Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([C:21]#[N:22])=[C:12]2[NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1>>[Cl:31][C:26]1[CH:25]=[C:24]([NH:23][C:12]2[C:11]3[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([NH:8][C:5](=[O:6])[CH:4]=[CH:3][CH2:2][Br:1])[CH:10]=3)[N:15]=[CH:14][C:13]=2[C:21]#[N:22])[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: O=C(Cl)/C=C/CBr
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr

Procedure:
By using the method of Example 15, 4-bromo crotonyl chloride and 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile was converted to the title compound which was obtained as a solid that could be purified with boiling methanol.
Reaction SMILES: [CH2:1]([Li])CCC.C(NCC)C.[C:11]([C:19]1[CH:20]=[C:21]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI>CCCCCC.O1CCCC1>[C:11]([C:19]1[CH:20]=[C:21]([CH:25]([CH3:1])[C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1
Solvent: CI
Solvent: CCCCCC
Solvent: CCNCC
Product: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.33 h

Procedure:
138 ml of a solution of 1.55N butyl lithium in hexane was introduced over 20 minutes at -40° C to a mixture of 775 ml of tetrahydrofuran, 775 ml of hexamethyl phosphor-triamide and 21.5 ml of diethylamine and after stirring for 20 minutes, a solution of 52.5 g of the above ester in 470 ml of tetrahydrofuran was added over 20 minutes. Then, 38 ml of methyl iodide were added thereto and the mixture was stirred for 30 minutes at about -40° C and then was progressively returned to 20° C. The reaction mixture was poured into 3 liters of water-ice mixture and was stirred and extracted with isopropyl ether. The extracts were washed with water and evaporated to dryness under reduced pressure to obtain methyl 2-(m-benzoyl-phenyl)-propionate which was used as is for the saponification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:13]1[CH2:17][CH2:16][NH:15][C:14]1=O)=[O:12].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:21]=1[NH2:22].P(Cl)(Cl)(Cl)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:22][C:21]1[C:20]([Cl:19])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:27])=[O:12]
Reactant: O=C1NCCN1C(=O)c1ccc2ccccc2n1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1ccc2ccccc2n1)N1CCN=C1Nc1c(Cl)cccc1Cl

Procedure:
Using the process described in Example 49, 1-(quinolin-2-oyl)-imidazolin-2-one and 2,6-dichloroaniline, in the presence of an excess of phosphorus oxychloride, give 1-(quinolin-2-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 196°-197.5° C.; the material is identical with the product obtained according to Example 46.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[CH:3]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(-c2ccoc2)cc1
Temperature: 150 °C
Yield: 59.2 %

Procedure:
In a microwave vial, 3-bromo-furan (590 mg, 4.02 mmol), 4-formyl phenylboronic acid (600 mg, 4.02 mmol) and 7 ml of actonitrile were mixed. 8 ml of 1N aqueous sodium carbonate was then added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 7 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried over sodium sulfate. The organic solvent was evaporated to give crude product, which was purified by ISCO to give 410 mg of 4-furan-3-yl-benzaldehyde, yield: 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35]COCC[Si](C)(C)C)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:22])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCOc1cc(COC2CN(C(=O)OCC[Si](C)(C)C)CCC2c2ccc(F)cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: C[Si](C)(C)CCOC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cc(O)c3ccccc3c2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
4.65 g (7.43 mmol) of β-trimethylsilylethyl (3RS,4RS)-4-(4-fluorophenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidin-1-carboxylate were dissolved in 40 ml of methanol, treated with 40 ml of a 2 N solution of hydrogen chloride in methanol and stirred at 50° C. for 90 minutes. Subsequently, the mixture was partitioned between methylene chloride and aqueous 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product (6.8 g) was purified by chromatography on silica gel with a 3:7 mixture of ethyl acetate and hexane. There were obtained 2.93 g (80% of theory) of β-trimethylsilylethyl (3RS,4RS)-4-(4-fluorophenyl)-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 496 (M+H)+.
Reaction SMILES: [CH2:1]1[S:27][CH:5]([C@H:6]([C@H:15]([CH2:24][CH2:25][OH:26])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH2:3]1[S:4][CH:5]([C@H:6]([C@H:15]([CH2:24][CH2:25][O:26][C:28](=[O:30])[CH3:29])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:27][CH2:1][CH2:2]1
Reactant: OCC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)C1SCCCS1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)C1SCCCS1

