Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:8]=2[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[O:17])[CH2:12][CH2:11]2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:8]=2[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:21])([F:22])[F:23])=[O:17])[CH2:14][CH2:15]2)[CH2:3]1)(=[O:44])[CH3:43]
Reactant: N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)C1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A 4 mL vial was charged with (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (28 mg, 0.057 mmol), a magnetic stirbar, CH2Cl2 (2 mL), and DIPEA (30 μL, 0.172 mmol). The reaction was cooled to 0° C. and an acetyl chloride solution (7 mg, 0.086 mmol, in 1 mL CH2Cl2) was added dropwise. After stirring for 30 min at 0° C., the reaction was quenched with sat Na2CO3 and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on a silica gel column (100% to 10% MeOH in CH2Cl2) and yielded (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-acetamidopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (30 mg, 35%). 1H NMR 400 MHz (CDCl3) δ 7.31 (d, J=8.2 Hz, 1H), 6.91 (dd, J=8.1, 1.8 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H), 5.84-5.70 (m, 2H), 4.62-4.50 (m, 1H), 3.59-3.53 (m, 4H), 3.50 (s, 2H), 3.48-3.44 (m, 1H), 3.43-3.33 (m, 1H), 3.20-3.10 (m, 2H), 2.50-2.42 (m, 4H), 2.34 (td, J=13.4, 7.6 Hz, 1H), 2.01 (s, 3H), 1.91-1.79 (m, 1H). LCMS (ESI, m/z): 531 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Cl)cc(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-chloro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.4 g, 17.5 mmol) and ytterbium(III) triflate hydrate (1.08 g, 1.75 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (1.59 mL, 17.5 mmol) and water (0.32 mL, 17.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-chloro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (7.67 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrClNO3 M+: 438.8, observed: 438.8, 440.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][NH:26][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:14]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
4-[2-(2-benzyloxy-3-pyridyl)ethyl]benzoic acid (0.48 g, 1.44 mmol) and 2-aminomethylpyridine (0.189 g, 1.748 mmol) were dissolved in DMF (20 ml) and cooled to 0° C. Triethylamine (0.15 g, 1.5 mmol) was added followed by diphenylphosphorylazide (0.41 g, 1.48 mmol). The reaction mixture was stirred under argon and allowed to warm to ambient temperature overnight. The reaction was partitioned between EtOAc/water, the organic phase was washed with aqueous sodium bicarbonate, water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (MeOH/CH2Cl2) followed by recrystallisation from EtOAc/hexane and then from EtOH/water to give the title product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][NH2:20])=[O:18])[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:22]#[C:23]Br>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[O:18][C:23]([NH2:22])=[N:20][N:19]=4)=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccnc2[nH]c(CCc3ccccc3)cc12
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1nnc(-c2ccnc3[nH]c(CCc4ccccc4)cc23)o1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a solution of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbohydrazide (104 mg, 0.371 mmol) in N,N-dimethylacetamide (1 mL) was added a solution of cyanogen bromide (47 mg, 0.445 mmol) in N,N-dimethylacetamide (0.5 mL) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from N,N-dimethylformamide/water to give the title compound (50 mg, yield 44%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[NH3:19]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:19])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: CC1=Cc2cc(Br)cc(S(=O)(=O)Cl)c2OS1(=O)=O
Reactant: N
Solvent: C1CCOC1
Product: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 180 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl chloride in 500 ml of tetrahydrofuran is added dropwise over 30 minutes to 307 ml of a 30% aqueous solution of ammonia. The mixture is stirred for 30 minutes at 20° C. and concentrated under reduced pressure at 45° C. The residue is triturated with 200 ml of ether. The precipitate is isolated, washed with water and dried at 45° C., affording 63.2 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 243°-245° C. (recrystallisation from ethanol).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[OH:16])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[OH:16])=[O:8])=[CH:31][CH:30]=1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1R,2S)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-chlorophenylboronic acid as starting materials, MS (ISP) 497.1 (M+H)+; [α]D20=+22.2°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=O)[CH2:19]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Yield: 80.5 %

Procedure:
