Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CS(C)=O.CN(C=O)C>[O:12]=[C:7]1[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:3][C:4]=2[CH:5]=[CH:6]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=c1ccc2cc(Br)cnc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)ccc2c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A reaction vessel was charged with 6-bromo-1,8-naphthyridin-2(1H)-one (1.5 g, 6.69 mmol), tert-butyl acrylate (4.86 mL, 33.45 mmol), and (i-Pr)2EtN (3.5 mL, 20.07 mmol) followed by DMF (40 mL). The solution was de-oxygenated with argon for 20 min. The mixture was treated with Pd(OAc)2 (150 mg, 0.67 mmol) and P(o-tol)3 (407 mg, 1.34 mmol) then heated to 100° C. for 15 h (overnight). A TLC analysis indicated that only the starting arylhalide is present. At this time the mixture was a yellow suspension. To this mixture was added 20 DMSO (20 mL) and an additional 75 mg of Pd(OAc)2. The mixture was heated at 100° C. for 24 h. After cooling, the dark mixture was filtered through celite and the filter cake was rinsed with EtOAc (100 mL). The filtrate was extracted with EtOAc (2×100 mL). The combined organic fractions were washed with brine (2×100 mL), H2O (100 mL), dried over MgSO4 and filtered through a pad of silica gel. The filtrate was concentrated to about 50 mL then treated with about 150 mL hexanes to form a precipitate. The precipitate was filtered to give the product as a light brown solid. Yield: 700 mg (39%); 1H-NMR (300 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.83 (d, 1H, J=2.3 Hz), 8.53 (d, 1H, J=2.3 Hz), 7.89 (d, 1H, J=9.0 Hz), 7.64 (d, 1H, J=18.0 Hz), 6.65 (d, 1H, J=18.0 Hz), 6.62 (m, 1H), 1.51 (s, 9H); ESI MS m/z 273 [C15H16N2O3+H]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.S(Cl)([Cl:21])=O.[CH3:23]O>>[ClH:21].[CH3:23][O:18][C:16](=[O:17])[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)CCC1CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.95 g; 7.58 mmol) in methanol (5 mL) is slowly added thionylchloride (0.99 g; 8.34 mmol) and the reaction mixture is stirred at room temperature for 30 minutes. All volatiles are then removed under high vacuum and the resulting residue triturated with diethyl ether, sucked to dryness and washed (diethyl ether) to afford the desired compound (1.49 g; 7.18 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:27][CH2:28][O:29]C)/[C:9](/[F:26])=[C:10](\[F:25])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](/[C:9](/[F:26])=[C:10](\[F:25])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[CH2:27][CH2:28][OH:29])=[CH:6][CH:7]=1
Reactant: COCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: OCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a stirred solution of 1-[(2E)-4-(4-chlorophenyl)-2,3-difluoro-6-methoxy-2-hexenyl]-3-phenoxybenzene (0.081 g, 0.189 mmol) in methylene chloride at −5° C. under nitrogen was added dropwise boron tribromide (0.5 ml of a 1 M solution in methylene chloride, 0.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was cooled to −5° C., diluted with methanol (10 ml) and concentrated in vacua. The residue was taken up in methanol (10 ml) and the solution again concentrated. The residue was taken up in methylene chloride (25 ml), washed successively with water, saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in vacuo to a brown gum. Chromatography of this gum on silica gel afforded the title compound as a tan syrup (0.057 g) which was characterized by 1HNMR, 19FNMR and mass spectral analysis.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[OH-].[Na+].C(Cl)C=C.[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/[CH3:17])[CH3:12]>C(O)C.O>[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH:16]=[CH2:17])[CH3:12].[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH:16]([O:3][CH2:2][CH3:1])[CH3:17])[CH3:12]
Reactant: CC[O-]
Reactant: C/C=C/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C=CCCl
Solvent: O
Product: C=CCC(=O)OCC
Product: CCOC(=O)CC(C)OCC
Yield: 89.5 %
Yield: 0.5 %

Procedure:
Same as Example 1, but with the use of 1.1 mole of sodium ethylate in the form of a solution of 14.5% by weight in ethanol with a content of 0.62 wt.-% of NaOH, and 200 ml of ethanol containing 0.28 wt.-% of H2O, one mole of allyl chloride is reacted at 1.5 at. and a pH of 10.0. The filtration and distillation yield 94.0 g of crotonic acid ethyl ester (yield 89.5%, 6.9 g of vinyl acetic acid ethyl ester (yield 6.6%) and 0.7 g of β-ethoxybutyric acid ethyl ester (yield 0.5%) for a transformation of 92.4% of the allyl chloride.
