Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[CH3:16][O:17][C:18]1[CH:19]=[C:20](OB(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=3)[CH:3]=[C:4]2[C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: COc1ccc2cc(Br)cc(C#N)c2c1
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2cc(C#N)c3cc(OC)ccc3c2)c1
Reaction time: 24 h
Yield: 53 %

Procedure:
The compound is prepared by the reaction of 3-bromo-7-methoxy-1-naphthonitrile (1.4 g, 1.76 mmol, 1 eq) with 3-methoxyphenylboric acid (320 mg, 2.11 mmol, 1.2 eq) according to method A in 24 h. Purification by column chromatography with hexane/ethyl acetate 9/1 as the eluent yielded the desired compound in a yield of 53%, 300 mg.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.CC(=O)CC>[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([O:12][C:4]2[CH:3]=[C:2]([I:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cc(I)c2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)C1CCC(Oc2cc(I)c3ccccc3c2)CC1
Temperature: 100 °C
Yield: 72.8 %

Procedure:
A mixture of 4-iodo-naphthalen-2-ol (1.0 g, 3.7 mmol) (See, for example, Australian Journal of Chemistry (1963), 16 401-10. b. Journal of the Chemical Society (1943), 468-9, which is incorporated by reference in its entirety), methanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.8 g, 7.4 mmol) and cesium carbonate (3.6 g, 11 mmol) in tert-butyl alcohol (10 mL) and 2-butanone (7 mL) was heated in a sealed vial at 100° C. for 4 hrs. The mixture was partitioned between water and dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 30% to give light yellow precipitate (1.10 g, yield: 73%). ESI-MS: 409.10 (M+H)+.
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][S:2][C:7]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)cc1SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Sodium thiomethoxide (91 mg; 1.3 mmol; 1.3 equiv) was dissolved in water (0.34 mL). Tetrabutylammonium bromide (48 mg; 0.15 mmol; 0.15 equiv) was added. Methyl 2-nitro-4-trifluoromethylbenzoate (5a; 249 mg; 1.0 mmol) was dissolved in toluene and added to the mixture. The reaction mixture was stirred at ambient temperature for 1 h to completely consume 5a according to gas chromatography (GC) analysis. The reaction mixture was diluted with ethyl acetate and water and the layers were thoroughly mixed and then separated. The organic layer was dried over Na2SO4 and concentrated to afford 0.26 g of 6a which contained a small amount of tetrabutylammonium bromide. The crude product was filtered through a pad of flash silica gel to afford 226 mg (90%) of 6a.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](O)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:8]2[S:4][CH2:3][CH:2]([C:5]([OH:7])=[O:6])[N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccccc1
Reactant: N[C@H](CS)C(=O)O
Product: O=C(O)C1CSC(c2ccccc2)=N1

Procedure:
(S)-Cysteine is reacted with benzoic acid to form 2-phenylthiazoline-4-carboxylic acid. 2-Phenylthiazoline-4-carboxylic acid is amidated with 4-benzyloxazolidone. The amidated 2-phenylthiazoline-4-carboxylic acid is alkylated with methyl iodide in the presence of TiCl4 and lithium diisopropylamide. The alkylated species is hydrolyzed by lithium hydroxide in methanol to obtain (S)-2-methylcysteine methyl ester.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([N:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11])[CH2:16][CH2:17][CH3:18]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCC(N)CO
Product: CCCC(CO)N1C(=O)c2ccccc2C1=O
Yield: 62 %

Procedure:
2-(1-hydroxypentan-2-yl)isoindoline-1,3-dione was prepared in a similar manner to example 9c using isobenzofuran-1,3-dione and 2-aminopentan-1-ol. Yield 62%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([Cl:17])=[O:14])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1nc(Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)COc1nc(Cl)c(Cl)cc1Cl
Temperature: 70 °C
Yield: 98 %

Procedure:
3,5,6-Trichloro-2-pyridyloxyacetic acid (20 g, 0.078 mole was stirred with toluene (46.5 ml). Thionyl chloride (26 ml) was added dropwise to the well-stirred mixture over 15 minutes. The mixture was then heated under reflux (70° C.) for 3 hours. The effluent gases (SO2 +HCl) were absorbed into aqueous 5N sodium hydroxide. The cooled reaction mixture was filtered and evaporated to yield the title compound (20.9 g, 98 percent) as a thick dark brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[F:18])[N:6]=[CH:5]2.[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH3:30])=[CH:29][CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[C:12]([F:18])[CH:13]=1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)c(F)c1
Product: CN(C)c1ccc(C(=O)Nc2ccc3c(cnn3-c3ccc(N)cc3F)c2)cc1

