Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)CC[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)C.FC1C(F)=CC(C2C=CC(OCC3C=CC=C4C=3C=CN4)=CC=2)=C(OC)C=1.[CH2:62]([O:64][C:65](=[O:68])[CH2:66]Br)[CH3:63]>>[CH2:62]([O:64][C:65](=[O:68])[CH2:66][N:7]1[C:15]2[C:14](=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:12]=[CH:11][CH:10]=2)[CH:9]=[CH:8]1)[CH3:63]
Reactant: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Reactant: CCOC(=O)CBr
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Product: CCOC(=O)Cn1ccc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21

Procedure:
[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic acid ethyl ester was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester from starting materials 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and bromo-acetic acid ethyl ester to yield the product as a white solid/wax (30 mg, 66%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[N:10](OCCC[Si](C)(C)C)[N:9]=1.[C:39]([NH:46][C@H:47]([C:51]([OH:53])=O)[CH:48]([CH3:50])[CH3:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[CH3:54]N(C=O)C>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][C@@H:19]([O:21][C:51](=[O:53])[C@@H:47]([NH:46][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:48]([CH3:50])[CH3:49])[CH3:20])[N:10]([CH3:54])[N:9]=1
Reactant: C[C@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2OCCC[Si](C)(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2C
Temperature: 120 °C

Procedure:
A solution of (S)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-(3-trimethylsilanyl-propoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (50 mg, 0.2846 mmol), Boc-(L)-Valine (68 mg, 0.313 mmol), 4-dimethylaminopyridine (7 mg, 0.057 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarodiimide (60 mg, 0.313 mmol) in 4 mL DMF was stirred at room temperature for three days, then heated to 120° C. for four hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was separate, washed with 0.5N aqueous HCl, saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (0% to 50% EtOAc in hexanes) to give 50 mg of (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (S)-2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-methyl1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl ester
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([NH:19][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: c1ccncc1
Product: CC(C)(C)Nc1ncnc2c([N+](=O)[O-])cccc12
Yield: 51 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 500 mg, 2.39 mmol), and tert-butylamine (350 mg, 4.78 mmol) in pyridine (5 mL) was stirred at rt for 3 h. Then the reaction mixture was concentrated and the residue was dissolved in EtOAc. Then the solution was washed with water and brine, separated, dried, filtered, concentrated and purified by column chromatography to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.67 (d, J=8.4 Hz, 1H), 8.53 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.63-7.58 (t, J=8.0 Hz, 1H), 1.54 (s, 9H); MS [M+H]+: 247.18.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27](=[O:29])C.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:16]([C:27](=[O:29])[CH3:26])=[C:15]([CH3:19])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=C([O-])[O-]
Reactant: CC(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution (120 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (6.4 g) synthesized in Example A82(1) in N,N-dimethylformamide were added potassium carbonate (10.8 g) and bromoacetone (4.8 g) at room temperature, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the obtained residue was dissolved in N,N-dimethylformamide (120 mL) again, and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.1 mL) was added to the solution. The reaction mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the obtained solid was washed with ethanol-isopropyl ether to give the title object compound (2.5 g, 34%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccc(-c2ccccc2)cc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 1 (2), but with 4-phenylphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (0.9 mg, 3%) having the following characteristics.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:44])[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:45][C:46]([F:50])([F:49])[CH2:47][NH2:48]>>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:44])[NH:48][CH2:47][C:46]([F:50])([F:49])[F:45])[CH3:14])=[O:43])[C:18]2[CH:42]=[CH:41][CH:40]=[CH:39][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)F
Product: C[C@H](OC(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester and 2,2,2-trifluoroethylamine, the title compound was prepared in the same manner as described for example 5c. Colorless, waxy solid (94%). MS: m/e=556(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[SH-:13].[K+:14]>C(O)(C)(C)C.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][NH:8][C:9](=[S:13])[S-:10])=[CH:11][CH:12]=1.[K+:14]
Reactant: S=C=NCOc1ccc(Cl)cc1
Reactant: [SH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: S=C([S-])NCOc1ccc(Cl)cc1

Procedure:
Potassium p-chlorophenoxymethyldithiocarbamate was prepared by the reaction of p-chlorophenoxymethyl isothiocyanate with potassium hydrosulfide in a mixture of t-butyl alcohol and acetone.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:16][C:14]2[N:15]=[C:8]3[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:12][CH:11]=[CH:10][N:9]3[N:13]=2)=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C(C)(C)C)cc4)nc23)cn1

