Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.BrC1C2C(=CC=CC=2)[N:29]([Si](C(C)C)(C(C)C)C(C)C)[CH:28]=1.CN1CCNCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:28][N:29]1[CH2:5][CH2:6][N:1]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccccc21
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCOCC2)c2ccccc21
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: CN1CCNCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCN(C)CC2)c2ccccc21
Yield: 32 %

Procedure:
Following a method similar to 3-morpholin-4-yl-1-triisopropylsilanyl-1H-indole using 3-bromo-1-triisopropylsilanyl-1H-indole (0.70 g, 1.99 mmol), 1-methyl-piperazine (0.30 g, 3.00 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.02 g, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.05 g, 0.05 mmol) and 1N solution of lithium bis(trimethylsilyl)amide in THF (2.40 mL). Purify by flash chromatography using 0 to 12% of MeOH in dichloromethane to give the title compound (0.23 g, 32%). MS (ES) 372.1 (M+1)+.
Reaction SMILES: [CH2:1]([CH:3]([C:7]([CH3:9])=[O:8])[C:4]([NH2:6])=[O:5])[CH3:2].[OH-].[Na+].[CH3:12]I>CO>[CH2:1]([C:3]([CH3:12])([C:7]([CH3:9])=[O:8])[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCC(C(C)=O)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C(C)=O)C(N)=O
Yield: 86.6 %

Procedure:
2-Ethylacetoacetamide (21.0 g, 163 mmol) and 50 mL of methanol were charged to a 100 mL, 4-necked flask which was equipped with a thermometer, a nitrogen blanket line atop a condenser, an addition funnel, and a magnetic stirrer. The mixture was stirred until a homogeneous solution was obtained. To the solution was added 14.3 g of 50% aqueous sodium hydroxide solution (179 mmol, 1.1 eq), and the resulting mixture was stirred at ambient temperature for 30 minutes. Methyl iodide (25.4 g, 179 mmol, 1.1 eq) was then added to the reaction mixture through the addition funnel in 30 minutes. Upon the completion of the addition, the reaction mixture was stirred for 14 hours at ambient temperature. After this period, all volatile components were removed at 60° C./20 mmHg. The solid residue was dissolved in 100 mL of water and extracted with ethyl acetate (3×100 mL). After the ethyl acetate was removed in vacuo from the combined extracts, 20.2 g of a white solid was obtained. Crude yield: 87%.
Reaction SMILES: C[Mg]I.COC(=O)/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1.[Cl-].[NH4+].C([O:27]CC)C>O1CCCC1>[CH3:7][CH:8]([OH:27])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: CCOCC
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cc2cccnc2)cc1

Procedure:
Under an atmosphere of nitrogen, 1.5 ml of a 3M solution of methylmagnesium iodide in diethyl ether were added to a solution of 830 mg of the aldehyde (prepared as described in Reference Example 1) in 20 ml of tetrahydrofuran at -70° C., the mixture was allowed to warm from -70° C. to room temperature over a period of one hour with stirring, poured into a saturated aqueous solution of amonium chloride, and extracted with diethyl ether. The extract was washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 547 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:8][C:9]=1[C:10](OCC)=[O:11])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:3][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:8][C:9]=1[CH2:10][OH:11])[CH3:1]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1CN(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1nc(-c2ccccc2)sc1CO
Reaction time: 8 h
Yield: 95.3 %

Procedure:
The compound prepared in Example 127 (0.65 g) was suspended in tetrahydrofuran (20 mL) and then lithium aluminum hydride solution (1 M; 4.44 mL) was added dropwise to the solution at room temperature and stirred overnight. The reaction mixture was transferred dropwise to a stirred room temperature saturated aqueous solution of Rochelle's salt (sodium potassium tartrate). The mixture was diluted with ethyl acetate and the biphasic mixture stirred rapidly for 30 minutes. The layers were separated and the organics washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material (0.53 g), which was used without further purification possessing the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>S1(CCCC1)(=O)=O.O>[CH2:13]([O:12][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Yield: 21 %