The general McMurry coupling procedure described for 14 was followed. To a stirred suspension of zinc powder (13.0 g, 0.2 mol) in THF (400 mL) was slowly added TiCl4 (11 mL, 0.10 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of (4-fluorophenyl)(4-hydroxyphenyl)methanone (4.32 g, 0.02 mol) and 3,3,5,5-tetramethylcyclohexanone (9.26 g, 0.06 mol) in THF (100 mL) was added to the reaction mixture. The reaction mixture was heated at reflux for an additional 2 h. Standar work-up followed by purification gave 5.450 g (80%) of compound 231 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=5.7 Hz, 1H), 7.12 (d, J=5.7 Hz, 1H), 7.04 (d, J=8.7 Hz, 2H), 6.97 (dd, J=8.7 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 4.68 (s, 1H), 1.99 (s, 2H), 1.96 (s, 2H), 1.31 (s, 2H), 0.95 (s, 6H), 0.94 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH2:10]([C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([S:21]([NH:24][CH3:25])(=[O:23])=[O:22])=[C:14]([NH:26][CH2:27][CH2:28][CH3:29])[C:13]=1[N+:30]([O-:32])=[O:31])[CH3:11].N1C=CC=CC=1>ClCCl>[CH2:10]([C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([S:21]([N:24]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:25])(=[O:23])=[O:22])=[C:14]([NH:26][CH2:27][CH2:28][CH3:29])[C:13]=1[N+:30]([O-:32])=[O:31])[CH3:11]
Reactant: CCCNc1c(S(=O)(=O)NC)cc([N+](=O)[O-])c(CC)c1[N+](=O)[O-]
Reactant: ClSc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCNc1c(S(=O)(=O)N(C)Sc2ccc(Cl)cc2)cc([N+](=O)[O-])c(CC)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
A 2.2 g (0.012 mol) sample of p-chlorophenylsulfenyl chloride was added dropwise to a cooled (-5° C. to 0° C.) solution of 3.5 g (0.1 mol) 4-ethylpropylamino-N-methyl-3,5-dinitrobenzenesulfonamide and 1.1 g (0.014 mol) pyridine in 25 ml dichloromethane. The reaction was stirred for 20 minutes and then diluted with 50 ml dichloromethane, washed with water, washed with aqueous sodium bicarbonate solution, and dried over magnesium sulfate. The dichloromethane was then evaporated under reduced pressure to give a solid residue. Recrystallization from ethanol gave the product as red-orange plates, m.p. 89°-91° C. Elemental analysis for C18H21ClN4O6S2 showed: % S, calc. 13.1, found 13.3; % Cl, calc. 7.3, found 7.8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.N1CCCC1>CO>[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:13][CH2:14]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21

Procedure:
The synthesis of compound 19A-19D is outlined in Scheme 19. The 2′-hydroxyacetophenone 1.1a was condensed with benzyl 4-oxopiperidine-1-carboxylate (19.1) in refluxing methanol in the presence of pyrrolidine to provide N-Cbz-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one (19.2). Conversion of the ketone 19.2 to the enol triflate derivative 19.3 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Conversion of the enol triflate 19.3 to the corresponding boron derivative 19.4 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2]. Suzuki type coupling of the boronate derivative 19.4 with tert-butyl 4-bromophenylcarbamate 19.5 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride, and an aqueous solution of sodium carbonate afforded the tert-butyloxycarbonyl (Boc) protected aniline derivative 19.6. Acidic hydrolysis of 19.6 provided the aniline derivative 19.7 which reacted with acyl chlorides 19.8a, 19.8b, isopropylsulfonyl chloride (6.5b) or ethyl isocyanate (19.11) to give the corresponding amide derivatives 19.9, sulfonamide derivative 19.10 or urea derivative 19.12, respectively. The derivatives 19.9, 19.10 and 19.12 were converted to compounds 19A-19D by treatment with iodotrimethylsilane.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C([Li])CCC.IC>C1COCC1>[F:7][C:8]1[CH:16]=[C:15]([CH3:1])[C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(F)c(C(=O)O)c1
Agent: [K+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(F)cc1C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Potassium tert-butoxide (7.92 g, 70.5 mmol) was dissolved in THF (150 mL) and cooled to −78° C. 2-Fluoro-5-methoxybenzoic acid (3.00 g, 17.6 mmol) in THF (100 mL) was added followed by n-butyl lithium (2.5 N in hexanes, 28.2 mL, 70.5 mmol). After 40 minutes, iodomethane (2.2 mL, 35.4 mmol) was added and allowed to stir at −78° C. for 70 minutes before warming to room temperature. The reaction was quenched with saturated ammonium chloride (100 mL) and extracted with ether. The aqueous layer was acidified using 6 N HCl then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by Gilson reverse-phase HPLC (acidic mobile phase) to yield 2-fluoro-5-methoxy-4-methylbenzoic acid as a white solid. MS m/z=185 [M+1]+. Calc'd for C9H9FO3: 184.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]2=[O:34])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]4[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]4=[O:34])=[CH:24][CH:25]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C4C(=O)N(C)CCN4C)cc3)nn12

Procedure:
3-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a yellow solid (55 mg, 42%). m.p.=249-251° C.; LCMS (m/e) 443 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.55 (d, 2H, J=8.4 Hz), 7.46-7.38 (m, 1H), 7.24 (d, 2H, J=8.4 Hz), 7.17-7.09 (m, 1H), 7.06 (d, 1H, J=8.3 Hz), 7.01 (d, 1H, J=4.6 Hz), 6.84 (d, 1H, J=4.6 Hz), 6.79 (bs, 1H), 3.84 (s, 3H), 3.77-3.68 (m, 1H), 3.66 (s, 1H), 3.24-3.17 (m, 1H), 3.05-2.97 (m, 1H), 2.98 (s, 3H), 2.71-2.61 (m, 1H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:30][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)=[C:6]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2C1(O)c1cc(Cl)ccc1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1Nc2cc(C(F)(F)F)ccc2C1(O)c1cc(Cl)ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 77.5 °C
