Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([O:10]C)=O)[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.C1(C)C(C)=CC=CC=1>CO>[F:26][C:22]1[N:21]=[C:20]([NH:19][C:8]([CH:7]2[C:6](=[O:12])[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[S:3](=[O:18])(=[O:17])[N:2]2[CH3:1])=[O:10])[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(F)n1
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cccc(F)n2)C(=O)c2ccccc2S1(=O)=O
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A mixture consisting of 7.68 g (0.0285 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 4.8 g (0.0428 mole) of 2-amino-6-fluoropyridine, and 29 ml of xylene was refluxed for 17 hours, during which the methanol formed by this reaction was continuously distilled off. After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration. The filtrate was concentrated and then cooled to obtain an additional precipitate, which was combined with the previously obtained precipitate and washed with hot chloroform. Thus, 7.2 g of crystals having a melting point of 246°-248° C. (decomp.) were obtained in a 72.3% yield.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C:12]1[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)n1nc2c(c1-c1ccc(Cl)cc1Cl)CCNCC2
Yield: 21.2 %

Procedure:
The title compound (37 mg) was prepared according to Example 189 using 230 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 308 mg of 2,4-dichlorophenylboronic acid. MS (ESI): exact mass calculated for C16H19Cl2N3, 323.10; found, m/z 324.4 [M+H]+, 326.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.73-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.37-7.35 (m, 1H), 4.65 (br s, 1H), 4.11-4.05 (m, 1H), 3.43-3.40 (m, 2H), 3.29-3.16 (m, 3H), 2.70-2.63 (m, 2H), 1.39-1.32 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH:6]=[C:5]2O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:6]=1
Reactant: COc1ccccc1-c1cc(O)c2cc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccccc1-c1cc(Cl)c2cc(Cl)ccc2n1

Procedure:
Prepared according to procedure S using 6-chloro-2-(2-methoxyphenyl)quinolin-4-ol (550.6 mg, 1.93 mmol) and POCl3 (3.5 mL, 37.5 mmol) to afford 4,6-dichloro-2-(2-methoxyphenyl)quinoline. Mass Spectrum (ESI) m/e=304.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:31][CH2:30][CH2:29][OH:33])=[CH:4][N:3]=1
Reactant: C#CCCO
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(I)cnc(N)c34)cc2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(C#CCCO)cnc(N)c34)cc2)c1
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A suspension of Example 144A (0.227 g, 0.45 mmol) in piperidine (3 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes, treated with 3-butyn-1-ol (0.069 mL, 0.91 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), and CuI (5 mg, 0.023 mmol), then heated to 80° C. in a sealed tube for 30 minutes. The resulting homogeneous solution was cooled to room temperature and concentrated under a stream of nitrogen. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 164 mg (81%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.65 (t, J=6.78 Hz, 2H), 3.63 (q, J=6.73 Hz, 2H), 4.92 (t, J=5.59 Hz, 1H), 5.70 (s, 2H), 6.81 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25-7.28 (m, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.49 (s, 1H), 7.60 (d, J=8.48 Hz, 2H), 7.93 (s, 1H), 8.65 (s, 1H), 8.85 (s, 1H); MS (ESI(+)) m/e 443 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C.CO>[ClH:43].[ClH:43].[ClH:43].[ClH:43].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.62 g of 1-[2-(4-Fluorophenyl)-2-(4-t-butoxycarbonylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyl)piperazine was dissolved in a mixture of 3 ml of ethyl acetate and 3 ml of methanol, and 4 ml of 4M hydrogen chloride/ethyl acetate solution was added, followed by stirring at room temperature for 6 hours. The precipitated crystals were collected by filtration, and the crystals were washed with ethyl acetate to give 0.42 g of 1-[2-(4-fluorophenyl)-2-piperazinoethyl]-4-(4-naphthalen-1-yl-butyl)piperazine tetrahydrochloride as an oil.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=1[F:17].ClCl>>[NH2:3][C:4]1[C:5]([F:17])=[CH:6][C:7]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:14])[CH3:15])=[CH:8][C:9]=1[Cl:1]
Reactant: Cl
Reactant: CC(C)NCC(O)c1ccc(N)c(F)c1
Agent: ClCl
Product: CC(C)NCC(O)c1cc(F)c(N)c(Cl)c1

