Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[C:10]([O:35][CH3:36])[CH:9]=1)(=O)=O.[CH3:37][O:38][C:39](=[O:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](=[O:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][O:5][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[C:39]([O:38][CH3:37])=[O:47])=[CH:9][C:10]=1[O:35][CH3:36]
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOS(C)(=O)=O)cc1OC
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1OC
Yield: 51 %

Procedure:
2-(4-{2-[(2,4-Difluorobenzyl)(heptyl)amino]-2-oxoethoxy}-3-methoxyphenyl)ethyl methanesulfonate (138 mg, 0.262 mmol) was dissolved in acetonitrile (10 ml). 2-Hydroxybenzoic acid methyl ester (40 mg, 0.262 mmol) was added and then potassium carbonate anhydrous (54 mg, 0.392 mmol) was added. The mixture was heated to reflux overnight and then evaporated to dryness. Water (10 ml) and ethyl acetate (10 ml) were added and the two phases were separated. The organic phase was washed with water and brine, dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (1:99) as eluant gave 78 mg the desired product, yield 45% (two steps).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][NH:33]N)=[CH:30][CH:29]=1.CCN(CC)CC.Cl>CO>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: COc1ccc(CNN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (675 mg, 2 mmol), (4-methoxybenzyl)hydrazine hydrochloride (755 mg, 4 mmol), and Et3N (0.558 mL, 4 mmol) in MeOH (20 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (367 mg, 43% yield) as an off-white solid: mp 159-161° C.; NMR (300 MHz, CDCl3): δ ppm 3.73 (3H, s), 5.67 (2H, s), 6.69-6.75 (3H, m), 6.81-6.86 (2H, m), 7.41 (1H, d, J=1.9 Hz), 7.45-7.51 (1H, m), 7.54-7.59 (1H, m), 7.65-7.71 (3H, m), 8.17 (1H, d, J=7.9 Hz). LC-MS (ESI) m/z 427 [M+H]+. Anal. Calcd for C22H17F3N4O2: C, 61.97; H, 4.02; N, 13.14. Found: C, 61.95; H, 4.14; N, 13.08.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].O.[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[CH3:22][O:14][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: COS(=O)(=O)OC
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 65 °C
Yield: 100.8 %

Procedure:
Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of 2,3,5,6-tetrafluoro-1,4-benzenedimethanol, 15.00 g of water and 6.85 g (46.3 mmol) of 27% aqueous sodium hydroxide solution were charged subsequently, and heated to 65° C. with stirring. The starting compound was completely dissolved to be clear solution. Then, the reaction mixture was allowed to cool to room temperature with stirring. At this time, some precipitate was observed. To the reaction mixture, 20.0 g of toluene was added and then 4.33 g (32.6 mmol) of dimethyl sulfate was added dropwise over 7.5 hours at room temperature. After the addition, the pH of the aqueous layer became 13.5. The layers of the reaction mixture were separated, and the pH of the aqueous layer was adjusted to about 3 by adding 10% sulfric acid. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layers were washed- with 30 ml of water, concentrated, and dried under a reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol. The crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol was subjected to content analysis by GC internal standard method (Analytical method 1 given later). GC area percentage of the crude product: 85% of the objective compound, 1% of the starting compound and 13% of the by-product compound Content analysis by GC internal standard method: 85% of the objective compound and 86% of the yield of pure compound
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N:19][CH:18]=[CH:17]2.CO.Cl>ClCCl.C(OCC)C>[ClH:1].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N+:19]([O-:9])[CH:18]=[CH:17]2
Reactant: COc1ccc2cnccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2c[n+]([O-])ccc2c1
Reaction time: 3 h
Yield: 80.3 %

Procedure:
At ambient temperature 133 g of m-chloroperbenzoic acid (purity 75%) was added in portions to a stirred solution of 6-methoxy-isoquinoline [Hendricks, J. B. and Rodriguez, C., J. Org. Chem. 1983, 48, 3344-3346; 79.8 g; 500 mmol] in 1.2 L of dichloromethane. Stirring was continued for 3 hours and subsequently methanol (1 L) was added. The bulk was reduced to 700 ml after which 800 ml of a saturated solution of hydrogen chloride in diethyl ether was added. Dilution with 1.5 L of diethyl ether resulted in precipitation of yellow crystals, which were separated by filtration, washed with chilled diethyl ether and dried in vacuo to give 6-methoxy-isoquinoline-N-oxide hydrochloride (85 g, 80%), (+)-FAB-MS 176 [M+H-HCl]+.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH:20][C:23](=[O:25])[CH3:24])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:21][CH:22]=1)([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Product: CC(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Yield: 63 %

