Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.P(=O)(O)(O)O.[CH2:28]([C:32](=[CH2:35])[CH:33]=O)[CH2:29][CH2:30][CH3:31].O.N>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[CH:35][C:32]([CH2:28][CH2:29][CH2:30][CH3:31])=[CH:33]2
Reactant: C=C(C=O)CCCC
Reactant: Nc1cc(F)ccc1Br
Agent: N
Agent: O=P(O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Solvent: O
Product: CCCCc1cnc2c(Br)ccc(F)c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.1 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (69.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, 2-butylacrolein (7.44 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane and then, dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 1.35 g of 8-bromo-3-butyl-5-fluoroquinoline as a brown solid (yield: 19.2%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14]C(=O)OC(C)(C)C)=[O:13])=[C:5]2[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.CC(C)([O-])C.[K+].[CH2:37]([SH:39])[CH3:38]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:37]([S:39][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]2[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH3:38]
Reactant: CCS
Reactant: COc1cccc(Nc2c(C(=O)NC(=O)OC(C)(C)C)cnc3ccc(I)cc23)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCSc1ccc2ncc(C(N)=O)c(Nc3cccc(OC)c3)c2c1
Temperature: 90 °C
Reaction time: 0.13 h

Procedure:
Intermediate 37 (0.100 g) was combined with (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.011 g), potassium tert-butoxide (0.025 g) and tris(dibenzylideneacetone)dipalladium(o) (0.008 g) in 1,4-dioxane (1 ml). Ethanethiol (available from Aldrich, 0.023 ml) was added and the mixture was stirred under microwave irradiation (power 40 W) for 8 min at 90° C. The reaction was quenched by addition of 4M HCl in dioxane, then partitioned between ethyl acetate and sodium bicarbonate solution. The organic layer was concentrated in vacuo to give 0.090 g of crude 6-(ethylthio)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[C:9]([F:10])=[C:8](Cl)[C:7]([F:12])=[C:6](Cl)[C:5]=1[F:14]>[Pd].O>[F:10][C:9]1[CH:4]=[C:5]([F:14])[CH:6]=[C:7]([F:12])[CH:8]=1
Reactant: Fc1c(Cl)c(F)c(Cl)c(F)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cc(F)cc(F)c1
Temperature: 140 °C
Yield: 98.3 %

