Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1CCCN(C)C1=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[C:21]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN1CCCN(C)C1=O
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 180 °C
Reaction time: 6 h

Procedure:
In a 300 mL three-neck flask were put 56 g (240 mmol) of 1,4-dibromobenzene, 31 g (180 mmol) of 9H-carbazole, 4.6 g (24 mmol) of copper(I)iodide, 2.1 g (8.0 mmol) of 18-crown-6-ether, 66 g (480 mmol) of potassium carbonate, and 8 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (abbreviation: DMPU). This mixture was stirred under a nitrogen stream at 180° C. for 6 hours. After that, this mixture was filtered. The resulting filtrate was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in that order. The organic layer was dried with magnesium sulfate. This mixture was filtered. The resulting filtrate was concentrated to give a compound, which was then purified by silica gel column chromatography (the developing solvent was a mixed solvent of a 9:1 ratio of hexane to ethyl acetate). The fraction obtained was concentrated to give a compound. This compound was recrystallized with a mixed solvent of chloroform and hexane to give the desired substance as 21 g of a light brown plate-like crystal in a yield of 35%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[CH2:8][CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][CH:7]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[CH2:8][CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-(2-azidoethoxy)-3-(5-chloro-2-methylphenyl)propyl(methyl)carbamate (270 mg, 0.707 mmol) was dissolved in THF/H2O (5 mL, 20:1), PPh3 (741 mg, 2.83 mmol) was added in portions. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[C:10]([O:14][CH2:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[CH:11]=[N:12][CH:13]=1>[Pd].CCOC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([O:14][CH2:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[CH:11]=[N:12][CH:13]=1
Reactant: CN1CCC[C@H]1COc1cncc(C#CCCCCO)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1CCC[C@H]1COc1cncc(CCCCCCO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of 5-(6-hydroxy-1-hexynyl)-3-(1-methyl-2(S) -pyrrolidinylmethoxy)pyridine (50 mg, 0.17 mmol), 10% Pd—C (10 mg), and EtOAc (5 mL) was stirred under H2 (1 atm) at room temperature for 3 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated to provide an oil (50 mg, 99%), [α]D−31 (c 1.6, CHCl3). 1H NMR (CDCl3) δ 8.12 (d, 1H, J=2.4 Hz), 8.03 (d, 1H, J=1.5 Hz), 7.03 (t, 1H, J=2.1 Hz), 4.02 (dd, 1H, J=9.3, 5.4 Hz), 3.92 (dd, 1H, J=9.3, 5.4 Hz), 3.62 (t, 2H, J=6.6 Hz), 3.16-3.09 (m, 1H), 2.72-2.63 (m, 1H), 2.58 (t, 2H, J=7.5 Hz), 2.48 (s, 3H), 2.50 (br s, 1H), 2.31 (td, 1H, J=9.3, 7.5 Hz), 2.10-1.97 (m, 1H), 1.93-1.28 (m, 11H); 13C NMR (CDCl3) δ 155.02, 142.17, 138.54, 134.89, 121.29, 70.93, 64.13, 62.48, 57.67, 41.67, 32.64, 32.58, 30.86, 28.79, 28.48, 25.48, 22.94.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[C:12]=1[Cl:33].O>O1CCOCC1>[Cl:33][C:12]1[C:13]2[CH:19]([CH2:20][CH3:21])[O:18][C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[C:14]=2[CH:15]=[N:16][C:11]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCN1CCOCC1
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)c(Cl)c21
Solvent: C1COCCO1
Solvent: O
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(NCCN3CCOCC3)c(Cl)c21
Temperature: 100 °C
Yield: 17.8 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (178 mg, 1.37 mmol) in 3 mL of dioxane is treated with 3-(6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) in one portion and the reaction mixture is heated to 100° C. for 12 hr. The reaction mixture is treated with 12 mL of water and then heated at reflux for 1 hr. The reaction mixture is cooled to room temperature and the precipitate which formed is collected by filtration and dried under vacuum to give the title compound as a yellow solid (22 mg, 18%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:33]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]([CH2:24][C:23]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]2=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1ccccn1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(F)cc2)ccc1OCCc1ccccn1
Reaction time: 48 h

