Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1([C:13]([F:16])([F:15])[F:14])[O:7][C:6]([CH:9]=[CH2:10])([F:8])[C:5]([F:12])([F:11])[O:4]1.C([Al](Cl)Cl)C.[CH:24]#[N:25]>C1(C)C=CC=CC=1>[F:16][C:13]([F:14])([F:15])[C:3]1([C:2]([F:1])([F:17])[F:18])[O:7][C:6]([CH2:9][CH2:10][C:24]#[N:25])([F:8])[C:5]([F:11])([F:12])[O:4]1
Reactant: C=CC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F
Reactant: C#N
Agent: CC[Al](Cl)Cl
Solvent: Cc1ccccc1
Product: N#CCCC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F
Temperature: 60 °C
Yield: 66 %

Procedure:
A mixture comprised of Ni[P(O-tolyl)3]4 (3.3 g, 2.2 mmole) and P(O-tolyl)3 (1.7 g, 4.8 mmole), 2,2-bis(trifluoromethyl)-4-vinyl-4,5,5-trifluoro-1,3-dioxolane (30 g, 0.103 mole), 25% EtAlCl2 in toluene (2.0 ml), and toluene (25 ml) was heated under nitrogen in an oil bath at 60° C. A 50% HCN in toluene solution was fed from an ISCO pump at a rate of 1.5 ml/hour for 4.5 hours and then 0.5 ml/hour overnight until the reaction was complete (GC determination). The mixture was allowed to cool and was purified by distillation to give 2,2- bis(trifluoromethyl)-4-(2-cyanoethyl)-4,5,5-trifluoro1,3-dioxolane as a clear, colorless liquid in 66% yield. Bp. 65°-68° C./7.0 mm. 1H-NMR (CDCl3): δ 2.72 (t, J=7.8 Hz, 2H), 2.50 (m, 2H); 19F NMR (CDCl3 ): -110.2 (m, 1F), -76.9, -77.6 (2m, 1F), -87.0, -87.7 (2d, J=9.3 Hz, 1F), -80.6 (m, 3F), -81.3 (m, 3F). Anal. Calc. for C8H4F9NO2 : C: 30.28, H: 1.27, F: 53.94; Found: 30.21, H: 1.34, F: 54.26. MS: [M]: Calc.: 317.0098; Found: 317.0081; MS (PCI): [M+H]: Calc.: 318.0177; Found: 318.0176. ##STR10##
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[CH:21])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:25])[CH2:2][CH3:3].I[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[O:25]=[C:5]1[N:6]([CH2:22][CH2:23][CH3:24])[C:7]2[N:8]=[C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[C:21][C:27]4[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=4)[CH:18]=3)[NH:10][C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C#CCn1cc(-c2nc3c([nH]2)c(=O)n(CCC)c(=O)n3CCC)cn1
Reactant: NS(=O)(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC#Cc4ccc(S(N)(=O)=O)cc4)c3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.4 %

Procedure:
A mixture of 1,3-dipropyl-8-(1-prop-2-ynyl-1H-pyrazol-4-yl)-3,7-dihydro-purine-2,6-dione (200 mg, 0.59 mmol), 4-iodo-benzenesulfonamide (166 mg, 0.59 mmol), copper iodide (10 mg, 0.059 mmol), dichlorobis (triphenylphosphine)-palladium (II) (21 mg, 0.03 mmol), triethylamine (2 ml), DMF (2 ml) was degassed for 10 min. and stirred for 20 hrs at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×10 ml). Organic layer was washed with brine (2×15 ml) and dried over Na2SO4. The organic volatile solvent was evaporated and the crude product was purified using HPLC to obtain pure 4-{3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzenesulfonamide (4.2 mg, 2%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11]I.O>C1COCC1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH3:11])[C:2](=[O:1])[CH:7]=1
Reactant: CI
Reactant: Oc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To an ice-cold solution of 2-hydroxy-4-bromopyridine (1.0 g, 5.75 mmol) in THF (20.0 mL) was added NaH (60% in mineral oil, 0.23 g, 5.75 mmol) portionwise. The reaction mixture was stirred at room temperature for 15 min followed by addition of methyl iodide (1.10 mL, 17.24 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water and extracted with EtOAc (3×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (0.99 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 3.38 (s, 3H), 6.44 (dd, J=2.0 and 7.20 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H) and 7.69 (d, J=7.20 Hz, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24].I.[NH2:27][C:28]1[C:29]([C:36]([NH:38][C:39](=[NH:42])SC)=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1>C(O)C>[NH2:27][C:28]1[C:29]([C:36]([N:38]=[C:39]([NH2:42])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCCCCCCCCC(N)=O
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CCCCCCCCCCCNC(N)=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
Diisopropylethylamine (0.24 mL, 1.38 mmol) was added to a suspension of 12-amino-dodecanoic acid amide hydrochloride (8) (0.068 g, 0.27 mmol) in absolute ethanol (5 mL). The resulting solution was stirred at 70° C. (oil bath) for 5 min, after which time 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (115 mg, 0.30 mmol) was added in one portion. The reaction mixture was then stirred at this temperature for 3 hours then cooled to room temperature. After removal of the solvent by rotary evaporation the resulting residue was dissolved in small volume of methanol, and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution concentrated in vacuo to a yellow residue. This residue was stirred in a minimal volume of methanol and the resulting solid was collected by suction filtration and washed with a small amount of methanol to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-dodecanoic acid amide 9 (0.065 g, 56%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) 1.23 (m, 14H), 1.49 (m, 4H), 2.01 (t, 2H), 3.11 (m, 2H), 6.65 (m, 4H), 7.21 (br, 1H), 9.06 (br, 1H). m/z (ESI) 427 [C18H31ClN8O2+H]+. mp 192-194° C.
Reaction SMILES: C(O)C.[NH3:4].[Cl:5][C:6]1[C:11]([C:12](OC)=[O:13])=[C:10]([S:16](Cl)(=[O:18])=[O:17])[CH:9]=[CH:8][CH:7]=1>O1CCOCC1>[Cl:5][C:6]1[C:11]2[C:12](=[O:13])[NH:4][S:16](=[O:18])(=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: COC(=O)c1c(Cl)cccc1S(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21
Temperature: 60 °C

Procedure:
150 ml of ethanol saturated with ammonia were added dropwise over a period of 30 minutes to a solution of 38.2 gm (0.141 mol) of methyl 6-chloro-2-chlorosulfonyl-benzoate in 150 ml of dioxane at 30°-50° C. Subsequently, the reaction mixture was heated for 2 hours at 40° C. and for 2 hours more at 60° C. After cooling, the reaction mixture was evaporated, treated with ether and filtered. The filter cake was boiled with water, filtered while hot, and the filtrate was acidified with hydrochloric acid. Yield: 19.8 gm (64.5% of theory) of 4-chloro-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][C:10]=2[CH3:19])=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:28])[C:10]=2[CH3:19])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c2ccc(F)cc2c1Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% disp. in oil) (0.12 g) was added portionwise to a stirred solution of the product from step (i) (0.75 g) in DMF (10 ml) at RT. After 10 min, ethylbromoacetate (345 ul) was added, the mixture stirred at RT for 3 h then quenched with water and extracted with diethylether. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 15% ethylacetate/iso-hexane. Yield 0.38 g
Reaction SMILES: C(O[C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[C:14](=[C:16]([CH2:20][CH3:21])[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:6][N:5]=1)C.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:20]([C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:22])[NH:11][C:10]([C:9]3[C:4]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[N:5][CH:6]=[C:7]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:24])=[O:25])[CH:8]=3)=[N:15][C:14]=12)[CH3:21]
Reactant: COCCN
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C)nc2c(=O)[nH]1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3NCCOC)[nH]c(=O)c2nn1C
Yield: 69 %

Procedure:
A mixture of the title compound of Example 78 (200 mg, 0.42 mmol), and copper (II) sulphate pentahydrate (150 mg, 0.60 mmol) in 2-methoxyethylamine (2 ml) was heated under reflux for 2 hours, then cooled. The reaction was partitioned between dichloromethane (20 ml) and aqueous sodium carbonate solution (5 ml), and the layers separated. The organic phase was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (98:2 to 95:5) to afford the title compound (150 mg, 69%). δ (CDCl3): 1.04 (3H, t), 1.40 (3H, t), 2.42 (2H, q), 2.55 (4H, m), 2.92 (3H, s), 3.01 (2H, q), 3.13 (4H, m), 3.50 (4H, m), 3.48 (3H, s), 3.68 (2H, t), 3.88 (2H, t), 4.07 (3H, s), 8.34 (1H, s), 8.58 (1H, s). LRMS: m/z 519 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C(F)(F)F)c1Cl
Product: Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1Cl
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
72 gms of the crude mixture of 2, 4, and 6 mono chloro 3-methyl benzotrifluoride (0.37 moles) from Example I was added dropwise to 200 gms of 98% HNO3 at about -5° C. to 0° C. over a period of about 1 hour. After addition, solution was stirred for an additional 20 minutes. The solution was then washed with ice water and solvent extracted with CH2Cl2 to give 87 gms of an amber colored liquid. The liquid was distilled at 100°-110° C./(<0.1 mm) to give 84.5 gms of a yellow colored liquid (96% yield)
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2cnccc12
Solvent: CN(C)C=O
Product: Clc1ncnc2cnccc12
Yield: 99.4 %