Procedure:
Palladium on carbon (10%, 300 mg), aqueous sodium hydroxide solution (35% strength, 26.5 g, 232 mmol, 3.7 equivalents), 62 g of water and 1,3,5-trichloro-2,4,6-trifluorobenzene (15 g, 62 mmol) were placed in a pressure vessel. After flushing with nitrogen, the pressure vessel was heated to 140° C. and pressurized with 30 bar of hydrogen. A hydrogen pressure of 30 bar was maintained at 140° C. for 12 hours. After cooling to 20-25° C., the pressure vessel was depressurized. The reaction solution was subjected to an azeotropic distillation via a distillation attachment; the distillate went over at a temperature of 99.5° C. After separation of the phases, the lower organic phase comprised the title compound. Washing with water and drying gave 8.05 g of 1,3,5-trifluorobenzene (98% of theory).
Reaction SMILES: [NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:16]([CH3:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[NH:30]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40](O)=[O:41])=[O:37])=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:30]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@@H:16]([CH3:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:41])=[O:37])=[O:33]
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
H-Glu(OtBu)-Thr(tBu)-OtBu (1.27 g, 3.05 mmol) and Z-Gly-Gly-Gly-OH (0.99 g, 3.05 mmol) were dissolved in DMF (20 ml). To the solution were added HOBT (453 mg, 3.35 mmol) and WSC (643 mg, 3.35 mmol). The mixture was stirred for 8 hours at 20° C. The reaction mixture was concentrated, which was suspended in 0.2M aqueous solution of citric acid (70 ml), followed by extraction with ethyl acetate (100 ml, 70 ml). The ethyl acetate layers were combined and washed with a 10% (w/v) aqueous solution of ammonium chloride, 5% (w/v) aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively, which was dried over anhydrous sodium sulfate, followed by concentration. To the concentrate was added ether-hexane. Resulting precipitates were collected by filtration to afford Z-Gly-Gly-Gly-Glu(OtBu)-Thr(tBu)-OtBu (Z-P-2) as a while powdery product (1.87 g, 85%).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16](=[O:34])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:33])[NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=[CH:10]2)C.[OH-].[Na+].Cl>C1COCC1.CO>[O:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[O:26][NH:25][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:35])=[O:3])=[CH:15][CH:14]=2)=[O:34])=[O:33]
Reactant: CCOC(=O)CCc1ccc2[nH]c(C(=O)NCCCCCCC(=O)NOC3CCCCO3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc2[nH]c(C(=O)NCCCCCCC(=O)NOC3CCCCO3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
3-{2-[6-(Tetrahydro-pyran-2-yloxycarbamoyl)-hexylcarbamoyl]-1H-indol-5-yl}-propionic acid ethyl ester (550 mg, 1.13 mmol) was dissolved in THF/methanol (50 ml/25 ml). 1.4 M NaOH solution (50 ml) was added and the reaction stirred at room temperature for 4 h. The solvent was reduced to ˜50% volume and 1M HCl added to pH 6-7. The mixture was extracted with DCM and further extracted with EtOAc. The combined organic layer was dried, Na2SO4 and the solvent removed in vacuo to give the required product 357 mg (69% yield) as a yellow powder which was used in the next step without further purification. LCMS purity 94%, m/z 460 [M++H]+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccncc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
Compound 454 (6.95 g, 25.0 mmol) was dissolved in DMF (100 mL), and isonicotinic acid (36.9 g, 300 mmol), EDC hydrochloride (57.6 g, 300 mmol)- and 1-hydroxybenzotriazole monohydrate (45.9 g, 300 mmol) were added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was poured into a mixture of a saturated aqueous solution of sodium hydrogencarbonate (600 mL) and water (200 mL), and the precipitated solid was collected by filtration. The resulting solid was recrystallized from ethanol to afford the entitled Compound 455 (4.41 g, 48%) as a grayish white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:5]3[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]5[NH:14][CH:15]=[CH:16][C:9]=45)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[CH:18][CH:19]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C=Nc1cccc(Cl)c1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and 3-chlorophenyl isocyanate provided the title compound. ESMS [M+H]+: 457.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH2:26][CH:27]=[CH2:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: C=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 31, 8-bromo-1-(chloromethyl)- 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-bromo-1-[(allylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:8]([CH:9]=[C:10]([CH3:12])[CH3:11])[NH:7][C:6]1=[O:13])(=O)C.C([O-])([O-])=O.[K+].[K+].N1C=CN=C1.[CH2:25]([Si:27](Cl)([CH2:30][CH3:31])[CH2:28][CH3:29])[CH3:26]>CO>[CH2:25]([Si:27]([CH2:30][CH3:31])([CH2:28][CH3:29])[O:4][C@H:5]1[C@@H:8]([CH:9]=[C:10]([CH3:11])[CH3:12])[NH:7][C:6]1=[O:13])[CH3:26]
Reactant: CC(=O)O[C@@H]1C(=O)N[C@@H]1C=C(C)C
Reactant: CC[Si](Cl)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CO
Product: CC[Si](CC)(CC)O[C@@H]1C(=O)N[C@@H]1C=C(C)C
Temperature: 5 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
(±)-cis-3-Acetyloxy-4-isobutenylazetidin-2-one (1.47 g, 8.0 mmol) was dissolved in methanol (15 mL) and was V stirred with K2CO3 (110.5 mg, 0.8 mmol) for 3 h at ambient temperature. The solution was then neutralized with Dowex 50W-X8 resin and then filtered. The filtrate was concentrated and the crude solid was dissolved in THF (25 mL) and cooled to 5° C. in an ice bath. Imidazole (544.0 mg, 8.0 mmol) was added and once dissolved, triethylsilyl chloride (1.34 mL, 8.0 mmol) was added dropwise via syringe. The resulting slurry was allowed to warm to ambient temperature and stir overnight. The solution was filtered and the filtrate was washed with water, then brine. The organic fraction was dried (MgSO4) and concentrated. The crude solid was purified by silica gel chromatography (eluted with hexanes/ethyl acetate 3:1) to furnish the desired product (612 mg, 30%) as a pale yellow solid; 1H NMR (300 MHz, CDCl3): δ 5.87 (bs, 1H), 5.31-5.26 (m, 1H), 4.90 (dd, 1H, J=2.2, 4.7 Hz), 4.42 (dd, 1H, J=4.7, 9.3 Hz), 1.74 (s, 3H), 1.28 (s, 3H), 0.98-0.91 (m, 9H), 0.71-0.55 (m, 6H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Brc1ccc2nc(N3CCNCC3)sc2c1