Procedure:
8-(1-Methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, as described earlier, is coupled with 1-bromo-4-tert-butyl-benzene according to general procedure 2.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[NH:23][C:24]([NH2:26])=[S:25]>>[BrH:1].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[NH:23][C:24]1[S:25][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:26]=1
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3c(Cl)cccc3Cl)n2)c(C)s1
Yield: 66.9 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2,6-dichlorophenyl thiourea (42 mg) as described in Example 154, step (a) to give 63.1 mg (65% yield) of methyl 4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ2.59 (s, 3H), 3.8 (s, 3H), 7.15 (s, 1H), 7.36 (m, 1H), 7.61 (m, 2H), 7.97 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C16H12Cl2N2O2S3, 431.38 (M+H), found 431.0, 433.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Cl:8][C:5]1[N:4]=[N:3][C:2]([N:1]=[CH:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccc(Cl)nn1
Yield: 81.2 %

Procedure:
A mixture of 3-amino-6-chloropyridazine (1.3 g, 10 mmol) and dimethylformamide dimethylacetal (1.35 ml, 10.2 mmol) was heated at reflux for 2 h and concentrated under vacuum to afford a brown solid. After recrystallization with EtOAc, 1.5 g of N′-(6-Chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine was obtained in 81% yield.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Br:18])=[C:14]([O:19][CH2:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1.[OH-].[Na+].[C:31](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:44][N:45](C)[OH:46].C(N(CC)CC)C>O1CCCC1>[Br:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([N:45]([O:46][CH3:31])[CH3:44])=[O:28])[C:12]([CH3:27])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([CH3:26])[S:24][CH:25]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)O
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
To a solution of 3-[5-bromo-2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step B (338 mg, 0.73 mmol) in tetrahydrofuran (2 mL) was added 1N sodium hydroxide (1 mL) and the solution stirred at ambient temperature for two hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to a brown oil and used without any additional purification. To a solution of the crude acid in tetrahydrofuran (3 mL) was added 1,1′-carbonyldiimidazole (177 mg, 1.1 mmol). After stifling at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (107 mg, 1.1 mmol) and triethylamine (0.2 mL, 1.46 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a yellow oil (71 mg, 20%). MS (M, M+2): 493, 495
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][NH:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][Cl:27]>CS(C)=O>[ClH:27].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][N:11]1[CH2:12][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C:10]1=[O:13]
Reactant: CN(C)CCCCl
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CN1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)CCCN1CC(c2ccccc2)(c2ccccc2)CCC1=O
Product: Cl
Reaction time: 8 h

Procedure:
To a vigorously stirred mixture of 5,5-diphenyl 2-piperidinone (5.0 g) and 45% potassium hydroxide (15 ml) in dimethyl sulfoxide (50 ml) was added in one portion 3-(dimethylamino)propyl chloride (5.5g) at room temperature. The reaction was stirred overnight, then it was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and dried. Evaporation of the solvents afforded a syrup which was chromatographed over ammonia-washed silica gel and the resultant title product amine was treated with isopropanol/HCl. The precipitated .hydrochloride salt was collected by filtration, recrystallized from absolute ethanol and dried to give the title product as the hydrochloride salt (3.6 g), mp 220°-5° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:20][C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:20][C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1nccs1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoate (2.07 g, 4.4 mmol) and sodium hydroxide (0.89 g, 22.23 mmol) in methanol (100 ml) and water (9 ml) was stirred under a nitrogen atmosphere at reflux for 18 hours, cooled to ambient temperature and the methanol evaporated off. The residue was treated with aqueous citric acid (1M, 40 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to dryness to give 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoic acid as a white foam, (1.48 g, 75%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:23][N:22]=[C:21]([O:24][C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][C:26]=3[Cl:36])[CH:20]=2)=[CH:15][CH:14]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:23]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:20][C:21]([O:24][C:25]2[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][C:26]=2[Cl:36])=[N:22]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: FC(F)(F)c1cc(Cl)c(Oc2cc(-c3ccc(Cl)cc3)[nH]n2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Potassium carbonate (0.25 g, 1.8 mmol) and ethyl isocyanate (0.11 g, 1.5 mmol) were added to a solution of 5-(4-chlorophenyl)-3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole (0.61 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of N-ethyl-5-(4-chlorophenyl)-3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.39 g, yield: 54.3%). mp: 88-89° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.17 (t, J=7.3 Hz, 3H), 3.30 (dq, J=6.1 and 7.3 Hz, 2H), 5.96 (s, 1H), 6.65-6.85 (m, 1H), 7.30-7.50 (m, 4H), 7.70 (s, 2H).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29]Cl.Cl.Cl.C(OC1CC2C3C(=CC=CC=3)NC=2CC1)(=O)C1C=CC=CC=1>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCCl
Reactant: O=C(OC1CCc2[nH]c3ccccc3c2C1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1c2c(c3ccccc31)CC(OC(=O)c1ccccc1)CC2

