Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:9]=2)=[N:6][CH:7]=1.[CH3:27][S:28]([O-:30])=[O:29].[Na+].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>CS(C)=O.[Cu]I>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:7][N:6]=2)=[N:9]1
Reactant: Fc1ccccc1Cn1nc(-c2ccc(Br)cn2)cc1-c1ccccn1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(-c3ccccn3)n(Cc3ccccc3F)n2)nc1
Temperature: 130 °C
Reaction time: 4.5 h
Yield: 61 %

Procedure:
A suspension of 5-bromo-2-(1-(2-fluorobenzyl)-5-(pyridin-2-yl)-1H-pyrazol-3-yl)pyridine, copper(I) iodide (3.0 eq.) and sodium methanesulfinate (3.0 eq.) in DMSO was warmed to 130° C. and stirred at that temperature until completion (by LC/MS analysis). Once complete (reaction time was typically 3-6 h), the reaction solution was cooled to rt and saturated solutions of NH4Cl and NaHCO3 (2:1 ratio) were added. The resultant mixture was stirred for 1 h and then extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate gradient (ethyl acetate/hexanes) to give 2-(1-(2-fluorobenzyl)-5-(pyridin-2-yl)-1H-pyrazol-3-yl)-5-(methylsulfonyl)pyridine as a white solid (61% yield). 1H NMR (400 MHz, CDCl3) δ 9.14 (br. s, 1H), 8.63 (d, 1H), 8.23 (m, 2H), 7.75 (app. td, 1H), 7.66 (d, 1H), 7.40 (s, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 7.00 (m, 1H), 6.96 (m, 1H), 6.92 (m, 1H), 6.13 (s, 2H), 3.13 (s, 3H) ppm. MS: [M+H]=409.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:12][CH:13]([CH3:29])[CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:9]1[C:8]2[C:3]([CH2:2][N:15]([CH2:14][CH:13]([CH3:29])[CH3:12])[CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]3)=[CH:4][CH:5]=[CH:6][C:7]=2[CH:11]=[CH:10]1
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1cccc2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN(Cc1cccc2ccsc12)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 57.7 %

Procedure:
To a solution of 7-bromomethyl-benzo[b]thiophene (0.63 g, 2.8 mmol, 1 eq) and 1,1-dimethylethyl 4-[(2-methylpropyl)amino]piperidine-1-carboxylate (0.71 g, 2.8 mmol, 1 eq) in acetonitrile (25 ml) is added potassium carbonate (0.62 g, 4.4 mmol, 1.6 eq). The mixture is heated to reflux for 16 hours. The solution is filtered and the solvent removed in vacuo. The resulting oil is purified on a 40 g Redisep column using a gradient of 0-20% ethyl acetate/iso-hexane to give 1,1-dimethylethyl 4-{[(benzothien-7-yl)methyl]-(2-methylpropyl)amino}-piperidine-1-carboxylate as an oil (0.65 g, 40%); mass spectrum (LCMS): m/z=403.3 (M++1), Rt=4.40 (6 minute gradient); 1H NMR (300 MHz, CDCl3): δ=7.79-7.65 (1 H, m), 7.46-7.40 (1 H, m), 7.37-7.30 (3 H, m), 4.18-4.06 (4H, m), 3.90 (2 H, s), 2.67-2.44 (3 H, m), 2.32-2.22 (2 H, m), 1.87-1.37 (8 H, m), 144 (4H, s) and 0.92-0.83 (6 H, m).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[N:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:11]=1[CH3:12]
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.35 g, 1.4 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.50 g, 2.12 mmol), palladium tetrakistriphenylphosphine (0.16 g, 0.14 mmol), potassium carbonate (0.49 g, 4.23 mmol) in toluene (2.8 mL) at 100° C. for 17.6 h to give 4-chloro-5,7-difluoro-2-(5-methoxypyridin-3-yl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=321.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2C(C)=CC=C2C)[CH:7]=[C:6]([CH3:17])[CH:5]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:10][C:8]1[CH:7]=[C:6]([CH3:17])[CH:5]=[C:4]([CH2:3][CH2:2][NH2:1])[N:9]=1
Reactant: Cc1cc(CCN)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)nc(CCN)c1

Procedure:
By analogy to Example 56, Step B, 6-(2-aminoethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was treated with 4.6 equivalents of hydroxylamine hydrochloride and 3.2 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-6-(2-aminoethyl)-4-methylpyridine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=O)(=[O:3])[CH3:2].C(O)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(F)c2c1CCCC2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(F)c(F)c2c1CCCC2
Temperature: 25 °C