Procedure:
Compound 388 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-amino-2-fluorophenyl)indazole and 4-dimethylaminobenzoate. [M+H]+ calcd for C22H20FN5O: 390.17; found: 389.96.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[OH-].[Na+]>C(O)C.O>[CH3:30][O:29][C:26]1[C:25]([CH3:31])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[C:27]=1[CH3:28]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
18.0 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 400 ml of ethanol and treated while cooling with ice with 15.6 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. Thereafter, a solution of 5.6 g of sodium hydroxide in 150 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 1000 ml of methylene chloride; the solution was washed firstly with 500 ml of 1.5N sodium hydroxide solution and then with 3×500 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 300 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 166°-168°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[C:7](C)=[O:8].[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([CH:7]=[O:8])=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CC(C)=O
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
In a nitrogen atmosphere, 51 g (0.33 mol) of phosphorus oxychloride (manufactured by Wako Pure Chemical Industries, Ltd.) were added dropwise to 88 ml of cooled dimethylformaldehyde (DMF). The dropping rate was adjusted so as to keep a temperature of 2° C. to 4° C. at the time of dropping, and stirring was further continued for 30 minutes at 2° C. after the completion of dropping. To this mixture, a 70-ml dimethylformamide solution of 54.8 g (0.33 mol) of N,N-dimethyl-3-nitroaniline (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added dropwise such that the reaction temperature does not exceed 5° C.; and the mixture was stirred for 2 hours as it was. Thereafter, temperature was gradually raised, and the mixture was stirred at 60° C. for one night. After being cooled to room temperature, the reaction liquid was poured into vigorously stirred 500 ml of ice water. The pH of the mixture was adjusted to about 8 with sodium acetate being added thereto, and the precipitated crystal was filtered out and dried, whereby 50.2 g of a crude product were obtained. This product was recrystallized from acetone/normal hexane, whereby 21 g of the aimed product were obtained (yield: 33%).
Reaction SMILES: [ClH:1].CO[C:4](=O)[C@H:5]([CH2:7][CH2:8][CH2:9][NH2:10])[NH2:6].Cl.[S-:13][C:14]#[N:15].[K+].C(O)C>O>[ClH:1].[NH2:10][CH2:9][CH2:8][CH2:7][C:5]1[NH:6][C:14](=[S:13])[NH:15][CH:4]=1
Reactant: COC(=O)[C@@H](N)CCCN
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NCCCc1c[nH]c(=S)[nH]1
Temperature: 5 °C

Procedure:
To an Erlenmeyer flask was prepared a solution of L-ornithine methyl ester hydrochloride (10.50 g, 47.9 mmol) in water (125 mL) The solution was cooled to 5° C. and pH adjusted to a value of 1.5 with concentrated HCl. While being careful to maintain the above stated temperature and pH, 5% Na(Hg) (250 g) was added slowly to the solution over a time period of 35 min After the addition was complete and bubbling had calmed the Hg was decanted from the solution. The remaining aqueous portion was drained into a separate flask where potassium thiocyanate (14.0 g, 144 mmol) and water (75 mL) was added. The pH of solution was adjusted to a value of 4.30 and the flask was then heated at 95° C. while open to the atmosphere for 1.5 h. After cooling to room temperature, ethanol (75 mL) was added and the reaction was evaporated to dryness. The residue was taken up in methanol and filtered to remove NaCl. After all of the NaCl had been removed the crude residue was purified by column chromatography (CH2Cl2/MeOH sat. with NH3 80:20) to afford the desired compound in its free base form. Addition of concentrated hydrochloric acid to a methanol solution (50 mL) of the free base followed by evaporation to dryness gave 4.51 g (48%) of the title compound 42 as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 11.69 (s, 1H), 7.77 (s, 2H), 6.58 (s, 1H), 2.73 (m, 2H), 2.42 (t, 2H, J=6.6 Hz), 1.76 (tt, 2H, J=7.5, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.23, 128.03, 111.69, 38.08, 25.75, 21.27; HRMS (FAB) calcd for C6H12N3S (MH+) 158.0752, found 158.0743.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[F:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(F)c4)n3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1F
Temperature: 70 °C
Yield: 21.4 %