Reaction SMILES: O[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12](=O)[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[OH2:23].[NH2:24][NH2:25].FC(F)(F)C([O-])=O>C(O)(=O)C.C(O)C>[CH3:9][O:8][C:7]1[CH:2]=[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:25][N:24]=2)[CH:4]=[CH:5][C:6]=1[OH:23]
Reactant: O
Reactant: COc1cccc(C=CC(=O)CC(=O)c2ccccc2)c1O
Reactant: NN
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2cc(-c3ccccc3)[nH]n2)ccc1O
Temperature: 67.5 °C
Yield: 10.7 %

Procedure:
To a mixture of 5-(hydroxy-3-methoxy-phenyl)-1-phenyl-pent-4-ene-1,3-dione (0.14 g, 0.48 mmol) and hydrazine monohydrate (0.02 g, 0.48 mmol) were added ethanol (24 mL) and acetic acid (1 drop) in a sealed tube. The reaction was heated at 65-70° C. overnight. The solvent was removed under reduced pressure to afford crude product. Purification on triethylamine treated silica (1:1 hexanes/ethyl acetate) afforded a mixture of two products. Reverse phase HPLC purification afforded 2-(methyloxy)-4-[(E)-2-(5-phenyl-1H-pyrazol-3-yl)ethenyl]phenol (0.015 g, 10% yield) as trifluoroacetate salt: 1H NMR (400 MHz, CDCl3): δ 9.21 (br s, 2H), 7.78 (br s, 2H), 7.42 (m, 3H), 7.20 (br d, 1H), 6.94 (m, 6H), 3.92 (s, 3H); MS (EI) for C18H16N2O2: 293 (MH+).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH3:16])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[C:24]1=[S:25])[CH:2]=[CH2:3]
Reactant: S=C(Cl)Cl
Reactant: C=CCNCCCNc1ccc(Cl)cc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1CCCN(c2ccc(Cl)cc2C)C1=S
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of the diamine of Step C (5.6 g) and triethylamine (6.6 mL) in dry chloroform (70 mL) under nitrogen was added thiophosgene (1.79 mL). After 30 minutes at ambient temperature, additional thiophosgene (0.6 mL) was added. After 15 minutes, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title compound (3.1 g, 47.0%) as a white solid, m.p. 101-103° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].O>CS(C)=O>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([I:22])[CH:24]=3)=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)Oc1ccccc1
Reactant: Nc1cccc(I)c1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccc(I)c1)Nc1cccc2c1CC(O)CC2
Temperature: 100 °C
Yield: 45.2 %

Procedure:
Next, a mixture of phenyl (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (30.0 mg, 0.11 mmol) and 3-iodoaniline (25.5 mg, 0.12 mmol) in 0.2 mL of DMSO was heated at 100° C. for 16 hours. After cooled to room temperature, water was added and the product was extracted with ethylacetate. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea (20.3 mg, 47% yield).
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]Cl)=[CH:16][CH:15]=1.C(Cl)(Cl)(Cl)[Cl:23]>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:4])=[O:5])[CH2:2][Cl:23])=[CH:16][CH:15]=1
Reactant: ClSc1ccc(Br)cc1
Reactant: C=CS(=O)(=O)c1ccc(Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCl)Sc1ccc(Br)cc1
Reaction time: 72 h

Procedure:
To a solution of 29.8 g (0.146 mole) of p-chlorophenyl vinyl sulfone in 50 ml of carbon tetrachloride at 25° C. was added 32.8 g (0.146 mole) of p-bromobenzenesulfenyl chloride. There was an exotherm of 4° within 52 minutes. The reaction mixture was allowed to stand for three days. Solvent was removed by evaporation at reduced pressure. The residue was recrystallized from 60 ml of ethyl acetate-petroleum ether (1:1) to give colorless needles, m.p. 76°-78°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].OO.C(O)(=[O:21])C.[OH2:23]>>[CH3:1][S:2]([C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])(=[O:21])=[O:23]
Reactant: CSc1ccc(-n2cnnn2)cc1C(=O)O
Reactant: CC(=O)O
Reactant: O
Agent: OO
Product: CS(=O)(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Combine 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.68 g, 0.29 mmol), 30% hydrogen peroxide (3 ml.) and glacial acetic acid (20 mL). After 2 hours, heat to 100° C. After 2 hours, cool to ambient temperature and add water (250 mL) to give a solid. Collect the solid by filtration and dry to give the title compound: Rf=0.21 (silica gel, 10% methanol/85% dichloromethane/5% acetic acid).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[NH:11][CH:12]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C.C(=O)([O-])O.[Na+]>C1COCC1>[N+:11]([CH:10]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)#[C-:12]