Procedure:
The procedure of Example 4 was repeated to react 2-(4-carboxybenzamido)-4-aminobenzoic acid with acetic anhydride, and the reaction product was treated as in Example 4 to yield 63% of 2-(4-carboxybenzamido)-4-acetamidobenzoic acid having a melting point in the range of from 302° to 304° C. (decompose).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30](=[O:54])[NH:31][CH:32](C=O)[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([CH2:43][CH:44]=[CH:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:35]=1)([CH3:28])([CH3:27])[CH3:26].[CH2:55]1COCC1>>[CH3:24][O:23][C:21](=[O:22])[CH:20]=[CH:55][C@H:32]([NH:31][C:30]([O:29][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:54])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([CH2:43][CH:44]=[CH:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:35]=1
Reactant: C1CCOC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C=O)Cc1cn(CC=Cc2ccccc2)c2ccccc12
Product: COC(=O)C=C[C@@H](Cc1cn(CC=Cc2ccccc2)c2ccccc12)NC(=O)OC(C)(C)C
Yield: 78 %

Procedure:
Methyl (triphenylphosphoranylidene)acetate (1.16 g, 3.465 mmol) and {1-formyl-2-[1-(3-phenyl-allyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester (1.4 g, 3.465 mmol) in THF (19 mL) were stirred overnight under argon. The solvent was removed, Et2O added and the solution filtered. The filtrate was concentrated and the residue subject to column chromatography (silica gel, 25% EtOAc/petroleum ether) to afford the title compound (1.238 g, 78%), mp 119.3-120.6° C. 1H NMR (CDCl3) δ 7.59 (1H, d, J=7.71 Hz), 7.36-7.01 (9H, m), 6.97 (1H, s), 6.45 (1H, d, J=6.45 Hz), 6.29 (1H, dt, J=5.58 15.93 Hz), 5.88 (1H, d, J=15.93 Hz), 4.82 (2H, d, J=5.4 Hz), 4.69 (1H, br s), 3.65 (3H, s), 3.04 (2H, br s), 1.38 (9H, s), 13C NMR (CDCl3) δ 166.6, 155.1, 148.7, 136.4, 136.1, 132.3, 128.5, 128.2, 127.8, 126.4, 124.7, 121.8, 120.4, 119.3, 119.0, 109.6, 109.5, 79.7, 51.7, 51.5, 48.2, 30.4, 28.2. ISMS: 461 (M+H).
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C(OCC)C>[CH2:6]([C:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(Cc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To 3.00 g (42.80 mmol) of cyclobutanone in 143 mL of tetrahydrofuran at 0° C. was added 51.36 mL (51.36 mmol) of a 1 M solution of benzyl magnesium chloride in diethyl ether and the mixture was allowed to warm to RT and stirred for 20 h. The reaction was quenched with methanol, followed by water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6.52 g (94%) of 1-benzylcyclobutanol. Then, 1.90 g (11.69 mmol) of the compound was dissolved in 12 mL of toluene and 2.00 g (11.69 mmol) of methyl(2S)-2-isocyanatohexanoate was added. The mixture was heated at 85° C. for 3 d. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:6) to give 2.44 g (63%) of methyl (2S)-2-({[(1-benzylcyclobutyl)oxy]carbonyl}amino)hexanoate. Rf=0.30 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.48 (d, J=8 Hz, 1H), 7.29-7.13 (m, 5H), 4.02-3.94 (m, 1H), 3.64 (s, 3H), 3.16 (ABq, JAB=16 Hz, Δ84 AB=12 Hz, 2H), 2.22-2.02 (m, 4H), 1.82-1.44 (m, 4H), 1.36-1.18 (m, 4H), 0.86 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][NH2:2].CO.[CH:5]([C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)=O.[BH4-].[Na+]>O>[CH3:1][NH:2][CH2:5][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CN
Reactant: N#Cc1c(C=O)[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1[nH]c2ccccc2c1C#N
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
Methylamine (6.2 mL, 49.4 mmol, 33% in EtOH) was added to a MeOH (50 mL) solution of 2-formyl-1H-indole-3-carbonitrile (2.80 g, 16.5 mmol) at 0° C. Upon stirring for 5 h at 0° C., NaBH4 (740 mg, 19.8 mmol) was added to the solution and the stirring was continued for 16 h. The mixture was diluted with water, extracted with methylene chloride; the organic layer was dried and evaporated. The crude residue was subjected to chromatography (1-5% MeOH in methylene chloride). The desired fractions were collected and concentrated; the residue was recrystallized from a methylene chloride/hexane mixture to afford the title compound (2.30 g, 75%). 1H NMR (300 MHz, DMSO-d6, 8): 7.54 (m, 1H), 7.48 (m, 1H), 7.21 (m, 2H), 3.93 (s, 2H), 2.31 (s, 3H). MS (ESI): m/e 186 (M+H)+.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][CH:13]([C:17]1([CH:22]([CH2:24][CH2:25][CH3:26])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18]1)[CH2:14][CH2:15][CH3:16].S(C1C=CC(C)=CC=1)(O[CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])(=O)=O>O1CCCC1.O>[CH3:34][N:33]([CH2:32][CH2:31][C:18]1[C:17]([CH:13]([CH2:14][CH2:15][CH3:16])[CH3:12])([CH:22]([CH2:24][CH2:25][CH3:26])[CH3:23])[CH:21]=[CH:20][CH:19]=1)[CH3:35]
Reactant: CCCC(C)C1(C(C)CCC)C=CC=C1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCC(C)C1(C(C)CCC)C=CC=C1CCN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a solution of n-butyllithium in hexane (24.0 ml; 1.6 mol/L; 38 mmol) was added dropwise to a cooled (0° C.) solution of di-(2-pentyl)cyclopentadiene (7.82 g; 38.0 mmol) in dry tetrahydrofuran (125 ml) in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, 2-dimethylaminoethyl tosylate (38.0 mmol) prepared in situ was added. After 18 hours of stirring, the conversion was found to be 92%, and water (100 ml) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether, and the combined organic phase was then dried with sodium sulphate, and evaporated to dryness. The residue was purified on a silica gel column, which resulted in 8.2 g of (dimethylaminoethyl)-di(2-pentyl)cyclopentadiene.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[N:18][OH:19])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([OH:23])(=[O:22])[CH3:21].[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[N:18][OH:19])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccsc1C(Cc1ccccc1[N+](=O)[O-])=NO
Solvent: c1ccncc1
Product: CC(=O)O