Procedure:
2-Chloro-6-bromobenzothiazole (2.29 g), piperazine (1.59 g) and sodium bicarbonate (3.10 g) were combined in isopropanol (75 mL) and the resulting orange solution was heated to reflux overnight, then concentrated to ˜15 mL, diluted with water, and extracted with DCM. The extracts were concentrated to yield an orange solid which was chromatographed (0 to 5% MeOH in DCM) to yield 6-bromo-2-(piperazin-1-yl)benzo[d]thiazole as a slightly pink solid. MS: 297.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:33][C:34]1([CH3:41])[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.O>CN(C=O)C>[CH3:33][C:34]1([CH3:41])[CH2:39][CH2:38][CH:37]([NH:40][C:8]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][N:5]=2)=[O:10])[CH2:36][CH2:35]1
Reactant: CC1(C)CCC(N)CC1
Reactant: Nc1ccnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCC(NC(=O)c2cc(N)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-amino-pyridine-6-carboxylic acid (250 mg, 1.81 mmol) with TBTU (600 mg, 1.87 mmol) and TEA (1 mL, 7.2 mmol) in 4 mL DMF was added 4,4-dimethyl-cyclohexylamine (300 mg, 1.83 mmol) and the mixture stirred at ambient temperature for 1 h. Then the mixture was poured into water at 0° C. and stirred for 5 min. The precipitate was filtered off, washed with water and dried at 55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1.C([O-])(=O)C.[Na+].[C:30]([C:38]1[CH:50]=[CH:49][C:41]([O:42][CH:43]([CH2:47][CH3:48])[C:44](Cl)=[O:45])=[CH:40][CH:39]=1)([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:31]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:44](=[O:45])[CH:43]([O:42][C:41]3[CH:40]=[CH:39][C:38]([C:30]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:31])=[CH:50][CH:49]=3)[CH2:47][CH3:48])[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1
Reactant: CCC(Oc1ccc(C(C)(C)CC(C)(C)C)cc1)C(=O)Cl
Reactant: Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC(C)(C)C)cc1)C(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Temperature: 25 °C
Yield: 863.6 %

Procedure:
Forty point four grams of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-aminoanilino)-5-pyrazolone were suspended in 120 ml of ethyl acetate, and to this mixture were added 40 ml of an aqueous solution containing 9.62 g of sodium acetate. At room temperature, 31.1 g of 2-(4-t-octylphenoxy)-butyric acid chloride were added dropwise to the liquid, and the mixture was stirred for another hour at room temperature. The organic phase was separated from the reaction liquid, and the solvent was distilled off under reduced pressure. The residuum was recrystallized from 300 ml of ethanol, whereby 58 g of objective 1-(2,4,6-trichlorophenyl)-3-[2-chloro-5-{2-(4-t-octylphenoxy)butaneamido}anilino]-5-pyrazolone were obtained. Melting point: 163° to 165° C. The structure was confirmed through the procedures of NMR, IR and MASS.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.CC(C)([O-])C.[K+]>C1COCC1.[Cl-].[NH4+]>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[CH:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:11]#[N:12]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: Clc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(C#N)c2cnccn2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A mixture of 2-(2,4,6-trimethylphenyl)ethanenitrile (1.6 g) and chloro-pyrazine (1.6 g) in THF (6 mL) is slowly added dropwise to an ice-cold solution of potassium t-butoxide (3.4 g) in THF (10 mL). After the addition, the mixture is further stirred at 0° C. for 30 minutes and then diluted with aqueous ammonium chloride. The resulting mixture is extracted twice with ethyl ether and the combined extracts are washed with saturated brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography (20 to 33% ethyl acetate in hexane) gives 2.15 g of the title compound as a beige solid 1H nmr (400 MHz, CDCl3) d 2.30 (s, 9 H), 5.78 (s, 1 H), 6.95 (s, 2 H), 8.46 (s, 1 H), 8.54 (d, 1 H), 8.60 (d, 1 H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:10]1C(=O)C2=CC=CC=C2C1=O)([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].O.NN>C(O)C>[NH2:10][C:3]([C:2]([F:1])([F:21])[F:22])([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(CCC(=O)O)(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)(CCC(=O)O)C(F)(F)F

