Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3([C:26]#[N:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>ClCCl>[C:1]([N:23]1[CH2:22][CH2:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:15][CH:16]=2)([C:26]#[N:27])[CH2:25][CH2:24]1)(=[O:3])[CH3:2]
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
Acetyl chloride (27 μl, 0.37 mmol) was added dropwise to a solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile (90 mg, 0.28 mmol) and triethylamine (78 μl, 0.56 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (15 ml) and washed with water (15 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2×10 ml). The organics were combined, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate:methanol:ammonia (95:5:0.5 by volume) to provide the title compound (28 mg, 28%). 1H NMR (400 MHz, CD3OD) δ 1.82-1.85 (m, 4H), 1.89-2.18 (m, 9H), 2.60-2.63 (m, 4H), 2.69 (t, 2H), 3.00 (t, 1H), 3.50 (t, 1H), 4.03-4.12 (m, 3H), 4.70 (d, 1H), 6.97 (d, 2H), 7.44 (d, 2H). HRMS ESI+ m/z 356.2329 [MH]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=O.[C:17]([NH2:25])(=[S:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([C:17]2[S:24][CH:2]=[C:3]([C:5]3[CH:6]=[N:7][C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][CH:10]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CBr)c1cnc(-c2ccccc2)nc1
Solvent: CCO
Product: c1ccc(-c2ncc(-c3csc(-c4ccccc4)n3)cn2)cc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A mixture consisting of 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone (Example 14, Step B, 50 mg, 0.18 mmol), thiobenzamide (TCl America, 25 mg, 0.18 mmol) and absolute ethanol (4 mL) in a capped scintillation vial was heated to near boiling for several minutes and was subsequently allowed to cool to room temperature. A white solid precipitated within minutes. The precipitate was collected by vacuum filtration. Light ethanol rinse, suction, and drying under high vacuum at room temperature afforded the title compound (26 mg, 46% yield) as an off-white solid; melting point 214.4-216.1° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.54 (s, 2H), 8.54 (s, 1H), 8.47 (m, 2H), 8.08 (m, 2H), 7.62-7.54 (m, 6H); LC/MS (ESI+) m/z 316.1, (ESI−) m/z 337.2 (M−1+Na+); H-PGDS FPBA IC50: >20 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:29])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1

Procedure:
125 g of crude omeprazole, obtained by oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole with 3-chloroperoxybenzoic acid, were dissolved while stirring in a mixture of 100 ml of 40% of aqueous methylamine and 125 ml of acetone at room temperature. To this clear solution was added 2000 ml of acetone, the combined solution was stirred for 1 hour at room temperature, and thereafter cooled to a temperature in the range of −10 to −15° C. The product formed was filtered off and then washed with acetone. The crystals formed still wet were suspended in 400 ml of water at room temperature and thereafter stirred vigorously for 1 hour while cooling to a temperature not exceeding 20° C. with an ULTRA-TURRAX® mixer (type 18/10, Janke&Kunkel). The product obtained—omeprazole form C was filtered off, washed with water, and dried in vacuo at room temperature to constant weight.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][N:8]=1.[I:17]N1C(=O)CCC1=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[I:17][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][C:10]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(-c2ccccn2)no1
Reactant: O=C1CCC(=O)N1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1onc(-c2ccccn2)c1I
Temperature: 120 °C
Yield: 40.6 %

Procedure:
A suspension of ethyl 3-(pyridin-2-yl)isoxazole-5-carboxylate (Preparation 63B, 6.25 g, 28.6 mmol), Palladium(II) acetate (1.61 g, 7.16 mmol) and 1-iodopyrrolidine-2,5-dione (12.9 g, 57.3 mmol) in acetonitrile (20 mL) was heated in the microwave for 30 minutes at 120° C. LC/MS analysis indicated that approximately 50% conversion had occurred. Additional 1-iodopyrrolidine-2,5-dione (12.9 g, 57.3 mmol) was added, and the reaction mixture heated for an additional 30 min. at 120° C. The reaction mixture was diluted with acetonitrile (25 mL) and filtered through a plug of Celite. The filtrate was concentrated and purified by silica gel column chromatography using an ISCO setup to afford ethyl 4-iodo-3-(pyridin-2-yl)isoxazole-5-carboxylate (4.00 g, 11.6 