Procedure:
A suspension of pyrido[3,4-d]pyrimidin-4-ol (33)(1.47 g, 10 mmol) in thionylchloride (30 ml) and dimethylformamide (50 μl, cat.) was heated to reflx (90° C.) for 1 hour. The mixture was then cooled and concentrated in vacuo and then diluted with CH2Cl2 (50 ml) which caused a suspension to form. The solid was removed by filtration, washed with cold CH2Cl2 (10 ml) to give the title compound (1.65 g, 99.4%) in sufficiently pure form to be used without any further purification. m/z (LC-MS, ESP): 166 [M+H]+, R/T=2.82 mins.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(O)C1C=C([N+]([O-])=O)C=CC=1OC>>[CH2:13]([O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][OH:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(O)c(CO)c1
Reactant: BrCc1ccccc1
Agent: COc1ccc([N+](=O)[O-])cc1C(O)OC
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(CO)c1
Yield: 84 %

Procedure:
This intermediate was prepared by alkylation of 2-hydroxymethyl-4-nitrophenol with benzyl bromide following the method described for preparation of 2-methoxy-5-nitrobenzaldehyde methyl hemiacetal in a yield of 84%: MP 81-83° C.; 1H NMR δ (DMSO-d6, 500 MHz) 8.26 (d, 1H, J=2.9 Hz H-6), 8.15 (dd, 1H, J=2.9 and 9.1 Hz, H-4), 7.46 (d, 2H, J=7.0, 2′, 6′-Hs)7.41 (dd, 2H, J=7.0 and 7.7, 3′, 5′-Hs), 7.34 (d, 1H, J=7 Hz, 4′-H), 7.25 (d, 1H, J=9.1 Hz, 3-H), 5.4 (br, 1H, OH), 5.29 (s, 2H, CH2 ), 4.57 (s, 2H, CH2).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:48]([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=3)(=[O:50])=[O:49])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran (5 mL), 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) under ice-cooling and the mixture was stirred for 10 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 477 mg, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:14]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:14]=2[OH:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)cc(F)c2C=O)C1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)cc(F)c2O)C1
Reaction time: 72 h
Yield: 45.6 %

