Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=c1[nH]nc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2n[nH]c(=O)o2)cc1

Procedure:
5-(4-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one, (0.65 g) in ethanol (100 ml) was hydrogenated at 276 kPa (40 p.s.i.) in the presence of palladium on carbon at room temperature for one hour. The reaction mixture was filtered, the filtrate was evaporated to dryness and the resultant yellow solid was recrystallised from ethanol to afford (5-(4-aminophenyl)-1,3,4-oxadiazol-2(3H)-one, 0.46 g, m.p. 172°-173° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]2[CH:27]=[C:28](F)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]2[CH:27]=[C:28]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1
Reactant: Fc1ccc2nnc(-c3ccccc3Cl)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4ccccc4Cl)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
Sodium hydride (60% in mineral oil, 840 mg, 21.9 mmol) was added portionwise to a stirred solution of Intermediate 1d (1.19 g, 7.31 mmol) in anhydrous DMF (30 mL) at RT under an argon atmosphere. Intermediate 31b (1.81 g, 7.31 mmol) was then added, and stirring at 60° C. was continued for 1.5 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of NH4Cl and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC, using 0-10% MeOH in DCM to afford the title compound (1.48 g, 52%) as a brown foam. LCMS (Method 3): Rt 0.42 and 2.33 min, m/z 391. [MH+].
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[N:49]=[C:48]([C@:50]2([CH3:68])[CH2:55][C@@H:54]([C:56]([F:59])([F:58])[F:57])[O:53][C:52]([NH:60]C(=O)OC(C)(C)C)=[N:51]2)[C:47]([F:69])=[CH:46][CH:45]=1.[Cl:70][C:71]1[C:72]([C:81]([NH2:83])=[O:82])=[N:73][CH:74]=[C:75]([C:77]([F:80])([F:79])[F:78])[CH:76]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.[Pd].[Pd]>[NH2:60][C:52]1[O:53][C@H:54]([C:56]([F:57])([F:58])[F:59])[CH2:55][C@:50]([C:48]2[N:49]=[C:44]([NH:83][C:81](=[O:82])[C:72]3[C:71]([Cl:70])=[CH:76][C:75]([C:77]([F:79])([F:78])[F:80])=[CH:74][N:73]=3)[CH:45]=[CH:46][C:47]=2[F:69])([CH3:68])[N:51]=1
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@]1(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 13.6 %

Procedure:
A sealable vial was charged with Pd2(dba)3 (Strem, 9.03 mg, 9.86 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Strem, 22.83 mg, 0.039 mmol) and dioxane (0.5 mL). The reaction mixture was stirred under Nitrogen atmosphere for 10 min. A solution of tert-butyl ((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7i, 60 mg, 0.132 mmol) in 1,4-dioxane (1.3 mL), 3-chloro-5-(trifluoromethyl)picolinamide (intermediate 22, 42.8 mg, 0.191 mmol), and cesium carbonate (Aldrich, 107 mg, 0.329 mmol) were added. The vial was sealed flushed with nitrogen for 10 min and the reaction was heated to 90° C. for 3 h. The reaction mixture was cooled to RT and filtered through a pad of celite. The filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 25 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (9 mg, 0.018 mmol, 13.69% yield) as white solid. MS m/z=500 [M]+. Calculated for C18H13ClF7N5O2: 499.7
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)C2C(=O)CC2C1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCSC1=C(C(=O)O)C2C(=O)CC2C1
Yield: 91.6 %

Procedure:
A solution of 150 mg of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, and 130 mg of anisole in 1 mL of trifluoroacetic acid was stirred at ambient temperature for 15 min. The solvent was then removed by a stream of nitrogen leaving a residue which was crystallized from ether to afford 85 mg (92%) of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid as colorless crystals, mp 150° to 152°. IR (Nujol): 1640, 1660, 1785, 3150 cm-1 ; NMR (CDCl3 /DMSO-d6): δ 1.93 (3H, s), 2.8-3.0 (5H, m), 3.1-3.4 (4H, m), 4.43 (1H, m), and 7.43 (1H, m). HRMS: The molecular ion (m/z 269) was not observed; however, a major fragment corresponding to loss of ketene from the molecular ion was mass measured: Calcd for C10H13O3NS, 227.0615; found, 227.0616.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=2)[N:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: COCc1n[nH]cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nn(-c2cccc(C(F)(F)F)n2)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (5.1 g) synthesized in Example 29(1) in N,N-dimethylformamide (70 mL) were added 2-chloro-6-trifluoromethylpyridine (5.0 g) and potassium carbonate (6.2 g), and the mixture was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature and filtered through celite, water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (6.5 g, 69%) as colorless crystals.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH3:44])[CH:37]=[C:38]([O:42]C)[C:39]=1[O:40][CH3:41].Cl>ClCCCl>[OH:42][C:38]1[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=[C:36]([CH3:44])[C:37]=1[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:3]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Temperature: 0 °C