Procedure:
m.p. of the hydrochloride: 152°-154° C. (decomp.), was prepared from 1-(4'-amino-3'-fluoro-phenyl)-2-isopropylamino-ethanol hydrochloride and chlorine analogous to Example 98.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=2)=[C:4](F)[CH:3]=1.[H-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=3)[C:14](=[O:15])[N:16]([CH3:17])[C:4]=2[CH:3]=1
Reactant: CNC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-N,6-dimethylnicotinamide (520 mg, 1.86 mmol) in tetrahydrofuran (20 mL) at 0° C. was added NaH (224 mg, 5.60 mmol). The reaction mixture was brought to room temperature gradually and stirred at room temperature for 15 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford 8-chloro-2,6 dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (480 mg, 1.51 mmol, 81% yield) as a brick-red solid. LC/MS (ESI) m/e 259.0 [(M+H)+, calcd for C14H12ClN2O 259.05]; LC/MS retention time (method C): tR=1.91 min. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.41 (s, 1H), 8.48 (d, J=8.59 Hz, 1H), 8.23 (s, 1H), 7.69 (d, J=1.98 Hz, 1H), 7.44 (dd, J=8.64, 1.94 Hz, 1H), 3.78 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[NH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38].[H-].[Na+]>CCN(CC)CC>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:33]3[C:34](=[O:37])[CH2:35][CH2:36][NH:31][C:32]3=[O:38])=[CH:22][CH:23]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: O=C1CCNC(=O)N1
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)CCNC2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 55 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of dihydropyrimidine-2,4-dione, and 63 mg of NaH, 28.4 mg of the product was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH2:11][CH2:10][C:9](=[O:16])[O:8][C:7]=1[CH:6]=[CH:5]2.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:23][C:22]([O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH2:11][CH2:10][C:9](=[O:16])[O:8][C:7]=1[CH:6]=[CH:5]2)([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCc2c(ccc3cc(O)ccc23)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc2c3c(ccc2c1)OC(=O)CC3
Temperature: 60 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
A mixture of 2.18 g (10.2 mmol) of 1,2-dihydro-8-hydroxy-3H-naphtho[2,1-b]pyran-3-one from the preceding example, 4.84 g (24.8 mmol) of t-butyl bromoacetate, 5.63 g (40.7 mmol) of anhydrous granular potassium carbonate and 55.5 mL of 2-butanone was heated at 60° C. for 24 hr. A second portion of t-butyl bromoacetate (0.5 mL, 3.1 mmol) was added and the reaction was allowed to proceed for another 17 hr. After being cooled to room temperature, the mixture was filtered and the solids were washed with ethyl acetate and ether. The filtrate and washes were combined and concentrated in vacuo, and the crude product was flash chromatographed on 360 g of silica gel, eluting with hexane-ethyl acetate (7:1 then 6:1) affording 3.04 g (91.0%) of the title compound as a white solid, mp 95°-96° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 70.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (518 mg, 1.30 mmol, 71%) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[C:18]([O:20]CC)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:23])[C:18]([OH:20])=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Yield: 50.8 %

Procedure:
To a stirred solution of ethyl 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetate (0.067 g, 0.21 mmol) in THF (3.0 mL) was added a solution of lithium hydroxide (0.025 g, 1.04 mmol) in water (2.0 mL) at room temperature. After 1 h the reaction mixture was extracted with ethyl acetate (1×5.0 mL) and the aqueous solution acidified with 1 M hydrochloric acid to pH 6. The aqueous layer was extracted with 3:1 chloroform/2-propanol (2×10.0 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure providing 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (0.031 g, 51%) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)[CH:12]=1)CCC.[C:22](N1CCC(Cl)=C(C2C=C(CCCC)ON=2)C1)(=[O:29])C1C=CC=CC=1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:22][O:29][CH2:7][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)[CH:12]=1
Reactant: CCCCc1cc(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)no1
Reactant: CCCCc1cc(C2=CCCNC2)no1
Agent: O=C(O)C(=O)O
Product: COCc1cc(C2=CCCNC2)no1

Procedure:
3-(5-Butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate starting from 1-benzoyl-4-chloro-3-(5-butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine. M.p. 188°-91° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(Cl)cc3)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 4-chlorobenzoyl chloride (11 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[CH2:1]([CH2:8][NH:9][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCOCC1
Product: c1ccc(CCNC2CCOCC2)cc1

Procedure:
The title compound was prepared according to Preparation 85 from N-benzylmethylamine and tetrahydro-4H-pyran-4-one. Purification of the crude material by chromatography using dichloromethane/methanol (98:2) as the eluent gave the title compound as a yellow oil. δH (CD3OD): 7.50-7.40 (5H, m), 4.08 (2H, m), 4.06-(2H, s), 3.49-3.40 (2H, ddd), 3.23-3.14 (1H, m), 2.51 (3H, s), 2.03-1.97 (2H, m), 1.89-1.76 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1.[H-].[Na+].P(O)(O)([O-])=O.[Na+].C(Cl)Cl.O1C[CH2:30][CH2:29][CH2:28]1>>[O:1]=[C:2]1[N:6]([CH2:30][C:29]#[CH:28])[C:5]([C:7]([F:8])([F:9])[F:10])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)F
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCn1c(C(F)(F)F)c(C(=O)OCC)sc1=O