Yield: 59.9 %

Procedure:
To a solution of (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indole-2-one (Preparation 5, 80 mg, 0.233 mmol) in 2-butanone (3mL), was added 4-(trifluoromethyl) benzyl bromide (61 mg, 0.256 mmol), K2CO3 (32 mg, 0.233 mmol) and a catalytic amount of KI. The reaction mixture was heated at 75-80° C. for 2 days. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to afford the title compound (70 mg, 60% yield); MS m/e 500 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].O>N1C=CC=CC=1>[C:22]([O:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[CH2:1][CH3:2])[C:8](/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Solvent: O
Solvent: c1ccncc1
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
440 mg of (E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 2.4 ml of pyridine and 0.42 ml of acetic anhydride was added, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and water in this order, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crystals were washed with hexane to obtain 390 mg of the titled compound as colorless crystals.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].CN(C)[CH:12]=[CH:13][C:14](=O)[C:15]([O:19][CH3:20])([O:17][CH3:18])[CH3:16]>CCO>[CH3:18][O:17][C:15]([C:14]1[CH:13]=[CH:12][N:2]=[C:3]([NH2:5])[N:4]=1)([O:19][CH3:20])[CH3:16]
Reactant: N=C(N)N
Reactant: COC(C)(OC)C(=O)C=CN(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(C)(OC)c1ccnc(N)n1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To guanidine hydrochloride salt (15 g, 156.68 mmol) was added sodium ethoxide, 21% wt in EtOH (59 mL, 156.68 mmol). After stirring for 5 min, 1-dimethylamino-4,4-dimethoxy-pent-1-en-3-one (Lipinski; J. Het. Chem., 22:1723 (1995)) (29.30 g, 156.68 mmol) in EtOH (50 mL) was added. The mixture was heated at 80° C. under N2 for 20 h, then cooled to RT. Solvent was evaporated in vacuo and the residue was re-dissolved in hot EtOAc (200 mL). The undissolved solid was separated by filtration and the solvent was evaporated in vacuo to give a pale yellow solid. MS m/z:184.3(M+H). Calc'd for C8H14N3O2: 184.21.
Reaction SMILES: [OH-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[NH:21][C:22]=2[CH:23]=1>O.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[N:21]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:22]=2[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]c3cc(Br)ccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CCC3)cc1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
6 N NaOH (10 mL), TsCl (0.48 g, 2.5 mmol) and (Bu4NH)2SO4 (50% solution in water, 0.17 mL) were added to a solution of tert-butyl 8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.76 g, 2.1 mmol) in toluene (17 mL), and the resulting solution was stirred for 18 h. Additional TsCl (55 mg, 0.29 mmol) was added, and the reaction was stirred for 18 h. The solution was partitioned with H2O and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO hexanes/EtOAC, 90:10 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes) provided the title compound (0.54 g, 50%) as a white foam: 1H NMR (500 MHz, DMSO-d6) δ 8.24-8.20 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H) 4.44-4.40 (m, 2H), 3.56 (t, J=5.5 Hz, 2H), 3.20-3.18 (m, 2H), 2.31 (s, 3H), 1.86-1.84 (m, 2H), 1.29-1.03 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
A mixture of 2.10 g (10.0 mmol) of 1-(t-butoxycarbonyl)-4-cyanopiperidine (from Step A), 1.95 g (30.0 mmol) of sodium azide and 1.60 g (30.0 mmol) of ammonium chloride in 20 mL of DMF was stirred at 100° C. for 20 h. The mixture was cooled and partitioned between 200 mL of methylene chloride and 200 mL of 1.0 N HCl and the layers were separated. The organic layer was washed with 200 mL of water, dried over magnesium sulfate and concentrated. Flash chromatography on 50 g of silica gel using 4:1 v/v methylene chloride/ethyl acetate+1% acetic acid, then 2:1 v/v methylene chloride/ethyl acetate+1% acetic acid as the eluent afforded 1.51 g (60%) of the title compound:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])C)=[C:4]([CH3:11])[CH:3]=1.II.[OH-:14].[Na+].Cl>N1C=CC=CC=1.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:14])=[C:4]([CH3:11])[CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: [OH-]
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4'-Hydroxy-2'-methylacetophenone (15 gm, 0.1 mol) was dissolved in pyridine and iodine (25.4 gm) was added. This mixture was heated to 100° C. for 1 hr and then allowed to stand at room temperature overnight. A thick precipitate was obtained and the mixture was diluted with Et2O before filtering. The solid so obtained was added to 5N NaOH (200 ml) and heated on the steam bath for 1 hr before being cooled and acidified with HCl. This mixture was extracted twice with Et2O and the pooled organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was crystallized from Et2O-hexane to give 9.8 gm of the title compound as a solid.