Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])=[CH:4][CH:3]=1.[N:21]([CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=1)=[N+:22]=[N-:23].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([CH:26]=[C:27]([O:33][CH3:34])[CH:28]=1)[CH2:24][N:21]1[CH:16]=[C:15]([CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][CH:19]=[N:20][C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:23]=[N:22]1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(F)cc1
Reactant: COc1cc(CN=[N+]=[N-])cc(OC)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Cn2cc(CNC(=O)c3cccnc3Nc3ccc(F)cc3)nn2)cc(OC)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 71.6 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of from 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 116 mg, 0.61 mmol)) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6b (182 mg, 71%); mp: 209-211° C.; mp: 140-142° C.; 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 8.19 (dd, J=3.0, 1.5 Hz, 1H), 7.81 (dd, J=3.0, 1.5 Hz, 2H), 7.52-7.47 (m, 3H), 7.20 (d, J=9.0 Hz, 2H), 6.83 (t, J=7.5 Hz, 4H), 6.55-6.51 (m, 1H), 5.41 (s, 2H), 4.58 (d, J=4.5 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H); MS (ESI m/z): 463 [M+H]+ Yield: 71%
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](O)[CH3:31]>>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
HCl is passed into a boiling solution of 4.04 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid in 50 ml of absolute ethanol for 2 hours. The mixture is boiled for a further hour and worked up in the customary manner to give ethyl 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylate. Rf 0.65 (silica gel; 8:2 CH2Cl2 /CH3OH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[NH:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1>>[NH:16]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[C:6]([CH:11]=2)[C:7]([OH:9])=[O:8])[CH:18]=[N:17]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Product: O=C(O)c1cc(C(=O)O)cc(-c2cn[nH]c2)c1

Procedure:
Following standard cross coupling procedure described herein, dimethy 5-bromoisophthalate (623 mg, 2.3 mmol) and 4-pyrazoleboronic acid pinacol ester (443 mg, 2.3 mmol) were reacted. The resulting aqueous layer was acidified to pH 5 and extracted with EtOAc to provide 5-(1H-pyrazol-4-yl)isophthalic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH:7](O)[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)[C@@H]1COCC(O)N1C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H]1COCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of example 1109C (522 mg, 2.0 mmol) in 4 mL of methylene chloride was cooled in an ice/acetone bath and triethylsilane (1.6 mL, 10.0 mmol) was added. The solution was then treated with a solution of boron trifluoride etherate (0.27 mL, 2.2 mmol) in 1 mL of methylene chloride. After stirring 30 minutes, the bath was removed and stirring continued for 30 minutes and the mixture was quenched by the addition of 2M aqueous sodium carbonate. The mixture was diluted with water and methylene choride and the layers separated. The aqueous layer was extracted with 2 portions of methylene chloride and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (40 g, 20% ethyl acetate/hexanes) to provide 200 mg (41%) of the title compound. MS (DCI, NH3): 246 (MH+); 263 (M+NH4)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[B-](F)(F)(F)[F:13].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CC#N>[F:13][C:3]1[C:2](=[O:1])[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c[nH]c(=O)c(F)c1
Temperature: 65 °C

Procedure:
To a solution of methyl 6-oxo-1,6-dihydro-3-pyridinecarboxylate (2.00 g, 13.06 mmol, Bionet Research) in MeCN (40 mL) was added SelectFluor® (4.63 g, 13.06 mmol, Aldrich). The resulting mixture was then heated at 65° C. for 18 h. Then, the mixture was cooled to rt and water (20 mL) was added. The solvent, (MeCN) was removed and the remaining aqueous solution was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in MeOH (100 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. Purification by silica gel flash column chromatography (0%-100% EtOAc/hexane) gave the title compound as a white solid. MS (ESI, positive ion) m/z: 172 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14]([OH:16])=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14]([N:29]([CH3:30])[CH3:28])=[O:16])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(C(=O)O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C(=O)N(C)C)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
70 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid (Example 141) was dissolved in 0.5 ml of dimethylformamide, 81 mg of dimethylamine hydrochloride, 37 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 32 mg of 1-hydroxy-7-azabenzotriazole, and 0.18 ml of diisopropylethylamine were added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off, and then the obtained residue was purified by silica gel column chromatography to obtain 45 mg of the objective compound as pale yellow powder.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C(OCC)(=O)C>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CCOC(C)=O
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
cis,trans-muconic acid (103 mg, 0.767 mmol) is dissolved in ethyl acetate (10 mL) at room temperature and a crystal of iodine (27 mg, 0.106 mmol) is added. The reaction mixture is allowed to stir at room temperature for 24 hours. The precipitate is filtered, washed with ice-cold acetonitrile and dried under reduced pressure to yield 60 mg of trans,trans-muconic acid, a 58 percent yield.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15](I)[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C(N(CC)CC)C.O1CCCC1.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>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCCSc1nn2c(=O)c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCSc1nn2c(=O)c(C#C[Si](C)(C)C)cnc2s1
Reaction time: 1 h
Yield: 80 %