Procedure:
Step (4'): The primary hydroxyl group of Compound 68 is acetylated with acetic anhydride to produce 5-O-acetyl-2,3-di-O-benzyl-4-deoxy-L-erythro-pentose trimethylene dithioacetal [Compound 69] of the formula ##STR109##
Reaction SMILES: [NH:1]1[C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:2]1=2.O.[BH4-].[Na+].Cl>C(O)C>[OH:16][CH:15]1[C:2]2[NH:1][C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a stirred suspension of 9H-indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione. 1H2O (5.0 g, 21.5 mmol) in 200 ml of ethanol and 30 ml of water was added sodium borohydride (1.76 g, 46.5 mmol) in four portions over 2 hours, then 200 ml of water was added and the mixture was stirred for 18 hours at room temperature. The reaction mixture was acidified with hydrochloric acid (70 ml, 1N) to pH 1.5 and the precipitate was filtered off, washed with water and dried to give 4.59 g (91%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 5.1 (d, 1H), 5.72 (d, 1H), 7.15 (t, 1H), 7.28 (t, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 12.0 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:5]2[C:6]([N:8]=1)=[N:7][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:3][N:4]=2
Reactant: Clc1ccc2ncc(Cl)nc2n1
Reactant: C1COCCN1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc2ncc(N3CCOCC3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of 3,6-dichloropyrido[2,3-b]pyrazine (E-28) (201 mg, 1 mmol, 1.0 eq) and morpholine (175 μL, 2 mmol, 2.0 eq) and triethylamine (270 μL, 2 mmol, 2.0 eq) in DCM (20 mL) was stirred at RT for 2 h. Then water (20 mL) was added. The organic layer was separated, washed with brine (2×10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product 6-chloro-3-morpholinopyrido[2,3-b]pyrazine (E-29) (100 mg, 40% yield). 1H NMR (300 MHz, CDCl3-d6) δ: 8.59 (s, 1H), 8.15 (d, J=6.6 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H), 3.90 (m, 8H); ESI-MS m/z: 251.00 [M+H]+.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.C(=O)=O.[F:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[O:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>C1COCC1.CCCCCC>[F:19][C:20]1[C:25]([C:29]2([OH:32])[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: Fc1cnccn1
Reactant: O=C1CCOCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2nccnc2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 2.5M solution of nBuLi (4.49 mL, 11.22 mmol)/hexane in THF (3 mL) was first cooled to −78° C. To the cooled solution was added dropwise, 2,2,6,6-tetramethylpiperidine (2.065 mL, 12.24 mmol). The dry ice bath was then switched to a 0° C. bath. The reaction mixture was stirred for 10 min at 0° C. and then the dry ice bath was switched back to recool the reaction mixture to −78° C. To the cooled solution was added 2-fluoropyrazine (1 g, 10.20 mmol), dropwise. After 5 min of stirring at −78° C., a solution of dihydro-2H-pyran-4(3H)-one (0.937 mL, 10.20 mmol) in 0.6 mL of THF was added dropwise. The resulting mixture was allowed to gradually warm to room temperature overnight. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Purification by Biotage (0-100% EtOAc/hexane) produced product.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:17]1C=CC=C[CH:18]=1.CN>ClCCl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:15])[NH:17][CH3:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70 %

Procedure:
A solution of 1-Boc-4-(chlorocarbonyl)piperazine (300 mg, 1.22 mmol), pyridine (288.4 mg, 3 equiv), and methylamine (1.83 mmol, 1.5 equiv) in dichloromethane was refluxed overnight. The solution was quenched by the dropwise addition of water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜70% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1sc(-c2ccc(F)cc2)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
A vigorously stirred mixture of 2-amino-5-(4-fluorophenyl)- 3-thiophenecarboxamide (0.01 mole) and pyridine (20 ml) at 0° was treated dropwise with acetyl chloride (0.011 mole). The resulting solution was stirred a further 30 minutes at 0° and then poured on to cold water. The precipitate was collected by filtration, washed with water and dried. Recrystallisation from ethanol yielded 2-acetamido-5-(4-fluorophenyl)- 3-thiophenecarboxamide (90°/o, m.p. 230°-3°).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].B.O1CCCC1>C1COCC1>[N:3]1([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]1
Reactant: COC(=O)c1cccc(N2CCCCC2=O)c1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N2CCCCC2)c1
Yield: 89.5 %