Procedure:
A mixture of 15.0 g of 1-(3-methyl-2-thienyl)-2-(2-nitrophenyl)ethanone oxime, 27 ml of pyridine and 14 ml of acetic anhydride was heated on a steam bath for 0.5 hr, with stirring. The solution was decanted into ice-water. The solid was collected and recrystallized from 95% ethanol to give 14.8 g of product, mp 60°-68° C.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[Br-].C([PH3+])CC.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.O>C1COCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1)[CH2:1][CH2:2][CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccncc1
Agent: CCC[PH3+]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
4-Butylpyridine was prepared by adding potassium-t-butoxide (0.68 g, 6 mmol) to propylphosphonium bromide (Aldrich) (2.4 g, 6.0 mmol) in THF (10 mL), at 0° C. and stirring at room temperature for 1 hour. Pyridine-4-carbaldehyde (428 mg, 4 mmol) was added and the reaction mixture stirred for 2 h. The reaction mixture was then poured into water and extracted with ethyl acetate. The product obtained after removing the solvent was taken as such in methanol (30 mL) to which palladium on carbon (10%, 300 mg) was added and hydrogenated at 1 atm pressure over night. Removal of solvent and purification on column chromatography using ethyl acetate resulted in pure product 4-butylpyridine (500 mg, 92%):
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:12][S:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34](O)[CH:35]1[CH2:37][CH:36]1[C:38]#[N:39]>ClCCl>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]([C:22]1[C:21]2[C:25](=[C:17]([CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH:18]=[CH:19][CH:20]=2)[NH:24][CH:23]=1)[CH:35]1[CH2:37][CH:36]1[C:38]#[N:39]
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
116 mg (0.53 mmol) of indium(III) chloride and 0.07 ml (0.86 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 86A and 120 mg (0.57 mmol) of the compound from Example 162A under argon in 5 ml of dichloromethane, and the mixture was stirred under reflux for 1 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 29.0 mg (15% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18].CCCCCC>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)c1cc(I)ccc1Cl
Reactant: C=C([Zn+])C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (53 mL) under nitrogen atmosphere was added 2-chloro-5-iodobenzotrifluoride (7.1 g), followed by the addition of dichlorobis(triphenylphosphine)palladium(II) (0.65 g). The mixture was stirred under reflux for 2.5 hours and then cooled to room temperature. To the resulting mixture was added hexane (100 mL) and filtered, and the filtrate was washed with water (50 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as colorless oil (4.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[CH:44]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:42][C:43]2[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=2)=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc(Oc2ccnc(Br)c2)c1
Reactant: Cc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(NC(=O)c2cccc(Oc3ccnc(Br)c3)c2)c1