Procedure:
The compound obtained in (5) above (1 gm) was dissolved into 20 ml of ethanol. To the solution was added 166 mg of sodium borohydride while stirring at room temperature. After stirring for 20 minutes, chloroform and 10% citric acid were added to the reaction mixture. The chloroform layer was extracted and concentrated. To the concentrate were added 20 ml of toluene and a small amount of p-TsOH, followed by heating under reflux for 1 hour. Upon addition of 100 ml of ethyl acetate, the reaction product was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved into a mixed solvent of 20 ml of ethanol, 20 ml of dioxane, and 0.2 ml of acetic acid. The mixture was catalytically hydrogenated with the addition of 200 mg of platinum oxide. The catalyst was removed, the filtrate was concentrated, and ether was added to the concentrate. 0.8 gm of the title compound was obtained by collecting the precipitate by filtration.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.[C:16]1([O:22][C:23](=O)[O:24]C2C=CC=CC=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:23]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])=[CH:6][CH:5]=1
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2

Procedure:
A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 2 g, 9.60 mmol) and diphenylcarbonate (4.11 g, 19.21 mmol) in THF (40 ml) at −15° C. was treated with LHMDS (1M in THF, 13.3 ml, 13.3 mmol) over 0.5 h. The reaction mixture was quenched with sat. aq. NH4Cl, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by normal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc 100:0 to 25:75) to give the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.65 (d, 1H), 7.46-7.38 (m, 2H), 7.27-7.18 (m, 4H), 5.17 (s, 1H), 3.87-3.80 (m, 2H), 3.26 (s, 6H), 2.83 (t, 2H), 2.00-1.92 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:17]3)=[CH:12][CH:11]=2)[N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 0 °C

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methanol (1.215 g, 3.49 mmol), phthalimide (566 mg, 3.85 mmol), and PS-PPh3 (loading 2.12 mmol/g; 3.29 g, 6.97 mmol) in dry THF (40 mL), cooled by ice/water, is added DIAD (830 μL, 852 mg, 4.22 mmol). The cooling bath is removed and the flask is vortexed at rt for 1d. More phthalimide (50 mg, 0.34 mmol), PS-PPh3 (300 mg, 0.636 mmol), and DIAD (80 μL, 82 mg, 0.41 mmol) are added, and vortexing is continued for 2d. The resin is filtered off on a glass frit (porosity M) and washed with CH2Cl2. The combined filtrates and washings are concentrated in vacuo and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-38)→5% (39-61)], mixed fractions are combined and chromatographed again [50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-33)→3% (34-55)→5% (5668)] to obtain the title compound as white foam. 1H NMR (CDCl3, 400 MHz) δ 7.14 (s, 1H), 7.43-7.55 (m, 3H), 7.72-7.79 (m, 3H), 7.82-7.90 (m, 4H), 8.09 (s, 1H), 8.09-8.14 (m, 2H), 8.22 (d, J=8.8 Hz, 111), 8.40 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 476.9/478.9 (100/38) [MH+]. HPLC: tR=3.5 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].CCN(CC)CC.O>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.[Cu]I.CCOC(C)=O>[O:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:6])[CH3:7]
Reactant: C#CCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)OC(C)(C)C)c(C#CCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1
Yield: 91.9 %

Procedure:
A mixture of tert-butyl-hexadecane-15-ynyloxy-dimethylsilane (757 mg, 2.15 mmol, 1.5 eq), tert-butyl (2-iodo-4-methoxyphenyl)carbamate (500 mg, 1.43 mmol, 1 eq), [Pd(PPh3)2Cl2] (45 mg, 0.064 mmol, 0.05 eq), CuI (12 mg, 0.064 mmol, 0.05 eq), and Et3N(5 mL) was refluxed for 24 hours. Water (50 mL) and AcOEt (60 mL) were added to the reaction mixture, and the solution was filtered through celite. The filtrate was extracted three times with AcOEt (100 mL). The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting concentrate was subjected to silica gel flush chromatography (eluate: hexane-AcOEt=98-2) to obtain pale yellow liquid of the title compound (754 mg, yield 92%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=[C:14]([C:18](=O)[CH3:19])[C:15](=[O:17])[CH3:16])=[C:8]2[C:3]=1[C:4](=[O:22])[CH:5]=[C:6]([CH3:21])[O:7]2.[NH2:23]/[C:24](/[CH3:33])=[CH:25]\[C:26]([O:28][CH:29]1[CH2:32][CH2:31][CH2:30]1)=[O:27]>CC(O)C>[C:15]([C:14]1[CH:13]([C:9]2[CH:10]=[C:11]([F:12])[C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:21])=[CH:5][C:4]3=[O:22])[C:25]([C:26]([O:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:27])=[C:24]([CH3:33])[NH:23][C:18]=1[CH3:19])(=[O:17])[CH3:16]
Reactant: C/C(N)=C/C(=O)OC1CCC1
Reactant: CC(=O)C(=Cc1cc(F)c(F)c2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCC2)C1c1cc(F)c(F)c2c(=O)cc(C)oc12

