Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:16]/[C:17](/[C:27]([F:30])([F:29])[F:28])=[CH:18]\[C@@H:19]1[C@H:21]([C:22](Cl)=[O:23])[C:20]1([CH3:26])[CH3:25]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:16]/[C:17](/[C:27]([F:28])([F:29])[F:30])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([O:9][CH:6]2[CH2:7][CH:8]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: C=CCC1=CCC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCC1=CCC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 78.3 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-3-cyclopenten-1-ol (115 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (100 mg) and toluene (10 ml), (IRS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (239 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 250 mg of (RS)-3-(2-propenyl)-3-cyclopenten-1-yl (IRS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 35). Yield 77% nD25 1.4713
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:29])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Br[C:31]([CH3:37])([CH3:36])[C:32](C#N)=[O:33]>C1COCC1.CC([O-])(C)C.[K+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:29][C:31]([CH3:37])([CH3:36])[C:32](=[O:33])[C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: CC(C)(Br)C(=O)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
To a room temperature, stirred solution of 1-(4-methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (100 mg, 0.26 mmol) in THF (5 mL), t-BuOK (1.0 mL, 1.0 N solution in THF) was added under an inert atmosphere and the resulting mixture was stirred for 30 min. 2-Bromo-2-methylpropanoyl cyanide (90 mg, 0.5 mmol) was then added to the reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (10-15% ethyl acetate in hexanes) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (10 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:26])[C:8]=2[NH:12][C:13](=[O:25])[CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)[N:3]=1.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][NH:32][CH3:33].[ClH:34]>>[ClH:1].[ClH:34].[Cl:26][C:7]1[C:8]([NH:12][C:13](=[O:25])[CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][NH:32][CH3:33])[CH:11]=[CH:10]2
Reactant: CNCCCNC
Reactant: O=C(CC1CCC(C(F)(F)F)CC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Product: CNCCCN(C)c1ccc2c(NC(=O)CC3CCC(C(F)(F)F)CC3)c(Cl)ccc2n1

Procedure:
Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-4-(trifluoromethyl)-cyclohexaneacetamide (Example 8 (c)) (150 mg) and N,N′-dimethyl-1,3-propanediamine (450 mg). The product was converted to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (40 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1.C(NC(C)C)(C)C.[Li].[C:38]([O:41]CC)(=[O:40])C.ClCCl>C1COCC1>[CH3:29][C:2]([CH3:28])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:38]([OH:41])=[O:40])=[C:7]([N:10]([C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)[CH:6]=1
Reactant: CCOC(C)=O
Reactant: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)[C@H]2CC[C@H](O)CC2)[C@@H](C)C1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1=CC[C@H](C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(O)CC2)[C@@H](C)C1
Temperature: 0 °C

Procedure:
(1S,6S)-4,6-Dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(trans-4-hydroxy-cyclohexyl)-amide (1.74 g, 4.2 mmol) in THF (50 mL) was cooled to −78° C. and treated with lithium diisopropylamine (8.4 mL, 2.0M in heptane/THF/PhEt, 16.8 mmol) and allowed to warm to 0° C. over the course of 2 hours. CO2 was vigorously bubbled through the reaction solution for 10 minutes. The reaction was then quenched with the addition of iPrOH, diluted with ethyl acetate, washed with saturated NH4Cl(aq), dried over MgSO4, filtered, and concentrated. Silica gel chromatography (0-100% ethyl acetate/dichloromethane) afforded 530 mg (1.2 mmol) of the title compound: MS (m/z): 458.1 [M+H]+; HPLC retention time 4.35 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>S([O-])([O-])(=O)=O.[Cu+2].C(C1C=CC=CC=1C(C)C)(C)C>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:17][CH:18]=1
Reactant: Cc1ccc(I)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Cu+2]
Agent: CC(C)c1ccccc1C(C)C
Agent: O=C([O-])[O-]
Product: Cc1ccc(N2c3ccccc3Sc3ccccc32)cc1
Reaction time: 24 h
Yield: 75.4 %

Procedure:
A mixture of 25 g (0.126 mol) of phenothiazine, 33 g (0.151 mol) of p-iodotoluene, 4 g (0.025 mol) of copper sulfate, 23 g of potassium carbonate, and 200 ml of diisopropylbenzene was reacted at 180° C. for 3 hours and then at 200° C. for 1 day. The mixture was then cooled and filtered through a Celite. The filtrate was concentrated, and the residual crystals were recrystallized from an ethanol/ethyl acetate mixed solvent to obtain 27.5 g of 10-p-tolylphenothiazine (4b).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (30 mL) was added dropwise 4-methoxybenzoyl chloride (95 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 143 mg (71%) of the title compound as white crystals: mp 186-187° C.; [α]21D -52° (c 0.50, CHCL3); EIMS (70 eV) m/z (relative intensity) 379 (23, M+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[NH:16][CH2:15][CH2:14]3)[O:5]1.[CH3:23]I>CN(C=O)C.C(OCC)(=O)C>[CH3:23][N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([B:6]3[O:5][C:4]([CH3:22])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]3)[CH:12]=2)[C:17]1=[O:21]
Reactant: CI
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.2 %

