Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=1)[CH2:10][NH:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)=[O:18])(C(C)(C)C)(C)C.[F-].[NH4+]>CO.O>[F:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[C:16]2[CH:29]=[CH:30][CH:31]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=3)([CH3:33])[CH3:32])[CH:15]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(Cc1cccc(C(=O)NCCc2cccc(F)c2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(Cc1cccc(C(=O)NCCc2cccc(F)c2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Yield: 52 %

Procedure:
3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxylmethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3-fluorophenyl)ethyl]benzamide (preparation 157), (343 mg, 0.58 mmol) and ammonium fluoride (213 mg, 5.76 mmol) in methanol (12 mL) and water (2 mL) were stirred at room temperature for 42 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were concentrated in vacuo and the residue was azeotroped (×2) in ethanol to give a white solid. This solid was then re-crystallised with ethanol/water and dried under vacuum to afford the title compound as very pale yellow crystals in 52% yield, 144 mg. 1H NMR (400 MHz, CD3OD) δ: 7.63 (2H, m) 7.38-7.23 (4H, m), 7.13 (1H, m), 7.05 (1H, m), 7.00 (1H, m), 6.91 (1H, m), 6.85 (1H, d), 4.65 (3H, m), 3.59 (2H, m), 2.96-2.84 (2H, m), 2.78-2.68 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm. LRMS ESI m/z 481 [M+H]+.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:26]1([N:23]2[CH2:24][CH2:25][N:20]([C:16]3[N:15]=[C:14]([C:12]4[S:4][C:3]5[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=5[C:1](=[O:10])[N:13]=4)[CH:19]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(N2CCN(c3ccccc3)CC2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(N3CCN(c4ccccc4)CC3)n2)sc2ccccc12
Yield: 33.3 %

Procedure:
A mixture of methyl thiosalicylate (0.25 g, 1.5 mmol), 2-cyano-6-(4-phenyl-1-piperazinyl)pyridine (0.40 g, 1.5 mmol), triethylamine (0.32 ml, 2.3 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure and the crude crystals were recrystallized from ethanol to give the titled compound (0.20 g, 33%) as crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:26]([CH:28]=O)[CH:25]=[C:24]3[C:20]=2[CH:21]=[N:22][N:23]3COCC[Si](C)(C)C)=[CH:13][CH:12]=1.Cl>>[N:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:26]([CH:28]=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[CH:25]=[C:24]3[C:20]=2[CH:21]=[N:22][NH:23]3)=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(/C=C/c3ccncc3)cc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Product: O=C1Nc2ccccc2C1=Cc1cc(/C=C/c2ccncc2)c2cn[nH]c2c1

Procedure:
According to the method of A54C, oxindole (10 mg, 0.07 mmol) was reacted with (E)-4-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carb-aldehyde (27 mg, 0.06 mmol) and then treated with HCl to give the title compound as a 3:1 mixture of E/Z isomers (4 mg, 28%). MS ESI [M+H]+, calcd for [C23H16N4O+H]+ 365.1; found m/z 365.2. E-isomer 1H NMR (400 MHz, DMSO-d6) δ 8.82-8.79 (m, 2H), 8.20-8.12 (m, 3H), 7.96 (s, 1H), 7.81-7.74 (m, 3H), 7.64 (s, 1H), 7.52 (d, 1H, J=8.1 Hz), 7.23 (t, 1H, J=7.8 Hz), 6.89 (d, 1H, J=8.0 Hz), 6.88-6.86 (m, 1H); Z-isomer 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.67 (s, 1H), 8.60-8.58 (m, 2H), 8.27 (s, 1H), 8.01 (s, 1H), 7.91 (d, 1H, J=16.8 Hz), 7.77 (d, 1H, J=7.5 Hz), 7.74 (d, 2H, J=5.5 Hz), 7.49 (d, 1H, J=16 Hz), 7.23 (t, 1H, J=7.8 Hz), 7.02 (t, 1H, J=7.6 Hz), 6.86 (d, 1H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])/[CH:9]=[CH:10]\[CH3:11])=[CH:6][CH:7]=1
Reactant: CC#CC(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: C/C=C\C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under nitrogen, hydrogenate a mixture of 10 g (0.055 mole) of 1-(4-chlorophenyl)-2-butyn-1-ol and 0.6 g Lindlar catalyst. Following the reaction via NMR the reaction is complete in about two days. The hydrogenation is stopped and the reaction stirred under N2 at room temperature overnight. Filter off the catalysts, wash with methylene chloride combine the filtrate and evaporate to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([Br:10])[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:7][C:6]1[C:2]([Br:1])=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:4][C:5]=1[Br:10]
Reactant: CCOC(=O)c1sc(Br)c([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(Br)c(N)c1Br
Temperature: 60 °C
Yield: 65.5 %