Procedure:
A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (170 mg, 0.58 mmol), HATU (265 mg, 0.69 mmol),) m-toluidine (93 mg, 0.87 mmol) and N,N-diisopropylethylamine (164 mg, 1.28 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 20 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-Bromo-pyridin-4-yloxy)-N-m-tolyl-benzamide as off-white solid. Yield: 150 mg, 68%.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[C:76]([CH:77]([CH3:79])[CH3:78])=[CH:75][C:74]([Cl:80])=[C:73]([CH3:81])[C:71]=2[N:72]=1>>[Cl:80][C:74]1[CH:75]=[C:76]([CH:77]([CH3:78])[CH3:79])[C:70]2[O:69][C:68]([S:67][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[O:36])[CH2:32][CH2:33]3)=[N:72][C:71]=2[C:73]=1[CH3:81]
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Reactant: Cc1c(Cl)cc(C(C)C)c2oc(S)nc12
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4c(C)c(Cl)cc(C(C)C)c4o3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-5-chloro-7-isopropyl-4-methylbenzoxazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH:7]=[CH:6][C@H:5]([CH2:8][CH3:9])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].CSC.[OH-:20].[Na+].OO>C1COCC1.CCOC(C)=O>[CH2:1]([C@@H:3]1[CH:7]([OH:20])[CH2:6][C@H:5]([CH2:8][CH3:9])[N:4]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH3:2]
Reactant: CC[C@H]1C=C[C@@H](CC)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: C1CCOC1
Product: CC[C@H]1CC(O)[C@@H](CC)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 148.7 %

Procedure:
To a solution of tert-butyl (2R,5S)-2,5-diethyl-2,5-dihydropyrrole-1-carboxylate (4.8 g, 10.5 mmol) in THF (50 mL) was added slowly BH3.DMS solution (2M in THF, 6.97 mL, 13.9 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours and then cooled to 0° C. NaOH solution (5 M, 12.6 mL, 63.2 mmol) was added to the reaction mixture, followed by addition of H2O2 (30%, 6.33 mL, 62.0 mmol). The resulting mixture was stirred for 5 hours before diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and dried over Na2SO4. The organic solvent was removed to give the crude product, which was purified by flash chromatography on silica gel to give the tert-butyl (2R,5S)-2,5-diethyl-3-hydroxy-pyrrolidine-1-carboxylate (3.8 g, 77%). 1HNMR(CDCl3, 300 MHz): 4.35 (s, 1H), 4.0-3.46 (m, 5H), 3.33 (m, 1H), 2.22-2.10 (m, 1H), 1.89-1.73 (m, 1H), 1.39 (s, 9H), 0.82 (s, 18H), −0.01 (s, 6H), −0.03 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[C:16]([C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)[CH:15]=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Yield: 71.4 %

Procedure:
Compound II (54 mg, 0.113 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), 4-fluorophenylboronic acid (32 mg, 0.23 mmol) and potassium carbonate (63 mg, 0.45 mmol) were stirred in toluene (1.5 mL) and water (0.7 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (5 mL) and extracted with EtOAc (3×5 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 80:20) to furnish III as a colourless oil (34 mg, 71%).