Procedure:
A solution of 15.2 g of 1-trifluoromethylpent-4-ene-1-one in 150 ml of methanol is heated at 0° C. with 1.7 g of sodium borohydride. The reaction mixture is stirred for 2 hours at 25° C. then neutralized with HCl. The residue obtained after evaporation of the solvent is extracted several times with chloroform, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1-trifluoromethylbut-4-ene-1-ol. A solution of 10 mmole of 1-trifluoromethylbut-4-ene-1-ol, 10 ml of triphenylphosphine and 10 ml of diethyl azodicarboxylate in 25 ml of tetrahydrofuran is stirred under nitrogen at 25° C. for 16 hours after which the solvent is evaporated under reduced pressure. The resulting residue is treated with benzene. The insoluble material is discarded and the semi-solid obtained after concentration of the filtrate under reduced pressure is recrystallized from methylene chloride-pentane to afford N-(1-trifluoromethyl-3-butenyl)phthalimide. To a solution of 25 mmole of the phthalimide in 25 ml of dioxane is added a solution of 12 mmole of potassium permanganate and 50 mmole of sodium metaperiodate in water. Potassium carbonate is added to adjust the pH of the solution to 8 and the reaction mixture is stirred for 24 hours at 25° C. then acidified with sulfuric acid to a pH of 1 and extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is recrystallized from methylene chloride-pentane to give 4-trifluoromethyl-4-phthalimidopentanoic acid. A solution of 20 ml of 4-trifluoromethyl-4-phthalimidopentanoic acid and 20 mmole of hydrazine hydrate in 20 ml of ethanol is heated at reflux temperature for 12 hours. The solid which separates on cooling is filtered and washed with water. The filtrate is concentrated under reduced pressure to give a solid which is recrystallized from water/acetone to give 4-amino-4-trifluoromethylpentanoic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1)=[O:6].[H-].[Na+].O>CN(C)C=O>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1
Reactant: COC(=O)/C=C/c1ccc(NC(=O)CCCBr)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1ccc(N2CCCC2=O)nc1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of methyl (E)-3-[6-(4-bromobutyramido)-pyridin-3-yl]acrylate (90 mg) in dimethylformamide was added sodium hydride (6.93 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give methyl (E)-3-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]acrylate (65 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([NH2:19])=[N:15][NH:16]2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([NH:19][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[N:15][NH:16]2)=[CH:12][CH:11]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1cccs1
Temperature: 6 °C
Reaction time: 17 h

Procedure:
0.64 cm3 of 2-thiophenecarbonyl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, after cooling to about 6° C. with an ice bath, the reaction medium is then allowed to return to room temperature over 17 hours and concentrated to dryness under reduced pressure (2 kPa; 45° C.), and the residue is then taken up in 20 cm3 of ethyl acetate, 20 cm3 of water and 20 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.), and the residue is then purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 15-40 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); after drying (90 Pa; 50° C.), 660 mg of N-(6-chloro-1H-indazol-3-yl)-2-thiophenecarboxamide are obtained in the form of a pale yellow solid melting at 215° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[F:11][C:12]([F:20])([F:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>O1CCCC1>[F:11][C:12]([F:20])([F:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: FC(F)(F)CCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)CCCCCc1cccs1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To a solution of thiophene (4.2 g) in dry tetrahydrofuran (25 ml) at -15° C. under nitrogen, was added n-butyllithium (20 ml, 2.5M) dropwise and the solution stirred at -15° C. for 2 hours. The solution was then cooled to -78° C. and 6,6,6-trifluorohexylbromide (10.95 g) in dry tetrahydrofuran (20 ml) was added and solution stirred at -78° C. for 1 hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice, extracted with ether (2×75 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was distilled under reduced pressure to give a colourless oil, b.p. 66° C./20 mm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14](=[N+]=[N-])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Reactant: OCc1ccccc1
Product: CCOC(=O)c1[nH]c2ccccc2c1OCc1ccccc1

Procedure:
React 3-diazo-3H-indole-2-carboxylic acid ethyl ester, 5, (305 mg, 1.4 mmol) with benzyl alcohol (5.0 equiv., 0.73 mL, 7.05 mmol) as described in General Synthetic Procedure VIII to afford 3-benzyloxy-1H-indole-2-carboxylic acid ethyl ester 6 (R1=benzyl) as a white solid [MS obs=296 (M+1)]. Hydrolyze the ester to the carboxylic acid 7 (R1=benzyl) using General Synthetic Procedure IX and then transform the carboxylic acid to the corresponding primary amide as described in General Synthetic Procedure V to afford the title compound Iu as a tan solid (115 mg), tlc (silica gel) Rf=0.1.