Procedure:
To a solution of the title compound of Step B (650 mg, 2.0 mmol) in CH2Cl2 (100 mL) was added 77% m-CPBA (510 mg, 3.0 mmol). After stirring for 72 h, the starting aldehyde remained as determined by analytical HPLC analysis. Thus an additional portion of m-CPBA (790 mg, 4.6 mmol) was added. After 18 h, analytical HPLC analysis indicated that the reaction was complete. A solution of 10% aqueous sodium bisulfite (100 mL) was added to the reaction mixture. After an additional 18 h, CH2Cl2 was added and the aqueous portion extracted three times with CH2Cl2. The combined organic extracts were washed with saturated NaHCO3 (2×) and concentrated. The residue was then treated with MeOH (500 mL) and 1 N NaOH (250 mL). The solution immediately turned dark brown. After 2 h, the MeOH was removed by rotary evaporation and 1 M KHSO4 was added to the residue until the pH of the solution reached pH=4. The reaction mixture was then extracted with EtOAc (3×). The combined organic layers were washed with brine and dried. The residue was purified by RP HPLC to provide the desired phenol (290 mg, 46%). 1H NMR (CDCl3): 6.74 (dd, J=10.1, 2.3 Hz, 1H), 6.30 (dd, J=2.0, 2.1 Hz, 1H), 4.87-4.80 (m, 1H), 4.26 (dd, J=9.9, 6.4 Hz, 2H), 4.00 (dd, J=9.9, 3.8 Hz, 2H), 3.29-3.13 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc2cccnc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.93 g of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 92°-94° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].O.[Cl:20][C:21]1[CH:22]=[C:23]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([N:54]3[CH2:59][CH2:58][CH:57]([C:60]([F:63])([F:62])[F:61])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)[CH:24]=[C:25]([Cl:45])[C:26]=1[CH2:27][C@@H:28]1[CH2:32][CH2:31][N:30]([C@H:33]2[CH2:38][CH2:37][C@H:36](OS(C)(=O)=O)[CH2:35][CH2:34]2)[C:29]1=[O:44]>C(#N)C>[Cl:20][C:21]1[CH:22]=[C:23]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([N:54]3[CH2:55][CH2:56][CH:57]([C:60]([F:62])([F:61])[F:63])[CH2:58][CH2:59]3)=[O:53])=[CH:48][CH:47]=2)[CH:24]=[C:25]([Cl:45])[C:26]=1[CH2:27][C@@H:28]1[CH2:32][CH2:31][N:30]([C@H:33]2[CH2:38][CH2:37][C@@H:36]([F:18])[CH2:35][CH2:34]2)[C:29]1=[O:44]
Reactant: [F-]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@@H](F)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve TBAF.3H2O (0.436 g, 1.36 mmol) in 5 ml of acetonitrile. Add water (0.05 ml. 2.72 mmol) and stir for 10 minutes. Add Methanesulfonic acid trans-4-{(R)-3-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-2-oxo-pyrrolidin-1-yl}-cyclohexyl ester (Preparation 24) (0.458 g, 0.68 mmol). Stir at 80° C. for 12 hours. Quench with saturated NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.036 g (9%) of the title compound: Mass spectrum (apci) m/z=599 (M+H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CN(C)CCN(C)C.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1.CCCCCC>[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH:30]=[O:31])=[CH:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccs2)OCCO1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(c2ccc(C=O)s2)OCCO1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of commercially available 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (5.00 g, 28.49 mmol) in THF (145.0 mL) at −78° C. was added dropwise N,N,N′,N′-tetramethyl-ethylendiamine (4.41 mL, 29.06 mmol) followed by n-BuLi (18.14 mL of a 1.6M solution in hexane, 29.06 mmol), maintaining the temperature at −78° C. The reaction mixture was then stirred for 2 h at −78° C. before DMF (6.74 mL, 87.22 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 16 h. The reaction mixture was poured on sat. aq. NaH4Cl (200 mL) and extracted with EA (2×200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-2-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.87 min; [M+AcCN]+=240.32. The crude material was dissolved, under inert atmosphere (N2) in MeOH (51.2 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.35 g, 34.19 mmol in five equal portions). The reaction mixture was stirred for 45 min at rt. The reaction mixture was poured on water (90 mL) and the aq. layer was extracted with EA (2×225 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound: TLC:rf (50:50 hept-EA)=0.40. LC-MS-conditions 02: tR=0.73 min; [M+H]+=201.46.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH2:13])([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCCCP(=O)(CCCN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCP(=O)(CCCNCc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.14 g of 3-aminopropyl(n-butyl)phosphinic acid ethyl ester are mixed with 2.51 g of p-chlorobenzaldehyde, and first 1.2 g of glacial acetic acid and then a solution of 0.42 g of sodium cyanoborohydride in 5 ml of methanol are added, whereupon an exothermic reaction takes place. The mixture is then stirred at room temperature for 2.5 hours and adjusted to pH 8, and the volatile constituents are removed under reduced pressure. The residue is dissolved in dichloromethane, washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=7.30-7.32 (4H,m); 4.02 (2H,q); 3.74 (2H,s); 2.67 (2H,t); 2.5-2.22 (1H,S); 1.79-1.64 (6H,m); 1.53 (2H,m); 1.42 (2H,m; 1.31 (3H,t); 0.81 (3H,t); 31P-NMR spectrum (in CDCl3 ): δ=58.16.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:22]3[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Product: Oc1cccc(C=C2c3ccccc3CCc3c(Cl)cccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 3-hydroxyphenylboronic acid (47 mg, 0.344 mmol) affords 8 mg (8%) of the Z-isomer of the title compound (MS (ES) 331 (M−H). HPLC shows 95% purity. Continue to elute and isolate 27 mg (26%) of the E-isomer of the title compound, MS (ES) 331 (M−H). HPLC shows 97% purity.