Procedure:
Sodium hydroxide (8 mg) was added to a solution of ethyl 3-[6-(5-{5-fluoro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D110) (60 mg) in iPrOH (5 mL) and water (5 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-fluoro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E84) (12 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.61 (2H, t), 2.96 (2H, t), 5.47 (1H, m), 7.35 (1H, d), 7.72 (2H, d), 8.11 (1H, t), 8.37 (1H, dd), 8.81 (1H, d), 11.23 (1H, d), 12.11 (1H, br s). MS (ES): C21H19FN4O4 requires 410; found 411.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17]([CH2:30]Br)=[C:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[O:21])[O:19][C:15]=2[CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17]([CH2:30][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[O:21])[O:19][C:15]=2[CH:14]=1
Reactant: COCCN
Reactant: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(Br)ccc2c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCNCc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a solution of 2-methoxyethylamine (118 mg, 1.57 mmol) in THF (6 mL) at 0° C. was added potassium carbonate followed by slow addition of (6-bromo-3-bromomethyl-benzofuran-2-yl)-(2,4-dichlorophenyl)-methanone (660 mg, 1.43 mmol) in several portions. The reaction mixture was stirred at rt for 2 h, and the resulting precipitate was removed by filtration and the filtrate was concentrated. The crude residue was purified by column chromatography (30-50% ethyl acetate in hexanes) giving the desired product (315 mg, 44% yield) as a light yellow viscous oil. 1H-NMR (acetone): δ 8.05 (d, 1H), 7.78 (d, 1H), 7.66 (m, 2H), 7.56 (dd, 1H), 7.50 (dd, 1H), 4.25 (s, 2H), 3.41 (t, 2H), 3.25 (s, 3H), 2.74 (t, 2H). LC-MS RT=2.71 min; [M+H]+=456.0.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][N+:4]([CH2:7][C:8]([NH:10][NH2:11])=[O:9])=[CH:3][CH:2]=1.[Cl-:12].[C:13]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=O)[CH3:14]>CO>[Cl-:12].[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:13](=[N:11][NH:10][C:8]([CH2:7][N+:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[O:9])[CH3:14])[CH:17]=1
Reactant: CC(=O)c1cccnc1
Reactant: NNC(=O)C[n+]1ccccc1
Agent: [Cl-]
Solvent: CO
Product: CC(=NNC(=O)C[n+]1ccccc1)c1cccnc1
Yield: 70.9 %

Procedure:
To 5.63 gm (0.03 mole) of Girard's Reagent P in 50 ml of anhydrous methanol is added 3.63 gm (0.03 mole) of 3-acetylpyridine. The solution is refluxed 3 hr and cooled. The solvent is evaporated The residue is slurried in 100 ml of anhydrous ether and filtered. The crude product is recrystallized from absolute ethanol to afford 6.18 gm (71%) of the title compound; mp 237.2° (decomp).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1>C(Cl)Cl.B(Br)(Br)Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a stirred solution of ethyl 3-(4-methoxyphenyl)isoxazole-5-carboxylate (1 g, 4.04 mmol, prepared according to literature method Tet. Lett 2009, 50(27), 3948-3951) in 8 mL DCM, Boron tribromide 1 M solution in DCM (8.0 mL, 8.08 mmol) was added dropwise at −78° C. After complete addition reaction mixture was allowed to warm slowly and further stirred for 16 hrs at RT. After completion of the reaction, solvent was removed under reduced pressure. The reaction mixture was diluted with ice cold water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate, filtered and concentrated under reduced pressure to get ethyl 3-(4-hydroxyphenyl)isoxazole-5-carboxylate (0.7 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:21][S:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[O:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=2[N:12]=1
Reactant: CSc1ccccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a mixture of N-(2-hydroxy-5-trifluoromethylphenyl)-2-methylsulfanylbenzamide (0.33 g), triphenylphosphine (0.34 g), and THF (7 ml), diethyl azodicarboxylate (40% in toluene) (0.57 g) was added dropwise, and stirred at room temperature for 1.5 hours. Triphenylphosphine (79 mg) and diethyl azodicarboxylate (40% in toluene. 0.13 g) were added to the mixture, and stirred for further 1 hour. The mixture was heated to 50° C., and stirred for 1.5 hours. The reaction mixture was cooled to room temperature, and then the mixture was allowed to stand at room temperature overnight. The reaction mixture was subjected to silica gel column chromatography to give 0.28 g of 2-(2-methylsulfanylphenyl)-5-trifluoromethylbenzoxazole (hereinafter referred to as Present Compound 77).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([NH2:23])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20].Cl.N1C2C(=CC=CC=2)C=CC=1>CNC>[C:19]([C:18]1[C:17](=[O:22])[NH:23][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:9]2)(=[O:20])[CH3:21]
Reactant: CC(=O)C1CC(c2ccncc2)CCC1=O
Reactant: CC(=O)CC(N)=O
Agent: CNC
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: CC(=O)c1c2c(c(C)[nH]c1=O)CC(c1ccncc1)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.8 %