Procedure:
Sodium hydride (29.3 mg, 0.732 mmol) was added to a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.366 mmol) in DMF (1.0 mL). The mixture was stirred at r.t. for 5 min, and then methyl iodide (57.0 μL, 0.915 mmol) was added. The mixture was stirred at 50° C. for 6 h, then diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.038 g, 36%). LCMS (M+H)+=274.2.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[Si:36]([O:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1>[Si:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([O:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]4[N:33]=[CH:34][N:35]=[C:9]34)[CH2:4][CH2:3]2)=[CH:48][CH:49]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 45 h

Procedure:
4′-{[4-(trans-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.46 g), 4-{[tert-butyl(dimethyl)silyl]oxy}phenol (0.49 g) and triphenylphosphine (0.29 g) were dissolved in tetrahydrofuran (2 mL), a solution of diisopropyl azodicarboxylate (0.58 mL, 1.9 M toluene solution) in tetrahydrofuran (1 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for 45 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as an oily compound (0.31 g, 47%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([N:15]([CH2:30][CH3:31])[CH2:16][CH2:17][N:18]1[C:28]2[C:23](=[C:24]([Br:29])[CH:25]=[CH:26][CH:27]=2)[C:21](=[O:22])[C:19]1=[O:20])[CH3:14].N1C2C(=CC=CC=2)C(=O)C1=O.[NH4+].[Cl-]>CCOCC>[CH2:30]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][N:18]1[C:28]2[C:23](=[C:24]([Br:29])[CH:25]=[CH:26][CH:27]=2)[C:21]([OH:22])([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:19]1=[O:20])[CH3:31]
Reactant: Brc1cccnc1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: O=C1Nc2ccccc2C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCN(CC)CCN1C(=O)C(O)(c2cccnc2)c2c(Br)cccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of n-BuLi (0.16 mL, 1.0 eq, 1.53 M in hexanes) at −78° C., in anhydrous Et2O (1.0 mL), and under a nitrogen atmosphere was added a solution of 3-bromopyridine (40.8 mg, 0.0249 mL, 1.05 eq) in anhydrous Et2O (0.5 mL). The resulting light yellow coloured precipitate was stirred at −78° C. for 30 minutes and then a solution of isatin 1-(2-diethylaminoethyl)-4-bromoisatin (80.0 mg, 2.46×10−4), in anhydrous Et2O (1.5 mL) was added dropwise. The solution was stirred for a further 7.5 hours. Saturated aqueous NH4Cl (1.5 mL) was added to the resulting brown coloured reaction mixture and the reaction was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, 1% to 1.5% to 2% MeOH in CHCl3) to yield the title compound as a light yellow oil (35.5 mg, 36%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[F:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[F:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (7 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzoic acid (520 mg) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (12 ml), and the solution was dropwise added to a solution of 4-aminopyridine (140 mg) and diisopropylethylamine (210 mg) in dichloromethane (5 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The mixture was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 560 mg of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]>CCCCCC>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2coc3c(C)c(C)c(N)c(C)c23)cc1
Solvent: CCCCCC
Product: CCc1ccc(C2COc3c(C)c(C)c(N)c(C)c32)cc1
Yield: 80 %

Procedure:
Using 3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtained in Reference Example 311, the title compound was synthesized in the same manner as in Reference Example 144. Yield 80%. Melting point: 88-89° C. (hexane).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]3=[O:20])=[N:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:3]=1.[B:39]1(B2OCC(C)(C)CO2)[O:44]CC(C)(C)C[O:40]1.C(Cl)Cl.C([O-])(=O)C.[K+]>CCCCCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH2:36]([O:35][C:33]([C:30]1([CH3:38])[CH2:31][CH2:32][N:27]([C:24]2[N:23]=[CH:22][C:21]([C:4]3[CH:3]=[C:2]([B:39]([OH:44])[OH:40])[C:10]4[S:9][C:8]([N:11]5[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]5=[O:20])=[N:7][C:6]=4[CH:5]=3)=[CH:26][N:25]=2)[CH2:28][CH2:29]1)=[O:34])[CH3:37]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(B(O)O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 130 °C
Yield: 125.3 %