Procedure:
In 60 ml of 1,2-dichloroethane is dissolved 8 g of methyl 21-chloroformylheneicosanoate, followed by addition of 5.5 g of aluminum chloride. The mixture is stirred. Then, under ice-cooling and stirring in a nitrogen stream, a solution of 5.67 g of 3,4,5-trimethoxytoluene in 1,2-dichloroethane (13 ml) is added dropwise. The mixture is stirred for 48 hours, after which 1.3 g of aluminum chloride is added. The mixture is stirred at room temperature for 16 hours and further at 35° C.-38° C. for 40 minutes. To this reaction mixture are added ice-water and 3N-HCl, followed by extraction with chloroform. The extract is washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order. After drying, the solvent is distilled off under reduced pressure and the residue is chromatographed on silica gel. The fractions containing the desired compound are pooled and recrystallized from methanol. The above procedure yields methyl 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoate as colorless needles. m.p. 73°-74° C. NMR(δ, in deuteriochloroform): 1.24(36H, b, CH2), 2.27(2H,t,CH2COO), 2.42(3H, s, nuclear CH3), 2.86(2H, t,COCH2), 3.64(3H,s,COOCH3), 3.84(3H,s,OCH3), 3.87(3H,s,OCH3), 6.22(1H,s,nuclear H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14]>N([O-])=O.[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1O
Temperature: 15 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
In a 500-ml flask, place 44.8 g (0.4 m) of 4-fluorophenol (1a; X=F) and 132 ml of acetic acid and stir to a solution. Add 0.6 g of sodium nitrite and cool the solution to 15° C. Add 36.0 g (0.4 m) of 70% nitric acid in drop wise keeping the temperature at 22-27° C. over 10-15 min. Stir the resulting yellow slurry at room temperature for 3 hrs. Warm the mixture to 65° C. to make a clear solution and add 132 ml of warm (65° C.) water slowly. Stir the resulting slurry and cool to 15° C. Collect solid, wash with water thoroughly, and dry in air to give 53.4 g (85%) of 4-fluoro-2-nitrophenol (2a; X=F) as yellow granular solids.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.C([Li])CCC>>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:4]1[O:3][C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: BrCCCCBr
Reactant: Cc1ccco1
Agent: [Li]CCCC
Product: Cc1ccc(CCCCBr)o1

Procedure:
2-methylfuran 26 is alkylated with 1,4-dibromobutane in the presence of a strong base, for example, n-butyllithium under anhydrous conditions, to produce 5-(4-bromobutyl)-2-methylfuran 27. The latter is then treated with ethylene or propylene glycol in the presence of an acid catalyst to afford the diketal bromide 28 (n=2 or 3). The bromide 28 is converted with a source of iodine ion, for example, sodium iodide, to the corresponding diketal iodide 29, which in turn is caused to react with triphenylphosphine to give the diketal phosphonium iodide 30. Treatment of the latter with phenyllithium in ether splits out the elements of HI resulting in a red solution of the ylide 25 which is not isolated as such but is used directly in condensation with aldehyde 8 (or 8a or 8b).
Reaction SMILES: [I-:1].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([CH2:17][OH:18])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15]Br)[C:4]#[CH:5]>CC(C)=O>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([CH2:17][OH:18])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][I:1])[C:4]#[CH:5]
Reactant: C#CCOc1cc(CO)ccc1OCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(CO)ccc1OCCI
Temperature: 50 °C
Yield: 95.5 %