Procedure:
To the solution of Ethyl 3,5-dibromo-4-nitrothiophene-2-carboxylate (compound 34a, 10.0 g, 27.85 mmol) in acetic acid (100 ml) was added iron powder (7.77 g, 139.27 mmol). The reaction mixture was then heated at 60° C. for 35 min under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. Acetic acid from the reaction mixture was then evaporated under reduced pressure. The pH of the resulting reaction mass was brought to between 8 and 9 by adding to it saturated sodium bicarbonate solution. To the mixture so obtained was added ethyl acetate (150 ml), the resulting emulsion was filtered and then the organic layer was separated. The aqueous layer remaining behind was re-extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (6.00 g, 65.50%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[C:21]1([CH:16]([OH:17])[C:15]2[CH:18]=[CH:19][CH:20]=[C:13](/[CH:12]=[CH:11]/[C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:14]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cccc(/C=C/c2ccc3ccccc3n2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(/C=C/c2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[2(E)-(quinolin-2-yl)ethenyl] benzaldehyde (5.9 g, 22.8 mmol) in tetrahydrofuran (20 ml) was added to a stirred solution of phenyl magnesium bromide [prepared from bromobenzene (4.3 g, 27.4 mmol) and magnesium turnings(0.66 g, 27.4 mg atom) in tetrahydrofuran (50 ml) at ca 40° C.] at 10°-15° C. The dark solution was stirred for 1 hour at room temperature, poured onto saturated ammonium chloride solution and extracted with dichloromethane. The extract was dried and evaporated and the residue was crystallised from ethyl acetate.
Reaction SMILES: S(=O)(=O)(O)O.S([O-])([O-])(=O)=[O:7].[Na+].[Na+].[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[C:19]([OH:7])[CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1cccc(O)c1
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 396.7 %

Procedure:
A four-necked flask (2 liters-volume) was charged with 98% sulfuric acid (1200 g). Anhydrous sodium sulfate (102 g, 6 mol %) and then ethylbenzene (424 g) were added thereto in 30 minutes while stirring. Temperature was gradually elevated to 200° C. over 2 hours while evaporated water was withdrawn. The heating was continued with stirring for 4 hours at the same temperature in order to isomerize. Then, the mixture was cooled to 170° C. Water (2000 g) was dropped at a uniform rate into the stirred mixture at the same temperature over 10 hours in order to hydrolyze. The obtained reaction mass was left to stand at 150° C. for 30 minutes to form layers. The layer of sulfuric acid (854 g) was removed. The layer of sulfonic acid (1074 g) was neutralized to pH 7.8 with 50% potassium hydroxide and added dropwise to a mixture of sodium hydroxide (563 g) and potassium hydroxide (83 g) mutually melting at 330° C. in a 2 liter reaction vessel. The mixture was heated to 340° C. and maintained with stirring at this temperature for 1 hour. Then, the mixture was dissolved in water (2000 ml) and neutralized to pH 7.2 with 35% hydrochloric acid. The produced phenols were extracted with ether and distilled to give crude m-ethylphenol (348 g, 71% yield based on consumed ethylbenzene), which showed a purity of 98.2% after fractional distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([O:14]C(=O)C2C=CC=CC=2)[CH3:13])[CH2:11][O:10]1.C[O-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](OC(=O)c1ccccc1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
In 800 ml of methanol was dissolved 15.9 g of [(1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl]benzoate. To the solution was added 28% methanolic solution (12.9 ml) of sodium methylate with ice cooling and the reaction mixture was stirred at room temperature for 6 hours. To the reaction mixture was added 63.2 ml of 1N aqueous solution of hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (gradient eluent; hexane:ethyl acetate=6:1→2:1) to give 9.7 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[C:3]=1[OH:19].[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=O.C(=O)([O-])O.[Na+]>O1CCOCC1>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](/[CH:9]=[CH:8]/[C:4]2[C:3]3[O:19][C:26]([C:22]4[N:21]([CH3:20])[CH:25]=[CH:24][CH:23]=4)=[N:1][C:2]=3[CH:7]=[CH:6][CH:5]=2)=[N:11]1
Reactant: Cn1cccc1C(=O)Cl
Reactant: Nc1cccc(/C=C/c2n[nH]c3ccccc23)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cccc1-c1nc2cccc(/C=C/c3n[nH]c4ccccc34)c2o1
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
A solution of (E)-2-amino-6-[2-(1H-indazol-3-yl)vinyl]phenol (0.10 g, 0.40 mmol) obtained in Step 2 in 1,4-dioxane (1.5 mL) was added with 1-methyl-1H-pyrrole-2-carbonyl chloride (63 mg, 0.44 mmol) and stirred at 210° C. for 15 minutes under microwave irradiation. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) and crystallized from ethanol to obtain Compound 148 (13 mg, 10%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([O:27][C:28]([F:31])([F:30])[F:29])[CH:21]=2)[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:11]2=[O:32])=[CH:21][C:22]=1[O:27][C:28]([F:30])([F:31])[F:29]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2ccc(N)c(OC(F)(F)F)c2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2ccc(N)c(OC(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
3-[3-(4-Amino-3-tri fluoromethoxy-benzyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester—20 mg (0.04 mmol) is dissolved in 1.5 mL of dioxane/water (1:1) and then lithium hydroxide (4.1 mg, 0.17 mmol) is added. The reaction is stirred at room temperature and monitord by LC/MS. Upon completion the reaction is acidified by the addition of 1N HCl. The solvent is evaporated and the residue partitioned between ethyl acetate (2 mL) and water (2 mL). The organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated and the resulting solid is purified by Combi flash chromatography, eluting with 0-20% methanol/dichloromethane to give the title compound (18 mg, 0.04 mmol 95%). LCMS (ESMS): m/z 438.4 (M+H+).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.C=O.[C:10](=O)([O-])[O-:11].[Na+].[Na+]>O>[OH:11][CH2:10][N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7]
Reactant: O=C1C=CC(=O)N1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: O
Product: O=C1C=CC(=O)N1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 18971.5 %