Procedure:
4-fluorobenzenesulfonyl chloride (0.22 mmol) is added to a room temperature solution of triethylamine (0.9 mmol) and 3-[3-Methoxy-4-(2-pyridin-2-yl-ethoxy)-benzylamino]-azepan-2-one (3) (0.22 mmol) in methylene chloride (0.2 M). After stirring for 48 hours, the reaction mixture is concentrated and the resulting residue is purified by reverse phase HPLC, to afford the desired product (4).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)[N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(O)C>[CH:27]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([CH2:3][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:9][CH:8]=4)[O:14][N:13]=3)=[CH:20][N:19]=2)[CH2:26][CH2:25]1)([CH3:29])[CH3:28]
Reactant: CC(C)N1CCN(c2ccc(-c3noc(-c4ccc(CCl)cc4)n3)cn2)CC1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(-c3noc(-c4ccc(CN5CCCCC5)cc4)n3)cn2)CC1
Yield: 100 %

Procedure:
A mixture of 1-(5-(5-(4-chloromethylphenyl)[1,2,4]oxadiazol-3-yl)pyridine-2-yl)-4-isopropylpiperazine, hydrochloride (280 mg, 0.65 mmol, prepared as described in Example 41, 96% ethanol (20 mL) and piperidine (0.2 mL, 2.1 mmol) heated at reflux temperature for 4 h. The mixture was evaporated to give a solid residue which was purified by column chromatography on silica gel (75 g, Kiselgel 60, mesh 0.040-0.63) eluting with a mixture of dichloromethane and methanol (7:3). Collecting the proper fractions afforded 310 mg (100%) of 1-isopropyl-4-{5-[5-(4-piperidin-1-ylmethylphenyl)[1,2,4]oxadiazol-3-yl]pyridin-2-yl}piperazine. The free base (310 mg) was dissolved into ethanol (20 mL) and a 1 N hydrochloric acid solution (1.5 mL) was added. When dissolved, the mixture was evaporated and the solid residue was re-crystallised from ethanol to give 240 mg (67%) of the title compound.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=O.[ClH:17]>C1COCC1>[ClH:17].[CH3:1][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc2c1CCCC2CNC=O
Agent: Cl
Solvent: C1CCOC1
Product: CNCC1CCCc2c(OC)cccc21

Procedure:
The product from Example 16 (3.8 g) in dry THF (80 ml) was treated with IM solution of BH3 in THF (38 ml). After the addition was complete, the reaction was heated at reflux for 1 hr, followed by cooling. The reaction was treated with saturated methanolic HCl (30 ml), heated at reflux for 1 hr and concentrated to afford a solid. Crystallization from Et2O/CH3OH afforded 4.1 g of desired product. Anal. calcd. for C13H20ClNO: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.68; H, 8.49; N, 5.78.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][S:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=O)=[CH:18][CH:17]=1.C(OCC)(=O)C>O1CCCC1>[CH3:14][S:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[CH:3][C:1]#[N:2])=[CH:18][CH:17]=1
Reactant: CSc1ccc2c(c1)C(=O)CCC2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(=CC#N)CCC2
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere and at 0° C., diethyl cyanomethylphosphonate (7.6 ml, 46.8 mmol) is added dropwise to a suspension of sodium hydride (2.25 g, 46.8 mmol) in 50 ml of tetrahydrofuran. Stirring is carried out at 0° C. for 30 minutes; the compound obtained in Step C (6 g, 31.2 mmol), dissolved in 50 ml of tetrahydrofuran, is then added and the reaction mixture is stirred at ambient temperature for 3 hours. After hydrolysis and extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel (eluant: petroleum ether/dichloromethane 50/50) to yield the unsaturated nitrile of the title.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[N:6][CH:7]=1.[CH:15]([C:17]1[N:18]=[CH:19][N:20]2[CH:24]=[CH:23][S:22][C:21]=12)=[O:16]>CCCCCC>[N:9]1([CH2:8][C:4]2[CH:3]=[C:2]([CH:15]([OH:16])[C:17]3[N:18]=[CH:19][N:20]4[CH:24]=[CH:23][S:22][C:21]=34)[CH:7]=[N:6][CH:5]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Brc1cncc(CN2CCOCC2)c1
Reactant: O=Cc1ncn2ccsc12
Solvent: CCCCCC
Product: OC(c1cncc(CN2CCOCC2)c1)c1ncn2ccsc12
Yield: 41.5 %