Procedure:
Sodium iodide (10 g, 70 mmol, 4 equiv) was added in one portion to the stirred solution of 10 (5 g, 18 mmol, 1 equiv) in acetone (40 mL). The mixture was heated to 50° C. under nitrogen overnight. Upon reaction completion, the solvent was removed under vacuum. The resulting solid was dissolved in CH2Cl2 (200 mL) and washed subsequently with sodium thiosulfate solution (2×200 mL), water (200 mL) and brine (200 mL). The organic layer was dried over MgSO4, filtered and solvent was removed under vacuum to afford product as a white solid (5.71 g, yield: 98%). 1H NMR δ=7.09 (d, J=1.8, 1H), 6.96 (dd, J1=1.8, J2=8, 1H), 6.91 (d, J=8, 1H), 4.78 (d, J=2.3, 2H, —OCH2C≡CH), 4.63 (d, J=5.8, 2H, —CH2OH), 4.30 (t, J=6.6, 2H, —OCH2CH2I), 3.45 (t, J=6.6, 2H, —OCH2CH2I), 2.51 (t, J=2.3, 1H, —C≡CH), 1.68 (t, J=5.8, 1H, —CH2OH). 13C NMR δ=147.80, 145.50, 135.14, 121.22, 115.33, 114.86, 78.74 (—C≡CH), 76.09 (—C≡CH), 70.44 (—CH2OH), 65.21 (—OCH2CH2I), 57.38 (—OCH2C≡CH), 1.32 (—OCH2CH2I). HRMS calculated for C12H11BrO3 (M−OH+), 267.0021; found, 267.0008.
Reaction SMILES: [C:1]([C@:6]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2]>C1(C)C=CC=CC=1>[C:1]([C@:6]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@]1(Cc2ccccc2)CCCNC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@]1(Cc2ccccc2)CCCNC1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
A mixture of piperidone 3 (349 mg, 1.34 mmol) Lawesson's reagent (594 mg, 1.47 mmol) and toluene (1.5 mL) was heated to 110° C. for 2 h. The mixture was cooled to 25° C., aged for 15 min, and filtered through a cotton plug, washing with toluene (3.5 mL). The filtrate was evaporated, and the residue containing thiolactam 4 was dissolved in THF (2 mL) and EtOH (2 mL). A 50% aqueous slurry of Raney nickel (1 mL) was added. After a 5 min age another portion of the Raney nickel (1 mL) was added followed by NaBH4 (25 mg). After 15 min the mixture was filtered through a pad of solkafloc, washing the pad with THF (5 mL) and EtOH (5 mL). The filtrates were evaporated to 4 mL and diluted with MTBE (20 mL). The mixture was extracted with 0.5M aqueous HCl (2×3 mL), and the aqueous extract was basified with 5M aqueous NaOH (0.7 mL). The aqueous mixture was extracted with CH2Cl2 (2×3 mL). The organic extracts were dried over Na2SO4 and evaporated to give piperidine 5 (100 mg, 30%) as a colorless oil: 13C NMR (62.9 MHz, CDCl3) δ 175.1, 136.5, 129.6, 127.8, 126.4, 60.2, 53.1, 47.8, 46.1, 44.3, 32.8, 24.3, 13.9. HPLC analysis of the Marfey's derivative of 5 indicated >99.5 % ee. Sample preparation for Marfey's derivatization: 0.5 mg tartrate salt, 0.5 mg Marfey's reagent {N-(2,4-Dinitro-5-fluorophenyl)-L-alaninamide}, 50 μL of 6M NaHCO3 and 0.5 mL acetone were combined. The mixture was heated at 55° C. (4-5 min.) until it turned red in color from light yellow and made up to 1 mL with 1:1 MeCN and H2O. HPLC conditions: B-03-5 YMC Basic (S-5 micron) 250×4.6 mm column, isocratic elution over 10 min (42/58) MeCN/0.025% H3PO4, then gradient elution over 5 min (42/58→62/38) MeCN/0.025% H3PO4, then isocratic elution over 15 min (62/38) MeCN/0.025% H3PO4, 1.0 mL/min flow at 25° C. with detection at 220 nm.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]([S:13](/[N:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])([CH3:12])[CH3:11]>CS(C)=O>[C:10]([S:13]([N:15]1[CH2:4][CH:16]1[C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])([CH3:9])([CH3:11])[CH3:12]
Reactant: C[S+](C)(C)=O
Reactant: CCCS(=O)(=O)c1ccc(/C=N/S(=O)C(C)(C)C)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCS(=O)(=O)c1ccc(C2CN2S(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Sodium hydride (0.33 g of a 60% dispersion in mineral oil, 8.37 mmol) was added portionwise to a stirred solution of trimethylsulphoxonium iodide (1.84 g, 8.37 mmol) in DMSO (30 mL). The mixture was stirred at room temperature for 1 h by which time effervescence had ceased and the mixture was mostly clear. 2-Methyl-N-{(1E)-[4-(propylsulphonyl)phenyl]methylene}propane-2-sulphinamide (1.76 g, 5.58 mmol) was added and the resulting solution stirred at room temperature overnight. The reaction mixture was quenched by addition of water and the product extracted into ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give the title compound (1.44 g, 88% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([CH3:45])[C:43]=1[F:44])[CH2:39]Br>C1COCC1>[F:44][C:43]1[C:36]([CH3:35])=[CH:37][C:38]([CH2:39][C@H:8]([CH2:7][CH2:6][CH2:5]/[CH:4]=[CH:3]/[CH:2]([CH3:24])[CH3:1])[C:9]([N:11]2[C@H:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][O:13][C:12]2=[O:23])=[O:10])=[CH:41][C:42]=1[CH3:45]
Reactant: CC(C)/C=C/CCCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Cc1cc(CBr)cc(C)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C[C@H](CCC/C=C/C(C)C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a cooled (−78° C.) solution of (R)-3-((E)-8-methylnon-6-enoyl)-4-benzyloxazolidin-2-one (2.000 g, 6.071 mmol) in 40 mL of THF, was added LiHMDS (9.1 mL, 9.1 mmol, 1.0 M in THF). The resulting mixture was stirred at −78° C. under N2 for 1 h and then a solution of 3,5-dimethyl-4-fluorobenzyl bromide (1.450 g, 6.678 mmol) in 10 mL of THF was added. After being stirred at −78° C. for 1 h the reaction mixture was warmed to room temperature for 2 h, and then quenched with 80 mL of NH4Cl solution and extracted with dichloromethane (60 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (1.925 g, 68% yield). GC-MS: tR=8.8 min; m/z 465 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11](=O)[CH2:12]Br)=[N:8][CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:9]3[S:10][C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cnc(C(=O)CBr)s1
Product: CCOc1ccc(-c2nc(-c3ncc(C(=O)O)s3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-2-(α-bromoacetyl)thiazole and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-thiazolyl)thiazole.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(OC)cc2)cc1
Temperature: 50 °C
Yield: 73.1 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.38 g). To the solution was added 1N sodium hydroxide solution (8 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.27 g) as yellow crystals.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:29])[C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34].O.Cl>N1C=CC=CC=1>[Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:29])[C@:16]2([O:24][C:25](=[O:28])[CH2:26][CH3:27])[C:17](=[O:20])[CH2:18][O:19][C:32](=[O:35])[CH2:33][CH3:34])[C@H:12]2[C@H:3]1[C@:4]1([CH3:31])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:30])[CH:6]=[CH:5]1
Reactant: CCC(=O)Cl
Reactant: CCC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)OCC(=O)[C@@]1(OC(=O)CC)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C

Procedure:
A solution of 11β-chloro-21-hydroxy-16β-methyl-17-propionyloxypregna-1,4-diene-3,20-dione(75 mg) in pyridine (1 ml) was cooled to 0° and treated with stirring with propionyl chloride (0.04 ml). After 90 minutes a little water was added and the solution poured into dilute hydrochloric acid. The precipitated solid was removed by filtration and recrystallized from methanol to give the title compound, m.p. 220°-222° (K), [α]D + 105° (c 0.6, chloroform) λmax 240nm (ε 15,060) (Found C, 65.9; H, 7.2; Cl, 6.7. C28H37ClO6 requires C, 65.7; H, 7.55; Cl, 7.0%).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:37][O:36][CH2:35][CH2:34][O:33][CH3:32])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: COCCOCCl
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 55.7 %

Procedure:
Following the procedure of Example 1(a), but reacting 980 mg (2.4 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 330 μl (28.6 mmol) of methoxyethoxymethyl chloride, 650 mg (55%) of the expected compound were obtained in the form of an oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[N:6][O:7][C:8]=1[CH3:9])([OH:3])=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][O:35][C:33]1[CH:34]=[C:29]([NH:28][C:26](=[O:27])[CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:1]([C:4]3[C:5]([C:10]4[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=4[F:17])=[N:6][O:7][C:8]=3[CH3:9])=[O:3])[CH:20]=2)[CH:30]=[C:31]([O:39][CH3:40])[C:32]=1[O:37][CH3:38]
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: Cc1onc(-c2c(F)cccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4c(F)cccc4F)noc3C)c2)cc(OC)c1OC
Yield: 52.8 %

Procedure:
4-Carboxy-5-methyl-3-(2,6-difluorophenyl)isoxazole (0.120 g, 0.50 mmol), 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (0.174 g, 0.55 mmol), EDCI (0.161 g, 1.00 mmol), DMAP (0.012 g, 0.10 mmol), and dichloromethane (5 ml) were allowed to react for 16 h in a fashion similar to that for example 5. Column chromatography (silica gel, hexanes/ethyl acetate gradient) afforded the title compound (0.142 g, 53%).