Procedure:
A mixture of 9.8 g (0.1 mole) maleimide, 9 ml 37% aqueous formaldehyde and 40 mg sodium carbonate was stirred at room temperature for 1 hour. The mixture was diluted with 30 ml water and the crystals formed (9.1 g N-hydroxymethylmaleimide) were collected by filtration.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+]>O>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
2,2,3,3-tetrafluoropropanol(406 g, 3.08 mol), 613 g tosyl chloride(3.22 mol), and 1200 ml water heated to 50° C. with mechanical stirring. Sodium hydroxide(139.7 g, 3.5 ml) in 560 ml water was added at a rate such that the temperature remained less than 65° C. After the addition was completed, the mixture was stirred at 50° C. until the pH of the aqueous phase was 6. The mixture was cooled and extracted with 1.5 liters methylene chloride. The organic layer was washed twice with 200 ml aqueous ammonia, 350 ml water, dried with magnesium sulfate, and distilled to give 697.2 g(79%) viscous oil.
Reaction SMILES: [H][H].Br[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][S:12]([C:15]2[N:19]=[C:18]([NH:20]C=O)[NH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([Cl:23])[C:5]=1[CH3:24]>C(O)C>[Cl:23][C:6]1[C:5]([CH3:24])=[CH:4][CH:9]=[C:8]([Cl:10])[C:7]=1[NH:11][S:12]([C:15]1[N:19]=[C:18]([NH2:20])[NH:17][N:16]=1)(=[O:14])=[O:13]
Reactant: [H][H]
Reactant: Cc1c(Br)cc(Cl)c(NS(=O)(=O)c2n[nH]c(NC=O)n2)c1Cl
Solvent: CCO
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl

Procedure:
A 3-necked flask equipped with a thermometer, reflux condenser with a nitrogen outlet, a sparge tube to introduce hydrogen and a spinbar was charged with the product of Example 11 (2 g, 4.66 mmol) and 100 mL of 95% ethanol. The mixture was stirred rapidly and purged with nitrogen and 150 mg of 10% Pd/C was added. Hydrogen gas was bubbled through the mixture while heating to reflux. After three hr of reflux the reaction was essentially complete. The mixture was purged with nitrogen and filtered. The filtrate was concentrated to yield the title compound as an off white solid, 1.5 g (98%) m.p. 198°-200° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[S:7][CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH:21]=[CH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:3][C:4]4[N:5]=[C:6]([CH2:9][N:10]5[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]5)[S:7][CH:8]=4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: CN1CCN(Cc2nc(CCl)cs2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN2CCN(C)CC2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 19.3 %