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc3c(c2)OCO3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: [C-]#[N+]C(c1ccc2c(c1)OCO2)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of N-[benzo[1,3]dioxol-5-yl-(toluene-4-sulfonyl)-methyl]-formamide (740 mg, 2.22 mmol) in THF (50 mL) was slowly added phosphorous oxychloride (0.41 mL, 4.44 mmol, 2 equiv). The resulting reaction mixture was stirred at ambient temperature for 2 hours, cooled to 0° C. and slowly treated with 2,6-lutidine (1.55 mL, 13.32 mmol, 6 equiv). The reaction mixture was stirred at ambient temperature for 48 hours, treated with saturated aqueous sodium hydrogen carbonate (80 mL), and then extracted with ethyl acetate (50 mL). The organics were dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography (20% ethyl acetate in hexane) provided 5-[Isocyano-(toluene4-sulfonyl)-methyl]-benzo[1,3]dioxole as a white solid (200 mg, 29%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl.[C:22](Cl)([O:24][CH2:25][CH:26]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22]([O:24][CH2:25][CH:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:23])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A portion (5.2 g; 20 mmol) of the methyl 4-Boc-piperazine-2-acetate product from the previous step was combined with 60 mL of THF and 60 mL of 1 N NaOH (aqueous) and stirred at room temperature for 6 hours to saponify the methyl ester. The reaction was cooled to 0° C., adjusted to pH 9-10 with 10% HCl (aqueous), and 5.2 g (20 mmol) of FMOC-Cl was added. The reaction was stirred at room temperature for 6 hours, (adding 1 N NaOH (aqueous) to maintain pH=9-10) 1 hour, then acidified with 10% HCl to pH=1. The reaction was extracted twice, the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 8.56 g of the desired 4-Boc-1-Fmoc-piperazine-2-acetic acid (the compound of formula (XXIV)); 1H NMR (CDCl3) δ 1.4 (s, 9), 2.5-3.0 (m, 5), 3.9-4.2 (m, 6), 4.5 (m, 1), 7-25 (t, 4), 7.32 (t, 4), 7.48 (d, 4), 7.75 (d, 4).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C@H:15]1[NH:27][C@H:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][N:27]1[C@H:15]([CH3:14])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[C@H:26]1[C:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:33]=1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)/C=C/c1ccc([C@H]2N[C@H](C)Cc3c2[nH]c2ccccc32)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2C[C@H](C)CF)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (291 mg, 1.30 mmol) was added to a solution of (E)-methyl 3-(4-((1R,3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (300 mg, 0.87 mmol) and N,N-diisopropylethylamine (0.226 ml, 1.30 mmol) in 1,4-dioxane (5 ml). The mixture was stirred at 90° C. for 1 hour then the mixture was evaporated to dryness and the residue was partitioned between DCM (30 nil) and water (30 ml). The aqueous layer was extracted with DCM (30 ml) and the extracts combined with the organic layer. The combined extracts were filtered through a phase-separating paper and evaporated. The residue was purified by flash silica chromatography, elution solvent 15% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (314 mg, 86%) as an off-white solid. 1H NMR (400 MHz, DMSO, 30° C.) δ 0.87 (3H, d), 1.06 (3H, d), 1.9-2.28 (2H, m), 2.55-2.8 (3H, m), 2.97-3.21 (1H, m), 3.72 (3H, s), 4.31-4.69 (2H, m), 4.88 (1H, s), 6.60 (1H, dd), 6.98 (1H, t), 7.04 (1H, t), 7.17-7.35 (3H, m), 7.44 (1H, d), 7.55-7.76 (3H, m), 10.65 (1H, s). m/z: ES+ [M+H]+ 421.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1>>[CH2:28]([C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1)[CH3:29]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: CCc1ccc(Br)cc1
Product: CCc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Yield: 38 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (210 mg, 0.765 mmol) synthesized in Reference example 61 and 1-bromo-4-ethylbenzene (212 mg, 1.15 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 110 mg (yield 38%).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][N:7]=1
Reactant: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ccc(Cc2ccc(F)nc2)cc1