Procedure:
Ethyl 1-[5-[7-bromo-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (100 mg, 0.166 mmol), bis(neopentyl glycolato)diboron (75 mg, 0.33 mmol), Pd(dppf)Cl2.DCM (14 mg, 0.017 mmol), potassium acetate (49 mg, 0.50 mmol) and toluene (2 mL) were sealed in a microwave reaction vial under argon and heated at 130° C. for 40 min. The reaction mixture was diluted with n-hexane (10 mL) before being filtered to remove particulate palladium residues. The filtrate was concentrated to obtain desired product (118 mg, light brown solid). 1H NMR (MeOD) δ 8.63 (s, 2H), 7.91 (d, J=1.9 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 5.20 (s, 2H), 4.44-4.34 (m, 4H), 4.21 (q, J=7.1 Hz, 2H), 3.50-3.42 (m, 2H), 3.33-3.28 (m, 2H, obscured by solvent), 2.65 (s, 3H), 2.21-2.13 (m, 2H), 1.69-1.38 (m, 2H), 1.33-1.19 (m, 9H). m/z [M+H]+ 568.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[C:29]([N+:36]([O-])=O)[CH:28]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>[Zn].CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([NH2:33])[CH:30]=[C:29]([NH2:36])[CH:28]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1ccc(C=CC(=O)OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCCCOc1ccc(C=CC(=O)OCCCCCCOC(=O)c2cc(N)cc(N)c2)cc1OC
Temperature: 40 °C
Yield: 102.6 %

Procedure:
3.80 g (6.98 mmol) 3,5-dinitrobenzoic acid 6-[3-(3-methoxy-4-butyloxyphenyl)acryloyloxy]hexyl ester and 1.47 g (27.48 mmol) of ammonium chloride were suspended in 75 ml of a mixture consisting of methanol:water 9:1. 9.07 g (0.139 mol) of zinc powder was then added in one portions. The reaction temperature rose to 36° C. The suspension was then heated at 40° C. for 1.5 hours. The reaction suspension was partitioned between dichloromethane and water. The resulting suspension was filtered, the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water. The organic phase was then dried over sodium sulfate, filtered and concentrated by evaporation to yielded 3.47 g (99%) 3,5-diaminobenzoic acid 6-[3-(3-methoxy-4-butyloxyphenyl)acryloyloxy]hexyl ester as yellow oil
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][CH3:17])=O.[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20].C[O-].[Na+].O>CN(C)C=O.C(O)(=O)C>[C:19]([C:21]1[C:22](=[O:23])[NH:24][C:5]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[O:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1)#[N:20]
Reactant: CCCOc1ccc(F)cc1C(=O)C=CN(C)C
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(F)cc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A stirred mixture of 3-dimethylamino-1-(5-fluoro-2-propoxyphenyl)-2-propene-1-one (2.46 g), cyanoacetamide (0.93 g), sodium methoxide (from 50% sodium hydride, 1.69 g, and methanol, 0.85 ml) in dimethylformamide (20 ml) was heated under reflux for 7 hours. The mixture was poured into water (150 ml) and acetic acid added to pH 4 to give a crude product. Recrystallization twice from acetonitrile gave a solid, 0.68 g, which was washed with petroleum ether and recrystallized again from acetonitrile to give the pure title compound, 0.15 g, m.p. 242-243° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22](Br)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([Sn](CC)(CC)CC)[CH3:41]>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.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Br)c1
Reactant: CC[Sn](CC)(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(CC)c1
Yield: 50.7 %

Procedure:
Ethyl 1-benzyl-3-[(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (2.07 g), tetraethyltin (2.07 g), tetrakis(triphenylphosphine)palladium (0.40 g) and toluene (50 mL) was stirred under an argon atmosphere while heating under reflux for 3 days. After concentration of the reaction mixture, the residue was subjected to silica gel column chromatography to give ethyl 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (0.96 g, 51%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:23]([OH:25])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[C:20]([F:19])=[C:28]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1F
Reactant: CCCCCCC(C)C(=O)c1ccc(O)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCC)c(F)c2)c1F
Yield: 56.5 %

Procedure:
Into a flask were charged 1.2 g (4.76 mmol) of (+)-3-fluoro 4-(2-methyloctanoyl) phenol, 1.51 g (5.94 mmol) of 3-fluoro-4-heptyloxy benzoic acid, 76.7 mg (0.63 mmol) of N,N-dimethylamino pyridine and 30 ml of dried methylene chloride, which were slightly heated with stirring to form a homogeneous solution. Then, the solution was added with 1.40 g (6.79 mmol) of dicyclohexyl carbodiimide and stirred over a night. The precipitated white crystal was filtered off, and the resulting filtrate was washed with 2 normal hydrochloric acid, an aqueous solution of 5% sodium hydrogen carbonate and water in this order and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and dried under a reduced pressure to obtain an oil. This oil was purified through a column chromatography and recrystallized with ethanol to obtain 1.02 g (2.69 mmol, yield: 44%) of a white crystal of the objective compound having the aforementioned physical and chemical properties.