mmol, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, 3H), 4.51 (q, J=7.04 Hz, 2H), 7.44 (ddd, J=7.48, 4.84, 1.32 Hz, 1H), 7.82-7.88 (m, 1H), 7.89-7.94 (m, 1H), and 8.81 (ddd, J=4.18, 1.32, 1.10 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH2:24][CH3:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Product: CCNC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (10.0 g) and ethylamine gas, the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethylaminoacrylate (9.0 g, white crystals), which is then treated with 60% sodium hydride (1.30 g) as in REFERENCE EXAMPLE 22 to give ethyl 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (6.76 g), as pale yellow needles (recrystallized from dichloromethane--n-hexane), m.p. 197°-198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.N1C2C(=CC=CC=2)C=CC=1.[CH2:21]([OH:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[S:10])[O:23][CH2:21][CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: S=C=Nc1cccc(Cl)c1
Solvent: c1ccc2ncccc2c1
Product: CCOC(=S)Nc1cccc(Cl)c1

Procedure:
A mixture of 45.5 gm (0.268 mol) of 3-chlorophenylisothiocyanate, 200 ml of anhydrous ethanol and 1 ml of quinoline was refluxed for 48 hours. Then, the reaction mixture was evaporated in an aspirator vacuum, the residue was taken up in ether, and the resulting solution was washed first with 5% hydrochloric acid and then thoroughly with water, dried, and evaporated again. After recrystallization from methanol/water, 49.5 gm (86% of theory) of colorless crystals with a melting point of 78°-79° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:29][CH2:28][CH2:27][C@@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1>>[CH2:25]([O:24][C:22]([C@@H:21]1[CH2:27][CH2:28][CH2:29][N:19]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (R)-(−)-nipecotic acid, ethyl ester (TCI America, Portland Oreg., USA) in the same manner as the R isomer. Colorless solid (220 mg, 70%). LC/MS 6.76 min, [M+1]+ 417.
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:20](=[O:21])[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:22][CH3:23])=[C:14]([O:24][CH3:25])[CH:13]=3)[N:9]=[C:8]1[C:26](OCC)=[O:27])([O:3][CH2:4][CH3:5])=[O:2].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][NH2:40]>C(Cl)(Cl)Cl>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][NH:40][C:26]([C:8]1[N:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:20](=[O:21])[C:19]2[C:10]([N:9]=1)=[N:11][C:12]1[C:17]([CH:18]=2)=[CH:16][C:15]([O:22][CH3:23])=[C:14]([O:24][CH3:25])[CH:13]=1)=[O:27]
Reactant: NCCOc1ccccn1
Reactant: CCOC(=O)Cn1c(C(=O)OCC)nc2nc3cc(OC)c(OC)cc3cc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C(=O)NCCOc2ccccn2)nc2nc3cc(OC)c(OC)cc3cc2c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 3-carbethoxymethyl-7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (0.415 g., 1mM) and 2-(2-pyridyloxy)ethylamine (0.276 g., 2 mM) in chloroform (10 ml.) is refluxed for 24 hours. It is then cooled to room temperature and concentrated in vacuo. The residue, an oil, is crystallized by addition of ether until precipitation is complete. Yield = 0.41 g. (81%) of product; m.p. 170°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:14][C:13](=[O:15])[CH:12]=[C:11]([OH:16])[CH:10]=1.[N+:17]([O-])([OH:19])=[O:18]>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([OH:16])[CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)cc(-c2c(Cl)cccc2Cl)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2c(Cl)cccc2Cl)cc(O)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 14 h

Procedure:
6-(2,6-Dichlorophenyl)-4-hydroxy-1H-pyridin-2-one (253 mg, 0.990 mmol, prepared as described in the previous step) was placed in a 8 mL vial equipped with a stir bar and AcOH (4 mL) was added. Concentrated HNO3 (0.540 mL, 12.0 mmol) was added via syringe and the vial was capped and stirred at 60° C. for 14 hr. The resulting mixture was cooled to room temperature and poured onto crushed ice (20 mL). The precipitate was isolated by filtration and washed with H2O (10 mL). The solid was air-dried to yield 6-(2,6-Dichloro-phenyl)-4-hydroxy-3-nitro-1H-pyridin-2-one as a yellow powder. The filtrate was extracted with EtOAc (3×10 mL) and the combined extracts were washed with H2O (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield an additional crop of 6-(2,6-dichloro-phenyl)-4-hydroxy-3-nitro-1H-pyridin-2-one. 1H-NMR (400 MHz, CD3OD) δ: 7.48-7.61 (m, 3H), 6.13 (s, 1H).