Reaction time: 0.08 h
Yield: 89 %

Procedure:
A solution of (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (1.716 g, 6.88 mmol) in DCM (3.0 mL) was treated with trifluoroacetic acid (2.56 mL, 34.4 mmol) resulting in a green solution. The mixture was stirred for 5 min, and then triethylsilane (3.30 mL, 20.65 mmol) was added dropwise. The green color dissipated rapidly to give a straw colored solution, and a brief exotherm was observed (DCM started refluxing). The mixture was stirred for 30 min, and then extracted into DCM from saturated aqueous NaHCO3. The DCM extracts were dried (MgSO4) and purified by flash chromatography (5% to 7.5% EtOAc/hexane) to give 2-fluoro-5-(4-(methylthio)benzyl)pyridine (89% over 2 steps) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.15 (s, 1H); 7.81 (t, J=8.22 Hz, 1H); 7.20 (s, 4H); 7.10 (d, J=8.41 Hz, 1H); 3.94 (s, 2H); 2.44 (s, 3H). 19F NMR (376 MHz, d6-DMSO) δ −72.37 (s, 1F). m/z (ESI, +ve ion) 234.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)[CH:6]=[N:7][C:8]=1[Cl:9])#N.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC[O:33]CC>>[C:1]([C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][NH:13]2)[CH:6]=[N:7][C:8]=1[Cl:9])(=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C#N)c1
Product: O=C(c1ccccc1)c1cc(OC[C@@H]2CCN2)cnc1Cl

Procedure:
The 5-cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine of example 92a in anhydrous Et2O at 0° C. is treated with 1.5 equivalents of phenylmagnesium bromide in Et2O and stirring is maintained at 0 to 35° C. until the nitrile is largely consumed. The solvent is evaporated and the residue is treated with 2M aqueous potassium hydrogen sulfate to hydrolyze the intermediate imine. The solution is made basic with potassium carbonate and extracted with EtOAc. The combined extracts are dried (Na2SO4) and concentrated to a residue which is chromatographed (silica gel) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:44][OH:45]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([NH:44][OH:45])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(N(C)C)c3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(N(C)C)c3C2=O)ccc1OC
Yield: 87.3 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-dimethylaminophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-dimethylaminophthalimido)propanoic acid (0.31 g, 0.75 mmol), carbonyldiimidazole (140 mg, 0.86 mmol) and hydroxylamine hydrochloride (66 mg, 0.95 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-dimethylaminophthalimido)propionamide as a yellow solid (280 mg, 87% yield): mp, 187.0–188.6° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=7.0 Hz, 3H, CH3), 3.01 (s, 6H, CH3), 3.08 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.63 (t, J=7.9 Hz, 1H, NCH), 6.88 (br s, 2H, Ar), 7.00 (br s, 1H, Ar), 7.19 (m, 2H, Ar), 7.57 (dd, J=7.1, 8.3 Hz, 1H, Ar), 8.78 (br s, 1H, OH), 10.57 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.66, 34.42, 42.96, 49.88, 55.45, 63.72, 111.75, 112.41, 112.71, 113.74, 119.63, 122.32, 131.61, 133.94, 134.92, 147.60, 148.43, 149.75, 166.11, 166.76, 167.56; Anal Calcd for C22H25N3O6: C, 61.82; H, 5.89; N, 9.83. Found: C, 61.79; H, 5.90; N, 9.58.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])/[C:23](/[F:34])=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:42]([O:45][CH2:46]Br)(=[O:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:22](=[O:35])/[C:23](/[F:34])=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])[CH2:43][C:42]([O:45][CH3:46])=[O:44])=[CH:17][CH:16]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OCBr
Reactant: C/C(=C(\F)C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)/C(F)=C(/C)c1cccc(C#N)c1)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-2-fluorobut-2-enamide (230 mg, 0.47 mmol) in 15 ml DMF was added cesium carbonate (460 mg, 1.41 mmol) and bromomethyl acetate (355 mg, 2.35 mmol). The reaction mixture was stirred at room temperature for 4 hours then diluted with 25 ml of ethyl acetate. Organic was washed with 3×25 ml water, 3×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl 2-{(2E)-N-[4-(2-{[(tert-butyl)amino]-sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-2-fluorobut-2-enoylamino}acetate (230 mg, 86%) as yellow foam. ES-MS (M+H+): 563.2.