Procedure:
80 mg (0.26 mmol) of 3-[(5,6-difluoro-2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are dissolved with 40.4 mg (0.26 mmol) of cyclobutyl 3-aminocrotonate in 2 ml of 2-propanol and heated under reflux under argon for 12 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: ethyl acetate/cyclohexane 1:2). 31.0 mg (27% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[CH3:12].ClC(C)[CH2:25][NH:26]C1C(C)=CC=CC=1C.CC1C=C(C)C=C(C)C=1N>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH:11]([CH3:12])[N:13]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:25]1=[NH:26]
Reactant: Cc1cccc(C)c1NCC(C)Cl
Reactant: Cc1cc(C)c(NC(C)CNc2c(C)cccc2C)c(C)c1
Agent: Cc1cc(C)c(N)c(C)c1
Product: Cc1cc(C)c(N2C(=N)N(c3c(C)cccc3C)CC2C)c(C)c1
Yield: 87.6 %

Procedure:
1-(2',6'-Dimethylphenyl-amino)-2-(2',4',6'-trimethylphenyl-amino)-propane, applied as starting substance, is prepared by reacting N-(β-chloropropyl)-2,6-dimethyl-aniline, a compound prepared according to Example 3, Method (b), point (a), with 2,4,6-trimethylaniline under the conditions specified in Example 16, point (c). The aimed compound is obtained with a yield of 87.6%; m.p.: 128°-130° C. (dihydrochloride).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[C:20]1([S:26]([C:29]2[S:33][C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([C:29]2[S:33][C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:8]([C:7]4[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=4[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:10])[CH2:36][CH2:35]3)=[N:31][CH:30]=2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccc3)s2)CC1
Yield: 45 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-benzenesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 4(d)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 45%). MS (m/e): 564.3 (M+H+, 100%), 581.3 (M+NH4+, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19]C)=O)[N:5]([CH2:7][C:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)=O)[CH:6]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[O:19])[N:23]3[CH2:22][CH2:21][NH:24][C:8]3([C:10]3[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=3)[CH2:7][N:5]2[CH:6]=1
Reactant: NCCN
Reactant: COC(=O)c1cc(Br)cn1CC(=O)c1cnc(C)cn1
Solvent: C1COCCO1
Product: Cc1cnc(C23Cn4cc(Br)cc4C(=O)N2CCN3)cn1
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of methyl 4-bromo-1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (111 mg, 0.33 mmol) in 1,4-dioxane (2 mL) was added ethane-1,2-diamine (0.6 mL, 9.0 mmol). The solution was heated at reflux. After 2 days the reaction was complete (monitored by LCMS). The mixture was then concentrated in vacuo to give a oily solid. The material was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient CH2Cl2 1 CV, 0-10% MeOH in CH2Cl2 15 CV and hold 10% MeOH 5 CV) to give 7-bromo-10a-(5-methylpyrazin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (33 mg, yield 29%). 1H-NMR (400 MHz, CDCl3): δ 2.53 (s, 3H), 2.95 (dt, 1H, J 10.8, 7.9 Hz), 3.31 (ddd, 1H, J 11.0, 7.6, 3.8 Hz), 3.37 (ddd, 1H, J 11.3, 7.7, 3.8 Hz), 3.94 (dt, 1H, J 11.2, 7.8 Hz), 4.16 (d, 1H, J 12.0 Hz), 4.77 (d, 1H, J 12.0 Hz), 6.51 (d, 1H, J 1.6 Hz), 6.87 (d, 1H, J 1.7 Hz), 8.34 (d, 1H, J 1.4 Hz), 8.40-8.41 (m, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[C:15]#[C:16][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>CN(C=O)C.[Cu]I>[C:1]([N:5]1[C:6]2[C:7](=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)[CH:15]=[CH:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (10 mg, 0.035 mmol) in DMF (2 mL), was added CuI (13 mg, 0.07 mmol) under N2 protection. The reaction mixture was stirred at 100° C. overnight. At this time, EtOAc (4 mL) was added to the mixture. The mixture was filtered and the filtrate washed with water, brine, dried over Na2SO4 and concentrated under vacuum to obtain 1-tert-butyl-5-nitro-1H-indole (7 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ 8.57 (d, J=2.1 Hz, 1H), 8.06 (dd, J=2.4, 9.3 Hz, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 6.63 (d, J=3.3 Hz, 1H), 1.76 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1COCC1>[C:1]1([N:7]2[C:11]([NH:12][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:10][C:9]([C:13]([F:15])([F:16])[F:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a suspension of 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (1.136 g, 5 mmol) and K2CO3 (1.035 g, 7.5 mmol) in THF (20 mL) was dropped a solution of phenyl chloroformate (0.939 g, 6 mmol) in THF (10 mL). After stirred at room temperature overnight, the mixture was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (1.714 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.55 (m, 5H), 7.39 (m, 2H), 7.28 (m, 2H), 7.14 (m, 2H), 6.86 (m, 1H); LC-MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=[O:3].CN(C)C=O.[C:18](=[S:20])=[S:19].[H-].[Na+]>CO.C1C=CC=CC=1>[SH:19][C:18]1[S:20][C:5]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH:1]=1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1ccc2c(=O)cc(S)sc2c1
Temperature: 17.5 °C
Yield: 74.5 %