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[Br:6][CH2:7][CH2:8][NH:9][C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(C)C>[Br:6][CH2:7][CH2:8][N:9]1[CH:2]=[CH:1][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C=C(CC(=O)OC)NCCBr
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
Sodium acetate (41.0 g, 500 mmol) was added to the 2-bromoacetaaldehyde solution, and stirred for 5 minutes, at which point the solution had a pH of 6. The flask was placed in a cool tap water bath and dimethyl 3-(2-bromoethylamino)-2-pentenedioate (20.0 g, 71 mmol) was added, followed by isopropanol (40 mL), and the solution was stirred at room temperature (25° C.). Within about 35 minutes, all the solids had dissolved, and a precipitate started forming within 90 minutes. Stirring was continued at room temperature for 20 hours, and the solution then cooled to 0° C. and stirred at that temperature for 1 hour, then filtered through a coarse frit. The precipitate was washed with ice-cold water (400 mL) and ice-cold isopropanol (150 mL) and dried, to give 15.7 g (72% yield) of crude methyl N-(2-bromoethyl)-3-methoxycarbonyl-2-pyrroleacetate as a light tan solid, m.p. 129°-130.5° C., NMR (CDCl3): δ:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH3:36][NH2:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH3:36])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 3.0 g (5.56 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 11.12 ml (22.24 mmol) of methylamine were stirred in 75 ml of THF overnight. About 300 ml of water were added to the reaction mixture, and the precipitate formed was filtered off and washed with water and dried under high vacuum. This gave 2.69 g (91% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cc1cnc(N)s1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cc(Br)cn(C)c2=O)s1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (50 mL), 5-methylthiazol-2-amine (2.28 g, 20.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (5.34 g, 20.0 mmol) cesium carbonate (13.0 g, 40.0 mmol), xantphos (1.16 g, 2.0 mmol), and tris(dibenzylideneacetone)dipalladium(0) (916 mg, 1.0 mmol). The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (3×50 mL). The combined filtrate was concentrated under reduced pressure and the residue was washed with acetonitrile (30 mL) to afford 120a (5 g, crude, 83%) as a yellow solid. MS-ESI: [M+H]+ 300.1.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([CH2:12][NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>O>[C:19]1([N:25]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([CH2:12][NH:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:9]([CH3:10])=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: C=CC(=O)NCC(C(C)=O)C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: C=CC(=O)NCc1c(C)nn(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 29.4 g of the 1-phenyl-2-(acrylamidomethyl)-butane-1,3-dione prepared according to Synthesis Example I, 12.9 g of phenylhydrazine, 180 ml of acetic acid and 180 ml of water was refluxed for 5 minutes, cooled to room temperature and then diluted with 600 ml of water. The crystals precipitated in this procedure were filtered off under suction and washed with diethyl ether. This gave 37.4 g of 1,5-diphenyl-3-methyl-4-acrylamidomethylpyrazole having a melting point of 157°-159° C. The 1H-NMR spectroscopic measurement confirmed the presence of this product:
Reaction SMILES: S(O[CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[I-]>CN(C=O)C>[N:26]([CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
(S)-tert-butyl 3-((tosyloxy)methyl)piperidine-1-carboxylate (8.85 g, 24 mmol) was dissolved in DMF (100 ml), and then NaN3 (6.24 g, 96 mmol) and NaI (0.36 g, 2.40 mmol) were added, followed by stirring at 70° C. for 4 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:10), to give (S)-tert-butyl 3-(azidomethyl)piperidine-1-carboxylate (5.38 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:24](=[O:26])[CH3:25])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1c(OC(C)=O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Yield: 79 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxy-benzofuran (1.2 gm, 3.87 mmoles), acetic anhydride (0.5 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 1.2 gm (79%) of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-acetoxybenzofuran, mp. 39°-41° C.