Procedure:
In 40 ml of 50% aqueous solution of dimethylamine was dissolved 20 g of the 2-acetyl-4-(4-pyridyl)-cyclohexanone obtained by the above method (b) under ice cooling, and 30 g of acetoacetamide was added thereto. After stirring at room temperature for 2 days, the reaction mixture was neutralized with 6N hydrochloric acid under ice cooling. After allowed to stand for 1 hour under ice cooling, the resulting mixture was filtered to afford 12 g of crude crystals containing 3-4% of the above-said quinoline compound (IV) which was impurities. The crude crystals were recrystallized with 300 ml of methanol to afford 8 g of purified 4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone. The physical property values were as follows.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].Cl[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1>CC(N(C)C)=O.O>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: N#Cc1ccc(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2cc(N)c(F)cc2Cl)cn1
Temperature: 25 °C

Procedure:
A solution of 5-amino-2-chloro-4-fluorophenol (100 mg, 0.619 mmol) in degassed dimethylacetamide (2 mL) was treated with potassium t-butoxide (83 mg, 0.743 mmol) and 5-chloro-2-cyanopyridine (86 mg, 0.619 mmol). The resultant mixture was heated to 80° C. overnight, then cooled to RT and diluted with water (10 mL). The mixture was extracted with EtOAc (30 mL). The organic phase was washed with water (3×30 mL) and brine (30 mL) dried (Na2SO4) and concentrated in vacuo to provide 5-(5-amino-2-chloro-4-fluorophenoxy)picolinonitrile as a dark oil which was used without further purification. MS (ESI) m/z: 264.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1>CCO>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCC(N)CC1
Solvent: CCO
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 40 °C
Yield: 54.2 %

Procedure:
Chloro-2,4-dinitrobenzene 1 (2.0 g, 9.874 mmol) was dissolved in anhydrous EtOH (40 mL) in a small argon purged flask and warmed in an oil bath to 40° C. Addition of 1-Methyl-piperidin-4-ylamine 50 (1.24 g, 10.862 mmol) occurred dropwise. The solution was heated to reflux in an oil bath for 48 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and ethyl acetate and IM ammonium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with H2O, brine (twice), dried over magnesium sulphate, filtered and then concentrated. Recrystallization of the crude solid from EtOH yielded a yellow solid 51 (2,4-Dinitro-phenyl)-(1-methyl-piperidin-4-yl)-amine Yield: 1.50 grams (54.2%). 1H NMR (DMSO) δ: 1.59-1.75 (m, 2H), 1.86-1.98 (m, 2H), 2.06-2.17 (m, 2H), 2.18 (s, 3H), 2.62-2.77 (m, 2H), 3.71-3.84 (m, 1H), 7.31 (d, 1H, J=9.7), 8.24 (dd, 1H, J=9.7, 2.7), 8.45 (d, 1H, J=7.7), 8.85 (d, 1H, J=2.6); MS (ESI): 281 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)(=[O:23])=[O:22])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccccn2)c1

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (190 mg) and pyridine-2-sulfonyl chloride (231 mg), the title compound was obtained as a pale-red solid (yield 183 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:38])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:17][N:18]=2)[CH2:4][O:3]1.[C:40](#N)[CH3:41].O>>[CH3:39][C:2]1([CH3:1])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@:5]([CH3:38])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[CH:41]=[CH:40][CH:33]=[CH:32][CH:31]=4)=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:17][N:18]=2)[CH2:4][O:3]1
Reactant: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Reactant: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1nnc(-c2ccc(OCCCCc3ccccc3)c(C(F)(F)F)c2)s1
Yield: 75 %

Procedure:
The title compound was prepared analogously to (R)-tert-butyl 2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate (14a) in 75% yield. MS (ESI): 592.14 (MH+), HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) is 3.55 min with gradient 50-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase