Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=[C:15]2[O:24][CH2:25][CH3:26])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]([O:24][C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[N:16]=1)[CH3:26]
Reactant: CCOc1nc2cc(C)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc2cc(C)ccc2n1C1CCNCC1

Procedure:
4-(2-ethoxy-5-methylbenzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (367 mg, 1.02 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (1 mL) and the solution was stirred at rt for 1 hour. The mixture was evaporated to dryness and the residue was extracted with CH2Cl2, brine and 2N NaOH solution. The organic layer was washed with brine and dried over Na2SO4. After the evaporation of solvents, an oily residue was obtained (217 mg, 0.84 mmol) as 4-(2-ethoxy-5-methylbenzoimidazol-1-yl)-piperidine which was then was mixed with (S)-(2-iodomethyl-indan-5-yl)-carbamic acid tert-butyl ester (224 mg, 0.60 mmol) and cesium carbonate (817 mg, 2.51 mmol) in acetonitrile (10 mL). The mixture was stirred at 85° C. for 16 hrs. The reaction mixture was filtered and solvents were evaporated. The residue was purified through a Biotage flash column chromatography using 5% CH3OH in CH2Cl2 to give a brownish fluffy material (206 mg, 68%) as (S)-{2-[4-(2-ethoxy-5-methylbenzoimidazol-1-yl)-piperidin-1-ylmethyl]-indan-5-yl}-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]([F:24])([F:23])[F:22])[NH2:16]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([O:20][C:21]([F:22])([F:23])[F:24])=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: Nc1ccc(OC(F)(F)F)c(F)c1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 3-fluoro-4-trifluoromethoxy-aniline to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.43 min, UPLC-MS (Condition 3) tR=1.29 min, m/z=413 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:28]C)[N:6]2[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCN(CCO)CC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3CCN(CCO)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
2-(4-{3-[6-Amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperazinyl)ethanol (for example, as prepared for Intermediate 39) (80 mg, 0.196 mmol) was dissolved in methanol (5.5 mL) and 4M HCl in 1,4-dioxane (1.2 mL) was added. The solution was stirred at room temperature overnight, then evaporated in vacuo. The solid residue was taken up in the minimum amount of methanol and put onto a 2 g aminopropyl SPE that had been pre-conditioned with 50 mL methanol. Appropriate fractions were evaporated in vacuo to give the title compound as a white solid (68 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][C:18]([O:35][CH3:36])=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:19][C:18]([O:35][CH3:36])=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)/C(=C/c1c[nH]c3ccccc13)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(CN2CCNCC2)c2c(c1)C(=O)/C(=C/c1c[nH]c3ccccc13)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.025 g, 0.051 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-2-[(1H-indol-3-yl)methylene]-5-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.017 g, 73%).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:18][C:5]1[CH:6]=[C:7]([CH:9]=[O:10])[NH:8][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1ccc(C=O)[nH]1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1[nH]c(C=O)cc1Br
Temperature: 50 °C
Yield: 58.9 %

Procedure:
15 g of 5-n-propyl-2-pyrrolaldehyde (0.11 moles) are dissolved in 600 mL of CCl4 under a nitrogen atmosphere. 23 g of NBS (0.13 moles) are added and the mixture is heated to 50° C. for 6 h. The succinimide is filtered out, the organic phase is washed with a saturated solution of NaHCO3, dried with Na2SO4 and evaporated. 14 g of product are obtained, which are used in the subsequent step. Formula: C8H10BrNO (m.w. 216.08). Yield 60%.
Reaction SMILES: [O:1]1[C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[BH4-].[Li+].C1COCC1.Cl>O>[O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CCOC(=O)c1cc2ccc3ccccc3c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccc3ccccc3c2o1
Yield: 85 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added ethyl naphtho[1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 6.85 g, 28.5 mmol), lithium borohydride (Aldrich, 0.62 g, 28.5 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid was filtered, washed with additional H2O (500 mL) then dissolved in CH2CL2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL), and placed in a vacuum oven overnight (80°) to give a total of 4.8 g (69.7%) of naphtho[1,2-b]furan-2-methanol, mp 105.5°-107°, (C,H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17](O)[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]>C(Cl)Cl.C(OCC)(=O)C>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17]([F:7])[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)OCCCC(O)CCCOC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCCCC(F)CCCOC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of (diethylamino)-sulfur trifluoride (571 mg, 3.54 mmol) in CH2Cl2 was added the solution of acetic acid, 7-acetoxy-4-hydroxy-heptyl ester (403 mg, 1.74 mmol) in CH2Cl2 (10 ml) at −78° C. The resulting mixture was allowed to stir for 15 minutes −78° C., 30 minutes at room temperature and then diluted with ethyl acetate (300 ml). The organic solution was washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by column chromatography on silica gel, using 15% ethyl acetate in hexanes, gave the title compound (386 mg, 94%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: COC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1

Procedure:
Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate (2.53 g, 8.18 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (40 psi) using a Parr hydrogenation apparatus overnight at rt. The solution was filtered through celite and the solvent was evaporated. Yield: 2.29 g (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.40 (ddd, J=25.09, 12.01, 4.49 Hz, 2H), 1.70-1.74 (m, 1 H), 1.74-1.77 (m, 1H), 1.81-1.92 (m, 1H), 2.99 (d, J=6.64 Hz, 2H), 3.34 (br.s, 2 H), 3.41 (dt, J=11.81, 2.15 Hz, 2H), 3.74 (s, 3H), 3.99 (d, J=3.51 Hz, 1H), 4.02 (d, J=3.51 Hz, 1H), 6.38 (br.s, 1H), 6.55-6.60 (m, 1H), 6.62-6.68 (m, 1H), 6.95 (br.s, 1H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=[N:21][NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)=[O:24])[CH3:20])[C:14]=2[OH:35])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO.[OH-].[Na+].Cl>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=[N:21][NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:24])[CH3:20])[C:14]=2[OH:35])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)OC)cc3)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)O)cc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To methyl 4-[(2-{1-[5-(4-n-hexylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.158 mmol, 75.2 mg), methanol was added, and 1 M aqueous sodium hydroxide (5 eq., 0.789 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.789 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (29.4 mg, yield 40%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:40]1[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:42][CH2:41]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
700 mg (1.78 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 341 mg (1.78 mmol) of 1-(3-methoxyphenyl)piperazine and a spatula tip of silica gel are stirred in 20 ml of dichloromethane at room temperature for one hour and then under reflux for 35 hours. The target compound is obtained after purification on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:10]=2)=[O:5])C.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[CH:10]=[C:9]3[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[N:7]=[CH:8]3)=[CH:13][CH:12]=2)=[CH:22][CH:21]=1
Reactant: NCCC(=O)O
Reactant: CCOC(=O)c1ncc2cc(-c3ccc(F)cc3)ccc2c1O
Product: O=C(O)CCNC(=O)c1ncc2cc(-c3ccc(F)cc3)ccc2c1O

Procedure:
3-{[7-(4-Fluoro-phenyl)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 7-(4-Fluoro-phenyl)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using beta-alanine. MS ESI(−) m/e: 353.1196 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.103 g, 0.24 mmol) and thiophenol (0.03 mL, 0.26 mmol) in 1,4-dioxane (2 mL) was added sodium hydride (60% in mineral oil; 0.013 g, 0.29 mmol), and the reaction was stirred for 30 minutes at room temperature. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was acidified and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(=O)([O-])[O-:21].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]([NH2:6])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2c[nH]c3ncccc23)ccc1C#N
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(-c2c[nH]c3ncccc23)ccc1C(N)=O
Yield: 93.5 %

Procedure:
The nitrile 30 (10 mg, 40 μmol) was dissolved in dimethyl sulfoxide (0.5 ml). To this was added potassium carbonate (20 mg) and 30% hydrogen peroxide in water (100 μl). The reaction was warmed to approximately 60 C for 15 minutes. The reaction was concentrated to dryness and triturated in water. The resulting precipitate was filtered and dried in-vacuo overnight to give 31 (10 mg, 93%). 1H NMR DMSO-d6 11.99 (s, 1H), 8.32 (d, 1H), 8.24 (m, 1H), 8.01 (m, 1H), 7.88 (d, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 7.37 (m, 2H), 7.15 (dd, 1H), 4.00 (s, 3H). LC/MS (M+1)=268.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH3:12].C([Li:17])CCC>>[Li:17][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH3:12]
Reactant: CCc1oc2ccccc2c1Br
Reactant: [Li]CCCC
Product: [Li]c1c(CC)oc2ccccc12

Procedure:
comprising contacting 3-bromo-2-ethylbenzofuran with n-butyllithium at a temperature less than −75° C. to form 3-lithio-2-ethylbenzofuran, contacting the 3-lithio-2-ethylbenzofuran at a temperature less than −75° C. with an isopropyl boronate cyclic ester corresponding to the formula:
Reaction SMILES: COC1C=CC(CNC2C=CC=CN=2)=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:29]([C:39]2[CH:44]=[CH:43][C:42](OC)=[CH:41][N:40]=2)[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:21]2[N:22]([C:24]([C:27]#[N:28])=[CH:25][N:26]=2)[N:23]=1>CO>[Cl:17][C:18]1[CH:19]=[C:20]([N:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21]2[N:22]([C:24]([C:27]#[N:28])=[CH:25][N:26]=2)[N:23]=1
Reactant: COc1ccc(CN(c2ccc(OC)cn2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: COc1ccc(CNc2ccccn2)cc1
Solvent: CO
Product: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C#N)cnc23)cc1

Procedure:
8A was prepared from a mixture of 1F and N-(4-methoxybenzyl)pyridin-2-amine following the procedure employed for the preparation of 5B. HPLC: Rt=3.881 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=391.0 [M+H]+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:29])[CH2:7][N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:9]1=[O:28])C.Cl>C(O)C.O>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH:10]2[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]2=[O:28])=[CH:17][C:18]=1[C:24]([F:27])([F:26])[F:25])#[N:23]
Reactant: CCOC(=O)CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CN(CC(=O)O)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (50% in water, 10 mL) was added to a stirring solution of [3-(4-cyano-3-trifluoromethyl-phenoxy)-4,4-dimethyl-2-oxo-pyrrolidin-1-yl]-acetic acid ethyl ester (3) (16.8 mmoles) in ethanol (50 mL) and water (40 mL). The reaction was stirred at ambient temperature overnight. The pH of reaction mixture was adjusted to 2.0 by adding hydrochloric acid (37% in water). The reaction mixture was concentrated in vacuo to remove the ethanol. The desired product (3′) that precipitated from the residue was filtered and dried in a vacuum oven overnight.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C@@H:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:24][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Fc1ccc(CN[C@H]2CCCc3ccccc32)cc1C(F)(F)F

Procedure:
4-Fluoro-3-(trifluoromethyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C(O)C.[OH-].[Na+]>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[NH:5][C:3](=[O:4])[C:2]([S:1][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)([CH3:13])[CH3:12])=[CH:18][CH:17]=1
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSC[C@H](NC(=O)C(C)(C)SCc2ccc(OC)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a stirred solution of N-(2-mercapto-2-methylpropionyl)-L-cysteine (2.0 g) in ethanol(10 ml), 4N sodium hydroxide solution(7.7 ml) and paramethoxybenzyl chloride(3.0 ml) were added dropwise under ice-cooling and under nitrogen atomosphere. After the addition, the reaction mixture was stirred for 2 hours under ice-cooling and 2 hours at room temperature. The reaction mixture was concentrated in vacuo, acidified with 2N hydrochloric acid and extracted with ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give crystals. The crystals were recrystallized with ether to give 2.8 g(67%) of the titled compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][CH:13]=1)([OH:3])=O>CS(O)(=O)=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:1](=[O:3])[C:13]3[C:12]([C:5]=2[CH:6]=1)=[CH:17][C:16]([O:18][CH3:19])=[CH:15][CH:14]=3
Reactant: COc1cccc(-c2cc(OC)ccc2C(=O)O)c1
Agent: CS(=O)(=O)O
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
7.5 g of 2-carboxy-5,5'-dimethoxybiphenyl was dissolved in 75 mL of methanesulfonic acid to obtain a dark brown solution. The solution was stirred at room temperature for one hour, heated at 40°-50° C. for 5 hours and then cooled to room temperature. The reaction mixture was then poured onto crushed ice to form a yellow colored precipitate which was collected by filtration. The precipitate was washed with large amounts of water and then air dried to yield 6.7 g of crude 3,6-dimethoxy-9-fluorenone. Recrystallization from ethanol followed by column chromatography on silica gel using methylene chloride as the eluent yielded pure 3,6-dimethoxy-9-fluorenone. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18]O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Br)(Br)[Br:21]>ClCCl>[Br:21][CH2:18][C:16]1[O:15][N:14]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:17]=1
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCc1cc(CO)on1
Solvent: ClCCl
Product: CCCCCCCCCCCCc1cc(CBr)on1
Reaction time: 1.5 h

Procedure:
To a stirred, chilled (+3° C.) solution of 3-dodecyl-5-isoxazole methanol (1.0 g, 0.0037 mol) in dichloromethane (20 mL) was added in one portion phosphorous tribromide (0.13 mL, 0.0014 mol), and the solution was stirred at +3° C. for 1.5 hours, then at room temperature for 3 days. The mixture was washed carefully with saturated sodium bisulfite, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried (MgSO4) and rotoevaporated to a yellow oil which solidified upon standing; yield 1.12 g (93%); mp 31.5°-35° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][OH:2]
Reactant: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
The method of Bascop, S. I.; Laronze, J. Y.; Sapi, J. Synthesis of 2-aminopropyle-3-indole-acetic(propionic) acid derivatives. ARKIVOC 2003, 46-61, was followed. To a solution of ester 12 (4 mmol, 1 equiv) in anhydrous THF (50 mL) was added lithium aluminium hydride (LiAlH4; 16 mmol, 4 equiv) in portions with the temperature maintained at 0° C. The reaction mixture was brought to room temperature and stirred for 30 min. Excess LiAlH4 was destroyed by careful addition of a saturated aqueous solution of Na2SO4 with the temperature maintained at about 0° C. The mixture was filtered and the filtrate washed with THF. The combined filtrates were concentrated under reduced pressure, the residue was acidified to pH 6 with 10% HCl and extracted with CHCl3. The combined organic layer was dried (anhydrous Na2SO4), filtered, evaporated to dryness and purified using flash column chromatography by elution with EtOAc/hexane to give the alcohol 13. Yield: 83%; NMR (300 MHz, CDCl3): δ 2.97 (t, J=18 Hz, 2 H), 3.86-3.93 (m, 2 H), 4.09 (t, J=21 Hz, 1 H), 7.09 (d, J=3 Hz, 1 H), 7.22 (d, J=9 Hz, 1 H), 7.75 (s, 1 H), 8.10 (s, 1 H); MS (APCI): m/z 241.2 [M+H]+.