Procedure:
The 3-benzoyloxy-9-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydrocarbazole was prepared by following an alkylation procedure similar to that described in Example 11 and using 29.1 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole and 4.3 g. of sodium hydride (50% in mineral oil) in 200 ml. of dimethylformamide, and 13 g. of 3-(dimethylamino)propyl chloride. The crude free base was extracted from the water diluted reaction mixture into ether and the ethereal solution was treated with ethereal hydrogen chloride. The resulting precipitate was recrystallized from isopropyl alcohol and ethyl acetate to give 6.2 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 162°-180° C.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl[CH:7](Cl)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[NH:27][NH2:28]>O.C(OCC)C>[Cl:22][C:20]1[C:19]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:18][C:17]([NH:27][N:28]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:16]([F:15])[CH:21]=1
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Reactant: O=C(C(Cl)Cl)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 5.3 g of sodium acetate dissolved in 100 ml of water was added 4.4 g of 1,1-dichloro-3,3,3-trifluoroacetone under ice cooling, and the reaction was allowed to proceed at 90° C. for 30 minutes. The reaction solution was left cooling to room temperature, to which a solution of 5.8 g of 2-fluoro-4-chloro-5-isopropoxyphenylhydrazine dissolved in 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed once with 10 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and evaporated to remove the diethyl ether to give 6.5 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone), compound 3-3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][NH:12][CH3:13].[CH2:14]=O.Cl>C(O)C>[CH3:11][N:12]([CH3:14])[CH2:13][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10]
Reactant: C=O
Reactant: CC(=O)c1cccc(F)c1
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1cccc(F)c1
Yield: 86.2 %

Procedure:
1-(3-Fluorophenyl)ethanone (17 g, 0.123 mol), dimethylamine (13.7 g, 0.172 mol), and paraformaldehyde (5.5 g, 0.185 mol) were suspended in ethanol (50 mL), and conc HCl solution (0.3 mL) was added. The mixture was heated at reflux overnight. The solvent was removed under vacuum, and the residue was washed with EtOAc (3×) to give 3-(dimethylamino)-1-(3-fluorophenyl)propan-1-one (20.7 g, 88%), which was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([C:10]([NH2:12])=O)[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1.[N+]([C:19]1[CH:23]=CNN=1)([O-])=O.[OH2:24]>P(Cl)(Cl)(Cl)=O.C(O)(=O)C.[Fe]>[C:10]([C:5]1[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([CH3:1])[C:6]=1[NH:7][C:23](=[O:24])[CH3:19])#[N:12]
Reactant: CCCn1nc(C)c([N+](=O)[O-])c1C(N)=O
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: O
Agent: [Fe]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCCn1nc(C)c(NC(C)=O)c1C#N

Procedure:
A solution of 46 g (0.2 mol) of 3-methyl-4-nitro-1-n-propyl-pyrazole-5-carbonyl chloride [J. Med. Chem., 16 1346 (1973)] in 50 ml of acetone is added slowly to 250 ml of cold (5° C.) concentrated ammonium hydroxide. The mixture is filtered to give 33 g (79%) of 3-methyl-4-nitro-1-n-propylpyrazole-5-carboxamide, mp 136°-138° C. The amide (33 g, 0.15 mol) is stirred under reflux in 100 ml of phosphorus oxychloride for 2.5 hours and evaporated in vacuo. The residue is stirred in 250 ml of ice water to give, after filtering, 25.5 g (86%) of 5-cyano-3-methyl-4-nitro-1-n-propylpyrazole. This nitropyrazole (25 g, 0.013 mol) is dissolved in 350 ml of glacial acetic acid and treated at 95° C. portionwise with 12 g iron filings and 20 ml of water. After stirring under reflux three hours the mixture is filtered and the filtrate is concentrated in vacuo. The concentrate is extracted with methylene dichloride and the organic extract is treated with 20 ml of acetic anhydride and refluxed for two hours. The cooled mixure is stirred with saturated aqueous NaHCO3 solution, the organic layer is dried (MgSO4), and evaporated in vacuo to give 16.5 g of N-(5-cyano-3-methyl-1-n-propylpyrazol-4-yl)acetamide, mp 129°-131° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6](N1C2C=CC=CC=2N=N1)=[O:7])[CH3:2].[Li+].CC([N-]C(C)C)C.[C:32]1(=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:6](=[O:7])[CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:32]1=[O:39])[CH3:2]
Reactant: O=C1CCCCCC1
Reactant: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCCCC1=O)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, 3-benzotriazol-1-yl-2-cyclohexyl-3-oxo-propionic acid ethyl ester (example 1.1) was treated with LDA and subsequently reacted with cycloheptanone (CAS Reg. No. 502-42-1) in THF to give the title compound as yellow oil.