Reaction SMILES: [Cl-].Cl[C:3](Cl)=[N+:4]([CH3:6])[CH3:5].[CH2:8]([N:13]1[C:21]2[N:20]=[CH:19][NH:18][C:17]=2[C:16](=[O:22])[NH:15]/[C:14]/1=[N:23]/[NH2:24])[CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH3:5][N:4]([CH3:6])[C:3]1[N:15]2[C:16](=[O:22])[C:17]3[NH:18][CH:19]=[N:20][C:21]=3[N:13]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[N:23][N:24]=1
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(N(C)C)nnc12
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
To methylene chloride (10 mL) was added [B] N-(dichloromethylene)-N-methylmethanaminium chloride (0.21 g, 1.3 mmol). After stirring for 5 mins, (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.10 g, 0.42 mmol) was added, and the mixture was stirred at rt for 5 hrs. LCMS analysis showed product as a major peak was formed. 1N NaoH was carefully added to neutralize the acid, and the mixture was extracted with methylene chloride three times. The combined organic layers were dried by MgSO4, filtered and concentrated in vacuo to yield the desired product (84 mg, 69%). LCMS calculated for C13H20N7O(M+H): 290.2; found 290.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:17])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc(O)cc(C)c1CN1CCCCC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a stirred solution 3-methoxy-5-methyl-4-piperidin-1-ylmethylphenol (563 mg, 2.4 mmol) and pyridine (0.77 mL, 10.0 mmol) in DCM (20 mL) at 0° C. was added trifluoromethanesulfonyl chloride (0.81 mL, 4.8 mmol). After the addition was complete the reaction was allowed to warm to ambient temperature. The mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil that was purified by flash chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a red oil (698 mg, 58%). 1H NMR (CDCl3, 300 MHz): 6.82 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.28 (s, 2H), 3.96 (s, 3H), 3.67-3.35 (m, 1H), 2.99-2.66 (m, 1H), 2.47 (s, 3H), 2.21-1.75 (m, 4H), 1.73-1.35 (m, 4H).
Reaction SMILES: CCN([C:6]1[CH:11]=[CH:10][C:9]2[C:12](C)=[CH:13][C:14]([O:16][C:8]=2[CH:7]=1)=[O:15])CC>C(OCC)(=O)C.[Pd]>[O:16]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:6][CH:7]=2)[CH2:12][CH2:13][C:14]1=[O:15]
Reactant: CCN(CC)c1ccc2c(C)cc(=O)oc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2O1
Reaction time: 6 h
Yield: 156.3 %

Procedure:
A solution of coumarin-1 (11.0 g, 47.5 mmol) in ethyl acetate (150 mL) was treated with 10% Pd/C (100 mg) in a parr bottle. The suspension was then hydrogenated at 80 psi and 80° C. for 6 hours. The suspension was filtered through a bed of celite to remove the Pd/C, and the celite bed washed with warm ethyl acetate (100 mL). The filtrate was concentrated and dried under vacuo to yield 11.0 g (100%) of the 3,4 -dihydrocoumarin (2) as an oil;