Procedure:
The compound of Example 37 (640 mg, 2.75 mmol) was dissolved in dry THF (30 ml) and borane-tetrahydrofuran complex (5 ml, 1M solution in THF) was added. The mixture was stirred under nitrogen under reflux for 1 h, then cooled and evaporated. The residue was taken up in MeOH/acetic acid (6/1, v/v, 70 ml) and heated under reflux for 3 h, then evaporated and chromatographed (eluant 10% EtOAc in hexanes) to provide a colourless oil (540 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Nc1ccccc1C1(O)CCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: OC1(c2ccccc2Nc2nc(Cl)ncc2Cl)CCC1
Temperature: 85 °C

Procedure:
1-(2-Aminophenyl)cyclobutanol (56 mg, 0.343 mmol), 2,4,5-trichloropyrimidine (40 μl, 0.349 mmol) and N,N-diisopropylethylamine (120 μl, 0.694 mmol) were suspended in 2-propanol (1.5 mL) in a sealed tube, and the solution was heated to 85° C. for 4 hours. The reaction mixture was partitioned between H2O (15 mL) and CH2Cl2 (3×15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (Analogix, 0 to 25% ethyl acetate-hexanes over 25 minutes, 4 g silica, 18 mL/minute) to give the title compound.
Reaction SMILES: C1(C2C3C=CC=CC=3OC=2)C=CC=CC=1.COC1C=CC(S(Cl)(=O)=O)=CC=1.C[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([C:39]2[O:40][C:41]3[CH:53]=[CH:52][CH:51]=[CH:50][C:42]=3[C:43]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[OH:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([C:39]2[O:40][C:41]3[CH:53]=[CH:52][CH:51]=[CH:50][C:42]=3[C:43]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: COc1ccc(S(=O)(=O)c2oc3ccccc3c2-c2ccccc2)cc1
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Agent: c1ccc(-c2coc3ccccc23)cc1
Product: O=S(=O)(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1

Procedure:
Acylation of 3-phenylbenzofuran with 4-methoxybenzenesulfonyl chloride as described hereinabove followed by demethylation of the 2-(4-methoxyphenylsulfonyl)-3-phenylbenzofuran thus formed as previously described gives 2-(4-hydroxyphenylsulfonyl)-3-phenylbenzofuran.
Reaction SMILES: C([NH2:5])(C)(C)C.[F:6][C:7]([F:14])([F:13])[CH2:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1>[F:6][C:7]([F:14])([F:13])[CH2:8][S:9]([NH2:5])(=[O:11])=[O:10]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: C1CCOC1
Product: NS(=O)(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
Tetrahydrofuran (6 mL) was added to tert-butylamine (220 mg, 3.0 mmol), and 2,2,2-trifluoroethanesulfonyl chloride (300 mg, 1.6 mmol) was slowly added dropwise thereto. The mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated off under reduced pressure. To the residue, trifluoroacetic acid (3.3 mL) was added and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=100/0 to 5/1) was performed to give 2,2,2-trifluoroethanesulfonamide (Compound GC) (66 mg, yield: 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:24][CH3:25])[CH:14]=2)[N:9]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:24][CH3:25])[CH:14]=2)[N:9]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (E)-3-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]acrylic acid ethyl ester (140 mg, 0.3 mmol) and 10% Pd/C (20 mg) in EtOH (4 mL) is stirred under hydrogen (1 atm) for 18 hour at room temperature. The mixture is filtered over celite and concentrated under reduced pressure to afford 3-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionic acid ethyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([NH2:22])=[CH:17][N:16]=1.C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:18]([NH2:22])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)ncc2N)CC1
Yield: 88.8 %