Procedure:
6.9 g of ethyl 2,3-dihydro-2-oxo-4-trifluoromethyl-5-thiazole-carboxylate [prepared by the process of CA 92 110 998P] were dissolved in 70 ml of tetrahydrofuran at 0° ± 5° C. and then, 1.44 g of 50% sodium hydride in oil were added. Once the gaseous evolution ended, 15 ml of 2-bromopropyne were added and the mixture was refluxed for 48 hours. The mixture was poured on to an iced solution of monosodium phosphate and extraction was carried out with methylene chloride, then drying, filtering and concentrating under reduced pressure. The residue was chromatographed and elution with a hexane-ethyl acetate mixture (85-15) yielded 5.57 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:36])[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([CH2:32][C:33]([OH:35])=[O:34])[CH:25]=1)[CH2:11][CH3:12]>CCO.[Pd]>[CH2:11]([N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([CH2:32][C:33]([OH:35])=[O:34])[CH:25]=1)[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:36])[CH3:12]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)Nc1ccccc1Br
Agent: [Pd]
Solvent: CCO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of {2′-[3-(2-bromo-phenyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (0.072 g, 0.13 mmol) in EtOH was added 10% palladium on carbon (0.020 g), and the reaction was stirred under H2 using a Parr apparatus overnight. The mixture was filtered through a pad of Celite and concentrated, and the residue was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were dried and concentrated, and the crude material was purified by silica gel chromatography (20-60% EtOAc in hexanes) to give the title compound. M+H is 487.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([N+:14]([O-])=O)=[CH:6][N:5]=1)[CH3:2].O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CC(=O)OCC>[CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]([NH2:14])=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12])[CH3:2]
Reactant: CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ncc(N)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a mixture of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.508 mmol) in EA (10 mL) was added tin(II) chloride dihydrate (459 mg, 2.033 mmol). The mixture was stirred at 50° C. for 16 h. Then the solution was distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=4:1, Rf=0.6) to yield a light yellow oil of 6-ethoxy-5-(trifluoromethyl)pyridin-3-amine (80 mg, 0.310 mmol, 61.1% yield): 1H NMR (400 MHz, CD3OD) δ 6.27 (d, J=2.5 Hz, 1H), 5.86 (d, J=3.0 Hz, 1H), 2.81 (m, 2H), 0.17 (t, J=7.0 Hz, 3H); ES-LCMS m/z 207.1 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[C:10]([OH:29])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>O>[CH2:30]([N:32]([CH2:33][CH3:34])[C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:31]
Reactant: CCNCC
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
In a nitrogen atmosphere, oxalyl chloride (0.46 mL, 5.4 mmol) was dropped into an absolute methylene chloride solution (8.5 mL) of oleic acid (503 mg, 1.8 mmol) under ice cooling. The solution was then stirred at room temperature for four hours. Thereafter it was concentrated under reduced pressure. Diethylamine (1.0 mL, 9.7 mmol) was added to the resultant residue, which was then stirred at room temperature for 0.5 hour. Water was then added, and extraction was performed with ethyl acetate. The organic layer thus obtained was washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The crude extract thus obtained was purified using column chromatography (n-hexane:ethyl acetate=1:2). Thus (Z)-N,N-diethyl-9-octadecenamide (495 mg, 82%) was obtained as a colorless oily matter.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:36].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:7]([C:16]([NH2:17])=[O:36])=[C:8]([CH:10]([OH:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.34 g of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide. 0.30 g of the title compound was obtained as a powder, melting at 157°-160° C.
Reaction SMILES: [OH:1][C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][O:3]1.[CH3:23]O>>[CH3:23][O:1][C:2]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][O:3]1
Reactant: O=C(O)c1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Reactant: CO
Product: COC1(c2ccccc2)OC=C(c2ccc(C(=O)O)cc2)C1=O
Reaction time: 17 h
Yield: 91.6 %

Procedure:
A solution of 1.50 g of 2-hydroxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone in 100 ml of methanol was heated under reflux with stirring for 17 hrs. The reaction mixture was concentrated to a volume of 20 ml, seeded with the product and the precipitate was collected after standing at 0° C for 3 days. The precipitate was collected, washed with cold methanol and ether and dried at 0° C for 4 hrs. to give 1.42 g (91.6%) of 2-methoxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone as colorless crystals, m.p. 212°-214° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[N+:11]([O-])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C)[C:22](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([N:21]([CH3:22])[CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: COC(=O)c1c(OCc2ccccc2)ccc[n+]1[O-]
Solvent: ClCCl
Product: COC(=O)c1nc(N(C)C)ccc1OCc1ccccc1

Procedure:
15 g (58 mmol) of methyl 3-benzyloxypicolinate-N-oxide, 6.7 g (67 mmol) of trimethylsilylnitrile and 8.3 g (61 mmol) of N,N-dimethylcarbamoyl chloride were added to 100 ml of dichloromethane, and the mixture was allowed to stand at room temperature while stirring. The organic layer obtained was washed with water, dried and concentrated, and the residue thus obtained was purified by column chromatography to obtain an aimed compound.