Procedure:
7-[[5-(Morpholin-4-yl)methylpyridin-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole (384 mg) was prepared in substantially the same manner as in step a) of Synthesis Example 5, except that 1.05 g of 4-(5-bromopyridin-3-yl)methylmorpholine, 2.70 ml of a 1.59 N nbutyllithium/n-hexane solution, and 426 mg of 7-formylimidazo[5,1-b]thiazole were used as the starting materials.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N+:18]([O-:38])[CH:19]=[CH:20][CH:21]=2)=[C:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[S:6]1(=[O:28])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C(NCCCOc2cccnc2)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc[n+]([O-])c2)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
2-tert-Butyl-5-phenyl-4-{[3-(pyridin-3-yloxy)propyl]amino}isothiazol-3(2H)-one 1,1-dioxide (Example 5) (0.202 g, 0.49 mmol) was dissolved in dry DCM (15 ml) and cooled to 0° C. with an icebath. mCPBA (70%) (0.120 g, 0.53 mmol) was added and the icebath was removed and the reaction mixture was allowed to reach rt. After stirring for 2 h the reaction mixture was extracted with saturated aqueous NaHCO3 solution (20 ml) and brine (20 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel column chromatography using a 10:90 mixture of heptane and EtOAc and then DCM:MeOH 97:3 as eluant, to give the title compound (0.160 g, 76%). 1H NMR (500 MHz, CDCl3): δ 7.90-7.83 (m, 2H), 7.51-7.37 (m, 5H), 7.16-7.09 (m, 1H), 6.80-6.74 (m, 1H), 5.68-5.57 (m, 1H), 3.85-3.76 (m, 2H), 3.09-3.02 (m, 2H), 1.85-1.76 (m, 2H), 1.70 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.8, 157.0, 135.1, 133.0, 131.8, 129.9, 128.9, 128.2, 125.7, 125.2, 113.5, 107.6, 67.0, 61.8, 60.6, 41.7, 32.1, 28.8, 27.8, 22.9; Mass Spectrum: M−H+ 432.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:15]3[CH3:18])=[C:11]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:10]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH3:3].[C:36]([O-])(=[O:40])[C@H:37]([CH3:39])[OH:38].[Na+].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1>[CH2:2]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:36](=[O:40])[C@@H:37]([OH:38])[CH3:39])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:10]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH3:3]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: C[C@H](O)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)[C@H](C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-ylmethyl-9H-purine hydrochloride (13 mg, 0.02 mmol), sodium L-lactate (5 mg, 0.04 mmol) and HOBt (4 mg, 0.03 mmol) in THF (1 mL) was added NMM (5 μL, 0.05 mmol) and EDCI (8 mg, 0.04 mmol) and the resulting mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between EtOAc and H2O, the organic layer washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, 2M NH3/MeOH:DCM, 0-10%) affording 862 (12 mg, 92%). LCMS (method I): RT 3.18 min, [M+H]+ 533.3. 1H NMR (MeOD, 400 MHz): δ 8.00-7.96 (1 H, m), 7.65-7.61 (1 H, m), 7.28-7.27 (2 H, m), 4.56-4.54 (2 H, m), 4.33 (4 H, brd s), 4.04-4.04 (1 H, m), 3.84 (4 H, t, J=4.75 Hz), 3.79 (3 H, s), 3.17-3.04 (2 H, m), 2.92-2.86 (2H, m), 2.76-2.64 (1 H, m), 2.28-2.25 (1 H, m), 1.92-1.82 (2 H, m), 1.38 (3 H, t, J=7.51 Hz), 1.36-1.26 (6 H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[S-:13][CH2:14][CH3:15].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[S:13][CH2:14][CH3:15]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccnc2ccc(Br)cc12
Reaction time: 15 h
Yield: 89.3 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (1.5 g, 6.18 mmol) in DMF (60 mL) was added sodium thioethoxide (624 mg, 7.42 mmol) at 0° C. After addition, it was turned to a dark green solution which then turned to a yellow cloudy solution after 15 h at room temperature. Then, the mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.48 g (89.6% yield) of 6-bromo-4-ethylsulfanyl-quinoline as an yellow solid: EI-HRMS m/e calcd for C11H10BrNS (M+) 266.9717, found 266.9715.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](O)(=[O:33])/[CH:30]=[CH:31]/[CH3:32]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:29](=[O:33])/[CH:30]=[CH:31]/[CH3:32])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C/C(=O)O
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Product: C/C=C/C(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 72 %

