Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[O-].[Na+].[CH3:26][C:27](=[CH:29][CH2:30][CH2:31]/[C:32](=[CH:34]/CO)/[CH3:33])[CH3:28].CO>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]
Reactant: CCCCCCCCN(CCCCCCCC)CC(=O)OC
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCN(CCCCCCCC)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N,N-dioctylglycine methyl ester (47.02 g, 150 mmol, 1 eq) in toluene (250 ml) under argon was slowly added some sodium methoxide (1.01 g, 0.019 mol, 0.125 eq) and geraniol (27.3 ml, 158 mmol, 1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction is distilled with toluene over one hour after which the reaction appeared completed by 1H NMR. Any remaining toluene is evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N,N-dioctylglycine geranyl ester as a light yellow oil (quantitative yield).
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[C:25]([CH:26]2[CH2:28][CH2:27]2)=[CH:24][C:9]2[C:10]([C:20]([O:22]C)=[O:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:12][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[OH-].[K+]>C(O)C.O>[CH:26]1([C:25]2[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[C:10]([C:20]([OH:22])=[O:21])[C:9]=3[CH:24]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(C3CC3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1C1CC1

Procedure:
A suspension of methyl 6-[bis(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate (2.88 g, 5.98 mmol) in ethanol (50 mL) and water (25 mL) was treated with potassium hydroxide (6.71 g, 120 mmol) and heated at reflux for 1 hour (the suspension went into solution upon heating). The reaction was concentrated under vacuum, water (100 mL) was added and the solution acidified with 2M HCl (50 mL). The resulting precipitate was filtered, washed with 0.5 M HCl, then dissolved in methanol. This solution was evaporated to dryness and azeotroped twice with toluene to give 5-Cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylic acid. LCMS (m/z, ES+)=390 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][N+:12]=1[O-:20].O>C1COCC1>[N+:17]([C:15]1[CH:14]=[CH:13][N+:12]([O-:20])=[C:11]([O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1)([O-:19])=[O:18]
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c(Oc2cccnc2)c1
Yield: 83 %

Procedure:
Sodium hydride (0.27 g of an 80% dispersion in oil, 9 mmol) was added to a solution of 3-hydroxypyridine (0.854 g, 9 mmol) in THF (3 ml) at 0° C. The mixture was then stirred for 1 h at room temperature before 2-chloro-4-nitropyridine-N-oxide* (2 g, 9 mmol) was added. The resulting solution was heated at reflux for 16 h, cooled, poured into water (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using ethyl acetate as eluant to afford the title compound (1.74 g, 83%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[O:8])=[C:5]([C:20]#[C:21][Si](C)(C)C)[N:4]=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]([C:5]1[N:4]=[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[N:2]([CH3:1])[C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][CH:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:13][CH2:14]1)=[O:8])#[CH:21]
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(C#C[Si](C)(C)C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1nc(-c2cccc(C(F)(F)F)c2)n(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 13, [3-methyl-2-(3-trifluoromethyl-phenyl)-5-trimethylsilanylethynyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 40) was reacted with potassium carbonate to give the title compound as yellow oil. MS: 431.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9]>CO.[Pd]>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[C:11]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2ncccc2c(=O)n1C
Agent: [Pd]
Solvent: CO
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CCCN2
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
In methanol (8 ml) was dissolved N-[3,5-bis (trifluoromethyl)benzyl]-8-(4-fluorophenyl]-5,6-dihydro-N, 6-dimethyl-5-oxo-7-pyrido[4,3-b]pyridinecarboxamide (Example 19) (50 mg). To the solution was added 10% Pd-C (50% hydrous) (40 mg). The mixture was stirred for 3 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off. From the filtrate, the solvent was distilled off to give the above-titled compound as colorless crystals (35 mg).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cscn3)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N)c(-c3cscn3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.030 g, 0.094 mmol) in tetrahydrofuran (0.3 mL) and water (0.068 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.113 mL, 0.113 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C12H13N4OS2(M+H)+: m/z=293.1. Found: 293.0.
Reaction SMILES: [CH:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:18](OCC)C>>[CH:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCCC=Cc1c[nH]nc1-c1cccnc1
Product: CCCCC=Cc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 46A (0.34 g, 0.97 mmol), 0.7 g of KOH and 1 ml of NH2NH2.H2O were combined in diethylene glycol (10 ml) and warmed to reflux for 1 hour under N2. The mixture was cooled, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH3/MeOH) and subsequent purification by flash chromatography (ethyl acetate) afforded 3-(4-hex-1-enyl-1H-pyrazol-3-yl)-pyridine (the deprotected analog of 46A). Yield 0.18 g (86%). (TLC diethyl ether Rf 0.18). 3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the title compound 47A, using the methodology described for the conversion of 21 A to 22A (see Scheme 3). Yield: 50% (amorphous). LCMS (method A); Rt: 2.30 min, ([M+H]+=246). 1H-NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 6.22 (bd, J=16 Hz, 1H), 6.03-5.98 (bs, 1H), 5.98-5.88 (m, 1H), 3.26-3.21 (m, 2H), 2.63 (bt, J=7 Hz, 2H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 2.19-2.11 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, J=7 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37][O:38]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:38][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.72 (d, 1H, J=3.52 Hz), 7.45 (d, 1H, J=3.52 Hz), 7.18 (d, 2H, J=8.60 Hz), 7.12-7.05 (m, 2H), 6.88 (d, 1H, J=7.82 Hz), 6.84-6.79 (m, 3H), 6.62 (d, 1H, J=6.65 Hz), 4.19 (t, 2H, J=6.26 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.08 Hz), 3.08 (d, 1H, J=14.08 Hz), 3.00 (t, 2H, J=6.26 Hz), 2.37 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C27H28NO6S 494.1637, found 494.1640.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[C:14]([CH3:15])=[CH:13][S:12][CH:11]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:34])N(OC)C)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([C:11]2[S:12][CH:13]=[C:14]([CH3:15])[C:10]=2[Br:9])=[O:34])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cscc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1csc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Under inert conditions, add a 2.0 M solution (in tetrahydrofuran/n-heptane) of lithium diisopropylamide (29.65 mmol, 14.83 mL, 1.05 equivalents) to a cold (−78° C.) solution of 3-bromo-4-methylthiophene (28.24 mmol, 5.00 g, 1.00 equivalents) in dry tetrahydrofuran (27.33 mL). Stir at −78° C. for 1 hour and add a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (28.24 mmol, 7.69 g, 1.00 equivalents), dropwise. Continue stirring at −78 ° C. for 3 hours. Quench the reaction mixture with saturated ammonium chloride (aqueous, 55 mL) and allow to warm to room temperature. Extract the reaction mixture with a mixture of ethyl acetate : diethyl ether (1:1, 3×40 mL). Combine the extracts and dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography using a mixture of n-heptane:ethyl acetate (4:1) to yield a yellow, crystalline solid (9.84 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[N+:21]([O-])=O)[CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].O>CO.[Fe]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH2:9][CH2:10][C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=2)=[C:14]([NH2:21])[CH:15]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1[N+](=O)[O-])=C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
To a suspension of 7-methoxy-3-(4-methoxy-2-nitrophenyl)-1,2-dihydronaphthalene (600 mg), iron (430 mg) and ammonium chloride (830 mg) in methanol (15 ml) was added water (6 ml), and the solution was stirred for 6 hours at 80° C. The solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (356 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[H][H]>[Pd].O1CCOCC1>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 97 %