Procedure:
In a mixture of 50 ml of triethylamine and 100 ml of tetrahydrofurane, 8.0 g of the thus obtained 2-heptylthio-6-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. To this solution, 0.68 g of bis(triphenylphosphine)palladium(II) chloride and 0.2 g of cuprous iodide were added as catalysts. To this mixture, a solution of 3.9 g of ethynyltrimethylsilane in 20 ml of triethylamine was added dropwise. The mixture was warmed to 60°~70° C. and stirred for 1 hour. Thereafter, further the same amounts as above of the catalysts and ethynyltrimethylsilane were added, and the mixture was stirred at 60°~70° C. for 3 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent, and 5.9 g of 2-heptylthio-6-trimethylsilylethynyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 80%.
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH3:14])[CH2:4][CH:5]=[CH:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C1(C=CC(O)=CC=1)O>C(#N)C>[CH2:13]([CH:3]([CH2:1][CH3:2])[CH2:4][CH:5]1[CH2:17][CH:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]1[N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:14]
Reactant: C=CC(=O)OCC
Reactant: CCC(CC)CC=CN1CCCCC1
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)C1CC(CC(CC)CC)C1N1CCCCC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-(4-Ethyl-1-hexenyl)piperidine (98.1 g) and acetonitrile (70 mL) were mixed. To the mixture were added ethyl acrylate (53.0 mL) and hydroquinone (271 mg). The mixture was stirred at 100° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (132 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13](=O)[CH:14]=[C:15](O)[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:27][NH:28][NH2:29].CN(C=O)C.O>CO>[CH3:27][N:28]1[C:13]([CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[CH:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:29]1
Reactant: O=C(C=C(O)c1ccc(Cl)cc1)C1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CNN
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1nc(-c2ccc(Cl)cc2)cc1C1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 34.3 %

Procedure:
1-(4-Chlorobenzyl)-4-(3-hydroxy-1-oxo-3-(4-chlorophenyl)-prop-2-en-1-yl)piperidine obtained from Example 1 (264 mg) and methyl hydrazine (62 mg) were stirred in methanol (5 ml) and DMF (2 ml) for 16 h. Water was added, the mixture extracted with ethyl acetate (3×20 ml), the combined organic layers washed with water and brine, dried (MgSO4), evaporated in vacuo, and purified by preparative thin layer chromatography, eluding with dichloromethane:methanol: triethylamine (98:2:1 v/v) to give 1-methyl-5-(1-(4-chlorobenzyl)-4-piperidinyl)-3-(4-chlorophenyl)pyrazole (93 mg): oxalate salt.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:16][C:15]([Br:25])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C1COCC1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:25][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(Cl)cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCCC(=O)O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(Cl)ccc12
Temperature: 80 °C
Yield: 85.9 %

Procedure:
1.2-Dichloroethane (4.4 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(4-chlorophenyl)isonicotinate (2.42 g, 6.58 mmol), rhodium octanoate dimer (0.41 g, 0.53 mmol) and crushed 4A° molecular sieves (2.5 gm) and heated at 80° C. for 24 hr. The reaction was diluted with THF and filtered. The collected solid was washed with multiple portions of hot THF to extract remaining product. The solvent was removed from the combined filtrates and the residue was suspended in MeOH and the product was collected by filtration to leave methyl 2-bromo-7-chloro-5H-pyrido[3,2-b]indole-4-carboxylate (1.92 g, 5.65 mmol, 86% yield) as a gray solid. MS (ESI) m/z 340.99 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89 (1H, s), 8.19 (1H, d, J=8.24 Hz), 7.92 (1H, s), 7.76 (1H, d, J=1.53 Hz), 7.35 (1H, dd, J=8.55, 1.83 Hz), 4.04 (3H, s).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH:5][N:4]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH3:20].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([N:5]2[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:7][C:3]([C:2]([F:1])([F:17])[F:18])=[N:4]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH3:20]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)n[nH]1
Reactant: CCOc1cc(C)cc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(C)cc(-n2nc(C(F)(F)F)cc2CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.6 %

Procedure:
To a mixture of tert-butyl (3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (251 mg, 0.947 mmol, 1 equiv.), 3-ethoxy-5-methylphenylboronic acid (341 mg, 1.89 mmol, 2 equiv.) and copper acetate (259 mg, 1.42 mmol, 1.5 equiv.) in dichloromethane was added pyridine (151 mg, 0.151 mL, 1.89 mmol, 2 equiv) and the mixture was stirred for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with 250 mL of dichloromethane and the filtrate was evaporated to give tert-butyl (1-(3-ethoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (354 mg, 94%).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])=[CH:6][CH:5]=1.[CH3:32][NH2:33]>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:12]2[C:13](=[O:17])[C:14]([CH3:15])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:33][CH3:32])=[O:31])=[CH:5][CH:6]=3)[C:11]2=[S:30])=[CH:19][C:20]=1[C:26]([F:29])([F:28])[F:27])#[N:25]
Reactant: COC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Reactant: CN
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Reaction time: 15 h
Yield: 51 %