Procedure:
In accordance with the process disclosed in Aust. J. Chem. 40, 1179 (1987), the mixture of 2-fluoro-4-methoxyacetophenone (3 g, 22.73 mmol), N,N-dimethylformamide (25 ml), benzene (17.5 ml) and carbon disulfide (3.78 g, 50.01 mmol) was stirred and added with 55% sodium hydride (2.42 g, 55.47 mmol) over about 2.5 hours while inner temperature was maintained at 15-20° C. After additional stirring for 30 minutes, the reaction mixture was added with methanol (0.5 ml) and further stirred for 15 minutes. Benzene was removed under heating to increase inner temperature up to 125-130° C.; at that temperature range, the mixture was heated for 45 minutes and was allowed to cool to room temperature. The reaction mixture was added with water (80 ml) and acetic acid (2.5 ml) and extracted with ether (50 ml×2 times); water layer was filtered out and acidified with concentrated hydrochloric acid. The resulting precipitates were collected by filteration and were recrystallized from methanol-1,2-dichloroethane (1:1) to obtain 3.8 g (yield: 75%) of the titled compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].C(O)(=O)/C=C/C1C=CC(O)=C(O)C=1.P(Cl)(OCC)(OCC)=O.[CH3:42][N:43]([CH3:54])[CH2:44][CH2:45][NH:46][C@H:47]1[CH2:52][CH2:51][C@H:50]([CH3:53])[CH2:49][CH2:48]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:42][N:43]([CH3:54])[CH2:44][CH2:45][N:46]([C@H:47]1[CH2:48][CH2:49][C@H:50]([CH3:53])[CH2:51][CH2:52]1)[C:10](=[O:12])[CH:9]=[CH:8][C:7]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:19])[CH3:18])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1OC(C)=O
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: O=C(O)/C=C/c1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1OC(C)=O

Procedure:
Using 3.4 g of 3,4-diacetoxycinnamic acid derived from caffeic acid by the acetylation thereof, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3.0 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 0.68 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,4-diacetoxycinnamamide (a compound of the present invention) was obtained as pale yellow crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[CH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Reaction time: 4 h
Yield: 71.7 %

Procedure:
A mixture of 18.0 g (50.0 mmol) of 19, 1.8 g of 10% Pd on charcoal, and 180 mL of anhydrous ethanol was hydrogenated in a stainless steel autoclave at 20 atm constant pressure of hydrogen and 80° C. The reaction was carried out for ca. 4 hr, i.e. until hydrogen consumption was finished. The resulting mixture was filtered through glass frit, and the filtrate was evaporated to dryness. The product was isolated from the residue using flash-chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate from 50:1 to 2:1, vol.) to yield 13.1 g (73%) of the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH3:2].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=1
Reactant: CCOc1ccc(C)cc1OCCCOC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc(CBr)cc1OCCCOC
Reaction time: 1 h

Procedure:
The mixture of 2.01 g of 1-ethoxy-2-(3-methoxypropoxy)-4-methylbenzene, 1.76 g of N-bromosuccinimide and 0.150 g of 2,2′-azobis(2-methylpropionitrile) in 90 ml of carbon tetrachloride is kept at reflux with stirring over 1 hour. The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F).