Procedure:
5-Methylsalicylic acid was reacted with methanol and sulphuric acid by the general method of Brunner (Monatsh. 1913, 34, 916) to give methyl 5-methylsalicylate, b.p. 115°-116° C./10 mmHg. This ester (12.0 g) was heated together with benzyl chloride (9.1 g) and anhydrous potassium carbonate (5.0 g) in dry sulpholane (90 ml) at 100° C. for 22 hours. The mixture was then poured into a mixture of ice and water (1200 ml) to give crude methyl 2-benzyloxy-5-methylbenzoate (17.6 g). This ester (4.3 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 100 ml) for 2 hours and the mixture was then cooled, diluted with water, and acidified to pH 2 by treatment with concentrated hydrochloric acid to give 2-benzyloxy-5-methylbenzoic acid (3.65 g), m.p. 98°-100° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH:87]1([NH2:91])[CH2:90][CH2:89][CH2:88]1>>[CH:87]1([NH:91][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:5])[CH3:4])[CH:31]=3)[CH:36]=2)=[O:41])[CH2:90][CH2:89][CH2:88]1
Reactant: NC1CCC1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CCC3)ccc2c1)c1c[nH]cn1
Yield: 119.1 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.78 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclobutylamine hydrochloride (405 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.36 g) as a colorless powder.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C1N(CC2C=CC=CC=2)N=C(C)C=1)=O.[OH-].[Li+].C(N1C(N2C[C@H](S(C3C=CC=CC=3C(F)(F)F)(=O)=O)C[C@@H]2C(O)=O)=CC(C)=N1)C1C=CC=CC=1>>[CH2:29]([N:24]1[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:20])[F:22])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1Cc1ccccc1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1Cc1ccccc1
Agent: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2C(=O)O)n(Cc2ccccc2)n1
Agent: [Li+]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(Cc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give a mixture of the title compound and (2R,4R)-1-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid as orange oil which was used in the next step without further purification. MS (ESI): m/z=492.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([C:23](=[O:25])[CH3:24])[C:5]([OH:22])=[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[C:7]=1[O:8][CH3:9].[Br:27][CH2:28][CH2:29][CH2:30]Br>>[Br:27][CH2:28][CH2:29][CH2:30][O:22][C:5]1[C:6]([O:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH3:26])[C:4]=1[C:23](=[O:25])[CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Reactant: BrCCCBr
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCCBr)c1OCCC(C)c1ccc(F)cc1

Procedure:
Example 7c (179 mg, 0.47 mmol) was reacted with 1,3-dibromopropane (10.0 eq.) as described under General Procedure F to afford the title compound (641 mg, quantitative yield) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.10 (t, J=5.9 Hz, 2H), 3.94 (t, J=6.7 Hz, 2H), 3.84 (s, 3H), 3.49 (t, J=6.5 Hz, 2H), 2.99 (m, 1H), 2.46 (s, 3H), 2.17 (m, 5H), 2.07-1.99 (m, 2H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 503.0 (M+H+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]3[C:12]4[C:17]([CH2:18][CH2:19][C:8]=23)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:3][CH:2]=1.C(O)C.O1CCOCC1>[Pd].CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]3[C:12]4[C:17]([CH:18]=[CH:19][C:8]=23)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCc1c-2n[nH]c1-c1ccncc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: c1ccc2c(c1)ccc1c(-c3ccncc3)[nH]nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6.0 grams of 4,5-dihydro-3-(4-pyridyl)-2H-naphtho [1,2-c]pyrazole, 6.0 grams of 5% palladium or carbon, 150 ml of absolute ethanol and 50 ml of dry dioxane are stired and refluxed for about 75 hours. The mixture is allowed to cool to room temperature, and is then treated with about 50 ml of 1:1 methanol/methylene dichloride. The mixture is stirred for about 15 minutes and then filtered through celite. The filtrate is concentrated in vacuo and the residue crystallized from ethanol/ether to give 3-(4-pyridyl)-2H-naphtho[1,2-c]pyrazole, (m.p. 273°-276°.)
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])=O>O>[OH:23][C:17]1[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=1[CH2:14][CH2:13][NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](CS)NCCc1ccc(O)cc1O
Reaction time: 1 h