Procedure:
(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and (E)-but-2-enoic acid using Method E (72% yield). HPLC: 95%, RT=4.079 min. MS: m/z=437 [M+H]+, RT=4.07 min. 1H-NMR (DMSO-d6) δ 8.51 (s, 1H), 8.42-8.39 (m, 2H), 7.53-7.52 (m, 2H), 7.43-7.37 (m, 3H), 7.28 (d, 1H), 7.19 (d, 2H), 7.14 (t, 1H), 7.08 (d, 2H), 7.02 (d, 2H), 6.78 (d, 1H), 6.63 (qd, 1H), 5.94 (d, 1H), 4.38 (d, 2H), 1.76 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([O:20]C)=O)=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.C1COCC1.[C:27]([Li])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18](=[O:20])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ccc1F
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)C(C)(C)C)c1
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a stirred solution of methyl 2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-carboxylate 66.13E (2.00 g, 7 mmol) in THF (138 mL, 7 mmol) at −78° C. was added t-butyllithium (1.7 M in pentane, 9 mL, 14 mmol). Stirring was continued for 3 hours. A saturated solution of ammonium chloride was added to quench the reaction, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 1-(2′-Fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanone 66.13F as a clear oil (2.00 g, 92% yield). MS ESI (pos.) m/e: 334.1 (M+H2O)+, 317.2 (M+H)+.
Reaction SMILES: [CH3:1]C(C)CCCCCCC(OCCC1C=CC(O)=C(OC)C=1)=O.[C:24]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][C:42]([OH:43])=[C:39]([O:40][CH3:41])[CH:38]=1)(=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]C>>[CH3:1][CH:31]([CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][C:42]([OH:43])=[C:39]([O:40][CH3:41])[CH:38]=1)=[O:34]
Reactant: COc1cc(CCOC(=O)CCCCCCC(C)C)ccc1O
Reactant: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O

Procedure:
Using vanillyl alcohol (1.70 g, 11.0 mmol) instead of homovanillyl alcohol, and n-decanoic acid (1.72 g, 10 mmol) instead of 8-methylnonanoic acid in Example 1, similar reaction was performed. The residue was purified by PTLC to find that the yield of the obtained vanillyl decanoate was 1.33 g (4.31 mmol, 43.1%), and vanillyl decanoate was decomposed (i.e., unstabilized) by the contact with silica gel. In contrast, the isolation yield of homovanillyl 8-methylnonanoate obtained by similar operation was 93.2% as mentioned above, suggesting that homovanillyl 8-methylnonanoate is far stabler than vanillyl decanoate even upon contact with silica gel. In addition, since good isolation yields were obtained in Examples 2 to 23 where isolation and purification were similarly performed by PTLC, it is clear that the compound of the present invention is superior to capsinoids in the stability.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(C1(C)CC1)#C>C(N(CC)CC)C.[Cu]I.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>[N+:9]([C:7]1[CH:8]=[CH:2][C:3]([NH2:4])=[CH:5][CH:6]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CC1(C)CC1
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 123.1 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1-ethynyl-1-methyl-cyclopropane (630 mg, 8.0 mmol) in triethylamine (20 mL) was added CuI (76 mg, 0.40 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.20 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 24(1-methylcyclopropyl)ethynyl)-4-nitroaniline (340 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 8.15-8.14 (m, 1 H), 7.98-7.95 (m, 1 H), 6.63 (d, J=6.9 Hz, 1 H), 4.80 (brs, 2 H), 1.38 (s, 3 H), 1.04-1.01 (m, 2 H), 0.76-0.73 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:6]1.[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][NH:28][CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][N:28]([CH:29]([CH3:30])[CH3:31])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CC(C)=CCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2ccc(F)cc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (161 mg, 0.63 mmol), 4-fluoro-N′-isopropylbenzohydrazide (82.4 mg, 0.42 mmol) and HATU (239.5 mg, 0.63 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.11 ml, 0.63 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (35% EtOAc) for refinement and dried so that ivory (E)-4-fluoro-N′-isopropyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (116.0 mg, 42.5%).