Procedure:
1-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-4-methylpiperazine hydrochloride (0.067 g, 0.238 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.080 g, 0.238 mmol) were suspended in DMF (4 mL) and potassium carbonate (0.164 g, 1.19 mmol) was added. The mixture was stirred at 70° C. for 21 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford the title compound as a colorless solid (0.025 g, 0.046 mmol, 19% yield). 1H NMR (400 MHz; CDCl3): 2.08 (s, 5H); 2.39 (s, 3H); 2.59-2.74 (m, 6H); 3.44-3.78 (m, 5H); 3.86 (s, 2H); 3.98 (s, 3H); 5.30 (s, 2H); 7.10 (s, 1H); 7.33 (s, 1H); 7.37 (s, 1H); 7.43 (d, 1H); 7.61 (dd, 1H); 7.99 (d, 1H); 8.60 (s, 1H); MS (EI) for C25H26Cl2N6O2S: 545 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=2)[CH:18]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-amino-5-bromo-benzotrifluoride (17.1 g, 71.24 mmol), 4-methylimidazole (17.6 g, 213.72 mmol), potassium carbonate (9.8 g, 71.24 mmol), cupper (1.1 g, 17.81 mmol), and cupper iode (II) (3.4 g, 17.81 mmol) were added to N,N-dimethylacetamide (100 ml) at room temperature, and mixed therewith at 140˜150° C. for 16 hr. After the reaction was completed, the temperature of the reaction vessel was cooled to RT. Then, ethyl acetate (200 ml) was added thereto and mixed therewith for 30 min. The reaction mixture was filtered with Celite, and an organic layer of the filtered solution was washed with water, dried with magnesium sulfate, distilled under vacuum, and washed with n-hexane to give the titled compound as pale white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:21][C:22]([C:29]([F:32])([F:31])[F:30])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[CH:23]=[C:22]([C:29]([F:32])([F:30])[F:31])[O:21][C:20]=2[CH3:19])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1oc(C(F)(F)F)cc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1oc(C(F)(F)F)cc1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2-methyl-5-(trifluoromethyl)furan-3-sulfonyl chloride (0.5 mmol) to form N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-methyl-5-(trifluoromethyl)furan-3-sulfonamide. 1H NMR (CDCl3) δ 2.2 (s, 3H), 5.3 (s, 1H), 6.0 (dt, 1H), 6.8 (s, 1H), 6.95 (s, 1H), 7.0-7.3 (m, 3H), 7.4 (dd, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=C>>[CH2:13]([O:12]/[CH:3]=[CH:2]\[CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C=CCc1ccccc1
Reactant: C=COCCCC
Product: CCCCO/C=C\Cc1ccccc1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Following the general procedure for enol ether cross metathesis, allyl benzene (50.0 mg, 0.423 mmol, 7) was treated with butyl vinyl ether (424 mg, 4.23 mmol), 2.5 mol % of in situ-generated complex 1a (106 μL, 0.10 M, 10.6 μmol; final substrate concentration=4.0 M), and allowed to stir for 2 h. The unpurified product is 98% Z (as determined by 400 MHz 1H NMR analysis). The resulting brown oil was purified by neutral alumina chromatography (100% hexanes) to afford 8a (61.3 mg, 0.322 mmol, 76.0% yield, >98% Z isomer) as a colorless oil. The physical and spectral data were identical to those previously reported for compound 8a.9 IR (neat): 3028 (w), 2959 (m), 2933 (m), 2872 (m), 1663 (s), 1495 (m), 1453 (m), 1373 (m), 1253 (m), 1108 (s); 1H NMR (400 MHz, CDCl3): δ 7.32-7.16 (5H, m), [diagnostic E isomer signal: 6.37 (1H, dt, J=16.0, 1.2 Hz)], 6.08 (1H, dt, J=6.0, 1.6 Hz), 4.57 (1H, td, J=7.6, 6.2 Hz), 3.79 (2H, t, J=6.4 Hz), 3.45 (2H, d, J=7.6 Hz), 1.69-1.61 (2H, m), 1.49-1.39 (2H, m), 0.97 (3H, t, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 145.7, 142.1, 128.4, 128.4, 125.8, 105.4, 72.2, 32.0, 30.4, 19.2, 14.0; HRMS (ESI+) [M+H]+ calcd for C13H19O: 191.1436, found: 191.1432.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+:16]>C(O)C>[NH2:16]/[C:1](/[CH2:2][CH2:3][CH3:4])=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [NH4+]
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCC/C(N)=C\C(=O)OCC
Temperature: 25 °C

Procedure:
Ethyl butyrylacetate (2.7 g, 17 mmol) in ethanol (7 mL) was treated with ammonium acetate (2.0, 26 mmol) and heated to reflux in a seated tube for 16 hours, cooled to ambient temperature and concentrated. The residue was purified by chromatography eluting with 2% methanol in ammonia saturated dichloromethane to provide the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:15](=[O:17])[C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: O=C(O)C#Cc1ccc(CN2CCCC2)cc1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C#Cc1ccc(CN2CCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 0.3 g (1.30 mmol) of (4-pyrrolidin-1-ylmethylphenyl)propynoic acid, 0.27 g (1.32 mmol) of 4′-chlorobiphenyl-4-ylamine, 0.42 g (1.32 mmol) of TBTU, and 0.18 mL (1.32 mmol) of triethylamine in 30 mL of DMF is stirred for 14 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted with water and dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (10:1)). Yield: 0.095 g (17.5% of theory); melting point: from 180° C.; C26H23ClN2O (M=414.93); calc.: molecular ion peak (M+H)+: 415/417; found: molecular ion peak (M+H)+: 415/417; Rf value: 0.3 (silica gel, dichloromethane/ethanol (5:1)).