Procedure:
Ingredients. (1) Water 97.3 (2) Sodium Bicarbonate 0.9 (3) L-Cysteine 1.2 (4) Resacetophenone 1.5. Procedure. Mix (1) to (3). Heat to 70 to 80 C. Add (4). An instantaneous reaction occurs and a clear yellow solution is obtained. The mixing and heating is continued for 1 hour, and then hydrogenated over Pt catalyst. After filtration of catalyst, solution of N-[(2,4-dihydroxyphenyl)ethyl]cysteine Sodium in water is thus obtained, pH 8.5. Water is evaporated to ⅓ in volume and the solution allowed to cool. The pH is adjusted to 6.5 with citric acid (2.0 grams of 50% solution). N-[(2,4-dihydroxyphenyl)ethyl]cysteine is obtained as a pale, yellow solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].B(F)(F)F.CCOCC.[CH:17]1[CH2:21][CH:20]=[CH:19][CH:18]=1.C1C2C3C=CC(C2C=C1)C3.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:20][CH2:21][CH:17]=[CH:18][CH3:19]
Reactant: C1=CCC=C1
Reactant: C=CC(=O)OCC
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: C1=CC2C3C=CC(C3)C2C1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC=CCCC(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Ethyl acrylate (200 g, 1.99 mol, commercially available at Aldrich Chemical Company, Inc.) was dissolved in 500 ml of toluene. The resulting solution was then cooled to 0° C. using a dry ice isopropanol bath. Boron trifluoride etherate (28 g, 0.19 mol, commercially available at Aldrich Chemical Company, Inc.) was added to the solution. Cyclopentadiene (197 g, 2.98 mol, freshly prepared by cracking dicyclopentadiene, which is commercially available at Aldrich Chemical Company, Inc.). was then added to the cold solution dropwise. After the feed was complete the reaction mixture was aged for 1 hr. The crude reaction mixture was poured onto 2 L of 10% sulfuric acid and wet ice. The organic layer was removed and then washed with sodium carbonate solution until basic. Fractional distillation afforded endo bicycle[2.2.1]hept5-ene-2-carboxylic acid, ethyl ester (300 g, 90% yield), which had a boiling point of 82° C. at a pressure of 10 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45]([N:48]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=1)[S:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)(=[O:51])=[O:50])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:55]2[CH:54]=[CH:53][C:52]([S:49](=[O:50])(=[O:51])[N:48]([CH:45]([CH3:46])[CH3:47])[CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=3)=[CH:57][CH:56]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: COc1ccc(CN(C(C)C)S(=O)(=O)c2ccc(B(O)O)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)C(C)C)cc2)c1C
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.200 g, 0.50 mmol) in dimethoxyethane (10 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.030 g, 0.110 mmol), palladium (II) acetate (0.013 g, 0.060 mmol), 4-(N-isopropyl-N-(4-methoxybenzyl)sulfamoyl)phenyl-boronic acid (0.247 g, 0.68 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford (6-chloro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (0.12 g, 42%) as a solid. MS calcd. for C31H31ClNO5S [(M−H)−] 564, obsd. 564.3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)=[O:31])[CH:17]=1>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)=[O:31])[CH:17]=1
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Trifluoroacetic acid (4.0 mL) was added to the obtained tert-butyl 4-(2-methoxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (61 mg), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration, and dioxane (3.0 mL), water, and a 2 mol/L aqueous solution of sodium hydroxide (0.080 mL) were added to the obtained residue. After adjusting the pH to 7.6 with 1 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 32 mg of 4-(2-methoxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:29][O:28][C:26]([NH:25][CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:10]1)=[O:27]
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 50.7 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (3 g, 7.04 mmol) in MeOH (60 mL) was added wet Pd(OH)2/C (300 mg). The reaction mixture was stirred under 50 of hydrogen psi at 50° C. for 3 hr. The suspension was filtered and the filtrate was concentrated hydrogen in vacuo. The crude product was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(2-(methoxycarbonylamino)ethoxy)(phenyl)methyl)piperidine-1-carboxylate (1.4 g, 51%). 1H NMR (CD3OD) δ 7.40-7.22 (m, 5H), 4.20 (m, 1H), 4.01 (m, 1H), 3.81 (m, 1H), 3.6 (s, 3H), 3.27 (m, 3H), 2.84 (m, 2H), 1.8-1.5 (m, 2H), 1.45 (s, 9H). MS ESI +ve m/z 393 (M+1).
Reaction SMILES: C([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:20][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[NH:8]1
Reactant: CCCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(=O)[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(ethyl propionyl)piperidine. (1.8 g, 6.01 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 75 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(ethyl propionyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 121.1-122.0° C.; 1H NMR (300 MHz) 89.44 (s, 2H), 5.68 (m, 2H), 4.19 (s, 1H), 3.56 (s, 1H), 2.2-1.2 (m, 17H), 0.88 (t, 3H); 13C NMR (75 MHz) δ 137.1 (s), 122.8 (s), 48.34 (s), 47.94 (s), 31.4 (s), 28.8 (s), 28.4 (s), 27.9 (s), 22.4 (s), 17.6 (s), 17.1 (s), 13.97 (s) ppm. FT-IR (neat): 3435, 3192, 2924, 1586, 1431, 1030, 673. Elemental Analysis. for C13H26NCl: C, 67.34%; H, 11.33%; N, 6.04%. Found: C, 67.44%; H, 11.23%; N, 5.98%.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl.CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[NH:14][C:15]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:39])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)c2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
To a mixture of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio]benzimidazole-5-carboxylic acid (1.00 g) in dichloromethane (30 ml) and methanol (3 ml) stirring in ice-salt-water bath, was added m-chloroperbenzoic acid (80%, 503 mg) in a small portions below 0° C. Further stirring for an additional 15 minutes, the mixture was evaporated, and the residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate-methanol (10:2:1), and recrystallized from ethanol-water to give the title compound (540 mg, 52.1%) as colorless crystals, mp 173-175° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31]C(=O)OC(C)(C)C)[CH:26]=4)=[CH:21]3)=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[NH2:31][C:27]1[CH:26]=[C:25]([O:24][C:20]2[CH:21]=[C:22]3[C:17]([CH:16]=[CH:15][C:14]([C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)=[O:13])=[CH:23]3)=[CH:18][CH:19]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3c2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc3ccc(Oc4ccnc(N)c4)cc3c2)c1
Reaction time: 3 h
Yield: 115.8 %

Procedure:
A solution of [tert-butyl {4-[(7-{[(3-tert-butylphenyl)amino]carbonyl}-2-naphthyl)oxy]pyridin-2-yl}carbamate (1.05 g, 2.05 mmol;) in 4M HCl in 1,4-dioxane (40 mL) was allowed to stir under an atmosphere of nitrogen for 3 h. The solvents were evaporated to give 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-2-naphthamide (977 mg, 98%).