Procedure:
1-t-Butoxycarbonyl-piperazine (2.36 g) was condensed with 2,4-dichloro-pyrimidin-5-ylamine (2.0 g) in dimethylsulfoxide (20 ml) in the presence of triethylamine (5.3 ml) according to the method described in Example 1, Step A. 4-(5-Amino-2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.4 g) was obtained as violet crystals. MS (ES+) 314/316 (M+H+). The title product (120 mg) was obtained from this intermediate according to the methods described in Example 1, step C and D. 2-Chloro-N-(2-chloro-4-{4-[(E)-3-(4-trifluoromethoxy-phenyl)-allyl]-piperazin-1-yl}-pyrimidin-5-yl)-isonicotinamide. M.p. 210-211° C.; 1H NMR (400 MHz, CDCl3) 2.5 (m, 4H), 3.1 (d, J=9 Hz, 1H), 3.6 (m, 4H), 6.1 (dt, J=18, 9 Hz, 1H), 6.4 (d, J=18 Hz, 1H), 7.1 (d, J=11 Hz, 2H), 7.3 (d, J=11 Hz, 2H), 7.6 (d, J=5 Hz, 1H), 7.7 (s, 1H), 7.8 (s, 1H, NH), 8.4 (s, 1H), 8.5 (d, J=5 Hz, 1H); MS (ES+) 553/555 (M+H+).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([CH3:18])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:18][C:12]1[C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]([NH2:8])=[CH:10][C:11]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1c([N+](=O)[O-])cc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])cc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
A mixture of N-t-butyloxycarbonyl-3,5-dinitro-4-methylaniline (7.8 g, from above) and trifluoroacetic acid (100 mL) was stirred at room temperature for 15 min. After evaporation of the solvent under reduced pressure, the residue was taken up in ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution, half-saturated sodium chloride solution, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash column chromatography on silica gel eluting with acetone:hexane (1:3) to give 4-methyl-3,5-dinitro-phenylamine (2.45 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)[N:5]=[CH:4][C:3]=1[C:26]#[N:27].N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)C.O>[Cl:13][C:12]1[C:7]([N:6]2[C:2]([NH:1][C:34]([CH2:35][CH3:36])=[O:37])=[C:3]([C:26]#[N:27])[CH:4]=[N:5]2)=[N:8][C:9]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:11]=1
Reactant: N#Cc1cnn(-c2nc(NCc3ccccc3)c(C(F)(F)F)cc2Cl)c1N
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCC(=O)Nc1c(C#N)cnn1-c1nc(NCc2ccccc2)c(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 113.6 %

Procedure:
A stirred solution of 0.5 gram (0.001 mole) of 5-amino-1-(3-chloro-5-trifluoromethyl-6-phenylmethylaminopyridin-2-yl)-4-cyanopyrazole and 1.0 gram (0.013 mole) of pyridine in 25 mL of methylene chloride was cooled to -10° C. A solution of 1.2 grams (0.013 mole) of propionyl chloride in 10 mL of methylene chloride was added dropwise. After completion of the addition, the reaction mixture was allowed to warm to room temperature and then was heated at reflux for approximately 19 hours. The reaction mixture was cooled and evaporated under reduced pressure, leaving an oil. This oil was partitioned between diethyl ether and water. The organic phase was washed in succession with water, dilute hydrochloric acid, and water. The washed organic phase was evaporated under reduced pressure, leaving a residue. This residue was dissolved in 13 mL of ethanol and 13 mL of water. The resultant mixture was stirred and heated at reflux. Potassium carbonate (0.20 gram, 0.0014 mole) was added, and the mixture was stirred and heated at reflux for approximately 15 minutes. The solvents were removed by distillation under reduced pressure, leaving a waxy solid. This solid was purified by crystallization from ethanol and water to yield 0.51 gram of 1-(3-chloro-5-trifluoromethyl-6-phenylmethylaminopyridin-2-yl)-4-cyano-5-ethylcarbonylaminopyrazole, m.p. 139°-142° C. (Compound 53 of Table 1). The rmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)Oc1ccccc1
Yield: 24.5 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)-2-phenoxypropanoic acid methyl ester (0.055 g, 0.18 mmol) with 1-(3-bromopropoxy)-4-phenoxybenzene (Step A) (0.055 g, 0.18 mmol) and potassium tert-butoxide (0.020 g, 0.18 mmol) were stirred in DMF (5 mL) overnight. The mixture reaction concentrated in vacuo with toluene (2 times), reconstituted in Ethyl acetate and washed with water (3 times) and brine, dryed (Na2SO4) and concentrated to afford a crude product that was purified by chromatographied in silicagel (hexanes/Ethyl acetate, 3:1) to give 0.022 g of the title compound (23%). 1H-NMR (200.15 MHz, CDCl3): δ 7.34–7.15 (m, 6H), 7.07–6.71 (m, 12H), 4.80–4.68 (m, 1H), 4.13 (t, 4H, J=15.1), 3.71 (s, 3H), 3.20–3.15 (m, 2H), 2.30–2.18 (q, 2H).