, 2.1 mmol), 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II) dichloride methylene chloride complex (CAN 95464-05-4, 30 mg) and cesium carbonate (CAN 534-17-8, 1.6 g, 4.8 mmol) was added into DMF (30 mL). The mixture was stirred at 80° C. overnight. After evaporation of solvents, the crude product was purified by column chromatography (silica gel, 12 g, petroleum ether/ethyl acetate 4/1 firstly, then methanol/methylene chloride 1/10) to give the title compound (0.14 g, 32%) as brown solid; MS (EI): m/e=268.0 [M+H]+.
Reaction SMILES: C(O)C.[F:4][C:5]([F:19])([F:18])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:13][O:14][C:15](=[O:17])[N:16]=2)[CH:7]=1.[CH:20]([CH:22]=[CH2:23])=[O:21]>C(N(CC)CC)C>[F:19][C:5]([F:4])([F:18])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:16]([CH2:23][CH2:22][CH:20]=[O:21])[C:15](=[O:17])[O:14][N:13]=2)[CH:7]=1
Reactant: C=CC=O
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=CCCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To 1 ml of ethanol were added 0.12 g of triethylamine, 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.05 g of acrolein, the mixture was stirred at room temperature for 18 hours, and concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-[3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]propionaldehyde (present compound (22)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[S:37][CH:36]=[C:35](B(O)O)[CH:34]=1)=[O:32])[CH3:29].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH2:28]([O:30][C:31]([C:33]1[S:37][CH:36]=[C:35]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:4][CH:3]=2)[CH:34]=1)=[O:32])[CH3:29]
Reactant: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)=N/O)ccn1
Reactant: CCOC(=O)c1cc(B(O)O)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(C(C/C(=N\O)c3ccnc(C)c3)c3ccc(Cl)cc3F)cc2)cs1
Temperature: 100 °C

Procedure:
In analogy to example 74, step 6, (E)-3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one oxime (example 147, step 5) was reacted with 5-(ethoxycarbonyl)thiophen-3-ylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution under heating by microwave irradiation to 100° C. for 30 min providing the title compound as an off-white solid, MS (ESI+): m/z=523.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[H-].[Na+]>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: N#Cc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2ccc(F)cn2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 2-bromo-5-fluoropyridine (5 g, 28.4 mmol) and 4-(hydroxymethyl)-benzonitrile (5.67 g, 42.4 mmol) was added sodium hydride (1.7 g, 42.4 mmol, 60% in oil) at room temperature. The mixture was stirred for 3 hours at 70° C. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1-ethyl acetate) to obtain the title compound (5.5 g, 85%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:18])[CH3:19])[CH:12]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1cccc(NCc2ccc(N(C)C)cc2)c1
Product: CC(C)c1cccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)c1
Yield: 22.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](3-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.83 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(3-isopropylphenyl)urea (0.40 g) was obtained.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6](=O)[C:7]1C=CC=[C:9]([CH:10]=[O:11])[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C:2]1[CH:1]=[C:9]([CH:8]=[CH:7][CH:6]=1)[CH:10]=[O:11])=[CH2:4]
Reactant: [Li]CCCC
Reactant: O=Cc1cccc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (27.2 g) in THF (200 mL) at 0° was added dropwise n-butyllithium (47 mL of 1.6M in hexane). The reaction mixture was stirred 30 min at 0° and cooled to -10°. The reaction mixture at -10° was transferred dropwise through a canula to a solution of isophthalaldehyde (10.0 g) in THF (300 mL) at -50°. The reaction was allowed to warm up to room temperature. After 3.5 hours at room temperature the reaction mixture was quenched with NH4OAc buffer (200 mL). The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate and evaporated. Flash chromatography of the residue starting with 10% and finishing with 15% of diethyl ether in hexane afforded the title compound.