Procedure:
A mixture of 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]benzoic acid methyl ester (49c) (0.02 g, 0.0435 mmol) and methylamine (2 ml distilled from its 40% aqueous solution) was kept at −20° C. for 15 hours. After evaporation of the methylamine, the mixture was chromatographed (dichloromethane:acetone, 80:20) to yield 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-N-methylbenzamide (49d) [RD153] (0.01 g, 0.0224, 51%), the structure of which is illustrated in Formula 20. The ester 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]benzoic acid methyl ester (49c) (0.08 g, 0.0179 mmol, 41%) was also recovered.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:33])[NH:19][CH2:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:33])[NH:19][CH:20]([CH3:37])[C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)C1CCC(CNC(=O)OCc2ccccc2)CC1)C(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
This compound was prepared using a procedure similar to the one described by Moriya et. al. (J. Med. Chem. (1986) 29:333–341) for the alkylation of α-(N-acylamino) ketones: {4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester (From Example 1A; 584 mg, 1.23 mmol) was dissolved in dry DMF and brought to −40° C. using a dry ice/acetonitrile cooling bath. NaH (61 mg, 1.53 mmol, 60% dispersion in oil) was added in one portion and the mixture was stirred for 15 minutes. MeI (192 mg, 1.35 mmol) was added all at once, the cooling bath was removed and the reaction mixture was allowed to come to room temperature. An excess of saturated aqueous NH4Cl solution was added and the resulting mixture extracted with EtOAc. The EtOAc layer was washed sequentially with 3N HCl, NaHCO3 (sat'd), and brine. The solution was dried (Na2SO4) and concentrated under reduced pressure to give {4-[1-Methyl-2-oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH2:19][CH3:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:18]([CH3:17])([CH3:21])[CH2:19][CH3:20])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 123 mg of 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.59 (t, 3H, J=7.2 Hz), 1.23 (s, 6H), 1.61 (q, 2H, J=7.2 Hz), 7.28 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.53 (m, 3H), 7.67-7.74 (m, 3H), 8.84 (m, 2H), 10.14 (s, 1H). MS: m/z 443.9 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:35]([O:37]CC)=[CH2:36])CCC.[F-].[Cs+].C(OCC)(=O)C>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10]([C:35](=[O:37])[CH3:36])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1cc(Br)sc1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reaction time: 0.17 h

Procedure:
(5-Bromo-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl)carbamic acid tert-butyl ester (the compound of Preparation Example 97) (5.5 g), tributyl(1-ethoxyvinyl)tin (6.7 g), cesium fluoride (5.3 g) and tetrakis(triphenylphosphine)palladium (0.73 g) were stirred in 1,4-dioxane (50 mL) at 100° C. for 2 hours. After ethyl acetate was added and insoluble matter was removed by filtration, 2N hydrochloric acid was added, and the solution was stirred for 10 minutes. After washing the organic layer with water, an aqueous solution of sodium bicarbonate and saturated sodium chloride water, and was dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (3.2 g9 was obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[C:32](OCCBr)(=[O:34])[CH3:33]>CN(C=O)C>[OH:34][CH2:32][CH2:33][O:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12
Reactant: CC(=O)OCCBr
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(OCCO)c3c(c12)OC(C)(C)C=C3
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.8 %

Procedure:
To a solution of 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (3.40 g, 10 mmol, 1.0 eq) in DMF (60 mL) was added potassium carbonate (13.8 g 100 mmol, 10.0 eq) followed by 2-bromoethyl acetate (5 g, 30 mmol, 3.0 eq). The reaction mixture was stirred for 2 days at ambient temperature, which was partitioned between water (600 mL) and ethyl acetate (300 ml). The organic layer was washed with an additional portion of water (600 mL), dried and concentrated. The solid residue was re-dissolved in methanol (200 mL) followed by addition of 2 N aqueous sodium hydroxide (20 mL). The mixture was stirred for 2 h at room temperature, pH adjusted to 6.0 with concentrated hydrochloric acid and concentrated under vacuum. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was separated, washed successively with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The solid residue was crystallized from cyclohexane/ethanol 80/20 and re-crystallized from methanol/water 95/5, affording 1.23 g of 31e (32% yield). 1H NMR (CDCl3): 1.05 (t, J=7.5 Hz, 3H), 1.21 (t, J=7.5 Hz, 3H), 1.52 (s, 6H), 1.67 (m, 2H), 2.92 (m, 4H), 3.29 (t, J=6.5 Hz, 1H), 3.81 (m, 2H), 4.13 (m, 2H), 5.66 (d, J=10.0 Hz, 1H), 6.03 (s, 1H), 6.54 (J=10.0 Hz, 1H); 13C NMR (CDCl3): 7.99, 13.89, 23.04, 27.60, 38.50, 38.54, 62.01, 78.08, 78.41, 106.17, 110.77, 112.63, 116.92, 117.04, 128.47, 152.27, 153.12, 154.78, 157.39, 159.38, 203.60; IR: 1708 cm−1; MS (ACPI+): 387 (M+1); Anal. Calcd. for C22H26O6: C 68.38, H 6.78; Found: C 68.21, H 6.90.