Procedure:
A mixture of racemic ethyl 2-ethoxy-3-(4-benzyloxyphenyl)propionate of the formula (12a) (40 g) obtained according to the procedure described in step (iv) above, 5% Pd/C catalyst (8 g) and 1,4-dioxane (200 ml) was subjected to hydrogenation at room temperature and 50-60 psi of hydrogen pressure for a period of 8-12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered off and the solvent was removed under reduced pressure,to afford the title compound of the formula (13a) (28-29 g, 97-98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(OC(C)C)c1
Temperature: 65 °C
Yield: 74.5 %

Procedure:
To a flask containing methyl 3-bromo-5-hydroxybenzoate (2.1 g, 8.9 mmol) in anhydrous DMF (10 mL) was added K2CO3 (2.47 g, 17.9 mmol) and 2-iodopropane (1.07 mL, 10.7 mmol). The reaction mixture was heated at 65° C. overnight then diluted with EA and washed with NaHCO3. The organic layers were dried and concentrated to provide 1.81 g (75%) of methyl 3-bromo-5-isopropoxybenzoate as a white solid. LCMS-ESI (m/z) calculated for C11H13BrO3: 273.12; no observed m/z ion, tR=4.17 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=CC(=O)Oc2ccc(C(=O)O)cc2)cc1
Reaction time: 1 h

Procedure:
This step illustrates the addition of an aryl group to the compound of Step 2 to increase the stiffness and rod-like characteristics of the alkyl or alkoxy substituted cinnamoyl group. The compound of Step 2 (1.0 gm=5.1 mmole) was slurried under N2 in 10 mL dry pyridine. N,N-diisopropylethylamine (0.7 gm=5.6 mmole) was added, followed by a spatula tip of 4-dimethylaminopyridine. A solution of p-hydroxybenzoic acid (0.7 gm, 5.1 mmole) in 7 mL pyridine was added dropwise to the above slurry. An amber-orange solution soon developed. The solution was stirred for 60 minutes after addition was complete, and it was dropped slowly into 200 ml ice/H2O containing 25 mL concentrated HCl. The resulting precipitate was collected by suction filtration, slurried twice with H2O on the funnel, and dried in a 40° C. vacuum oven. The white solid was recrystallized from boiling acetone. White needles, K280° l.c. Yield 0.6 gm. Elemental Analysis: C17H14O 5, mol. wt. 298.3. Calcd: C, 68.5, H, 4.7, O, 26.8. Found: C, 68.5, H, 4.7. 1H NMR (DMSO-d6): δ (ppm) 6.7 (1H, d), 8.0 (1H, d).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](S(C)(=O)=O)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[C:35](C1C=CC(B(O)O)=CC=1)#[N:36].BrC1C=CC([C@H](N[C@H](C(NC2(C#N)CC2)=O)CCC)C(F)(F)F)=CC=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:35]#[N:36])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(C#N)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was synthesized in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between 4-cyanophenylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH:6]([OH:8])[CH3:7].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C(OCC)C>CN(C=O)C.[Cl-].[Na+].O.O>[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH:6]([CH3:7])[O:8][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: ClCc1ccccn1
Reactant: COC(OC)C(C)O
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(OC)C(C)OCc1ccccn1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Sodium hydride (1.80 g, 45.0 mmol, 60% dispersion in mineral oil) was added slowly to a solution of 1,1-dimethoxypropan-2-ol (2.16 g, 18.0 mmol) (Prepared according to the method described by Hunter et al. Tetrahedron, 1994, 50, 871-888.) in DMF (25 mL) immersed in an ice bath. After the addition was complete, the ice bath was removed to allow the solution to warm to r.t. Then the reaction flask was placed in an ice bath and 2-picolylchloride hydrochloride (2.95 g, 18.0 mmol) was slowly added. After warming to r.t. overnight, diethyl ether, water and brine were added. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (hexanes/ethyl acetate, first 4:1 then 1:1) resulting in the isolation of 1.74 g (46% yield, 8.22 mmol) of the title compound.
Reaction SMILES: C[N+]1([C:8]2[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][CH3:17])[N:9]=2)CCOCC1.[Cl-].[CH:19]1([C:25]2[NH:29][C:28](=[O:30])[C:27]3([CH2:35][CH2:34][N:33]([S:36](/[CH:39]=[CH:40]/[C:41]4[C:49]([CH3:50])=[CH:48][C:44]([C:45]([OH:47])=[O:46])=[CH:43][C:42]=4[CH3:51])(=[O:38])=[O:37])[CH2:32][CH2:31]3)[N:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:17][O:16][C:10]1[N:11]=[C:12]([O:14][CH3:15])[N:13]=[C:8]([O:46][C:45](=[O:47])[C:44]2[CH:48]=[C:49]([CH3:50])[C:41](/[CH:40]=[CH:39]/[S:36]([N:33]3[CH2:32][CH2:31][C:27]4([N:26]=[C:25]([CH:19]5[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)[NH:29][C:28]4=[O:30])[CH2:35][CH2:34]3)(=[O:37])=[O:38])=[C:42]([CH3:51])[CH:43]=2)[N:9]=1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: Cc1cc(C(=O)O)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Agent: [Cl-]
Solvent: CCO
Product: COc1nc(OC)nc(OC(=O)c2cc(C)c(/C=C/S(=O)(=O)N3CCC4(CC3)N=C(C3CCCCC3)NC4=O)c(C)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.9 %

Procedure:
DMT-MM (181 mg, 0.50 mmol) was added to a solution of 4-[(E)-2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-vinyl]-3,5-dimethyl-benzoic acid (160 mg, 0.33 mmol) in anhydrous ethanol (3.3 ml), and the mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (dichloromethane-methanol) to give 4-[(E)-2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-vinyl]-3,5-dimethyl-benzoic acid 4,6-dimethoxy-[1,3,5]triazin-2-yl ester (109 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([OH:20])[C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:10])=[CH:5][CH:4]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:38]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[O:20][C@H:11]([C@H:12]([CH:18]=[CH2:19])[CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C@@H:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[CH3:10])([CH3:40])[CH3:39]
Reactant: C=C[C@H](CCC(C)C)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=C[C@H](CCC(C)C)[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To an ice-cooled solution of (2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol (3.70 g, 12.07 mmol) in anhydrous CH2Cl2 (60.4 ml) were added 2,6-dimethylpyridine (1.97 ml, 16.9 mmol) and triisopropylsilyl trifluoromethanesulfonate (3.89 ml, 14.5 mmol), and the mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate (NaHCO3) solution and mixed thoroughly. The phases were separated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (gradient, hexanes/ethyl acetate) to furnish the title product as a colorless oil (4.76 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.19 (m, 2H), 6.88-6.81 (m, 2H), 5.63-5.50 (m, 1H), 5.05-4.89 (m, 2H), 4.51-4.29 (m, 2H), 3.84 (dd, J=6.6, 3.0 Hz, 1H), 3.79 (s, 3H), 3.55-3.46 (m, 1H), 2.11-1.98 (m, 1H), 1.75-1.61 (m, 1H), 1.56-1.41 (m, 1H), 1.24-1.17 (m, 1H), 1.15 (d, J=6.2 Hz, 3H), 1.13-0.97 (m, 20H), 0.85 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.88, 139.86, 131.19, 129.19, 115.64, 113.50, 78.34, 76.39, 70.08, 55.24, 49.46, 36.94, 28.35, 28.23, 22.83, 22.51, 18.43, 18.41, 13.71, 13.18; ESIMS m/z 485.4 ([M+Na]+).