Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of 2-hydroxy-3-nitro-benzoic acid methyl ester (2.3 g, 11.67 mmol, 1.0 equiv) in ethanol (50 mL) was added palladium on activated charcoal 10% (0.47 g, 0.47 mmol, 0.04 equiv), the reaction vessel filled with hydrogen (3.5 bar) and stirred at 80° C. for 2 h. The catalyst was removed by filtration over celite and the solvent removed under reduced pressure yielding 1.9 g (95%) of the title compound which was used directly without further purification. 1H NMR (300 MHz, CDCl3): δ 3.88 (br s, 2H), 3.93 (s, 3H), 6.71 (t, J=7.9 Hz, 1H), 6.87 (dd, J=7.9 Hz, J=1.5 Hz, 1H), 7.24 (dd, J=7.9 Hz, J=1.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 52.13, 111.83, 118.71, 118.98, 119.55, 135.85, 149.70, 171.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH3:17][O:18]C=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:17]=[O:18]
Reactant: COC=O
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cncc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dichloropyridine (296 mg, 2.0 mmol) in THF (6 mL), cooled to −78° C., under N2 protection, was added dropwise LDA (1.2 mL of a 1.8 M solution in THF, 2.2 mmol). After 30 min, a solution of formic acid methyl ester (240 mg, 4.0 mmol) in THF (1.0 mL) was added slowly to the solution. After 1.5 h, the reaction mixture was rapidly poured into a 0° C. sat. aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc and the organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) as eluent to give 3,5-dichloro-pyridine-4-carbaldehyde as a white solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+]>OS(O)(=O)=O>[O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[NH:12][CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1NCCOc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution containing 4-chromanone (1, 2 g, 13.4 mmol) in 15 mL conc H2SO4 at 0° C. was added sodium azide (1.131 g, 17.4 mmol) and the reaction mixture was stirred initially at 0° C. for 1 hour and then stirred at room temperature for 2 hours. The reaction was quenched by the slow addition of water and then subsequently basified with 10% NaOH. The aqueous solution was extracted with ether (2×150 mL). The combined ether layers were dried (Na2SO4) and filtered. The solvent was removed under vacuo and the crude product was recrystallized from EtOAc/hexanes to afford 1.3 g, 61% of 2 as white needles. mp 118°-120° C. 1H NMR (CDCl3) d 8.0 (d, 1 H ArH), 7.6-7.7 (bs, 1H, NH), 7.4 (t, 1H, ArH), 7.2 (t, 1H ArH), 7.0 (d, 1H, ArH), 4.4 (t, 2H, CH2), 3.5 (t, 2H, CH2). EIMS M+ 163 (98), 134 (99), 105 (100).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+].[OH-].[K+]>S(=O)(=O)(O)O>[O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[NH:12][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCOc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: O=C1NCCOc2ccccc21
Temperature: 25 °C

Procedure:
The chroman-4-one (5.0 g, 33.8 mmol) was dissolved in sulfuric acid (10 mL) and the mixture was cooled at 0 oC. Sodium azide (2.88 g, 44.3 mmol) was added portionwise followed by some sulfuric acid (5 mL). The reaction mixture was stirred at room temperature over night. The mixture was then pour into ice-water and basified to pH=7 with potassium hydroxide pellets. This aqueous layer was extracted with ether (twice).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[NH2:14].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=1>C(OCC)(=O)C>[NH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:15][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=2)=[CH:9][C:8]=1[F:7]
Reactant: Nc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Potassium tert-butoxide (5 g, 23.47 mmol, 1.4 eq) was dissolved in N,N-dimethylacetylamide (DMA, 12 mL). A solution of 3-fluoro-4-aminophenol (4.2 g, 32.86 mmol, 1.4 eq) in DMA (15 mL) was slowly added dropwise at 0° C. After the addition, the mixture was stirred at room temperature for 30 min. The mixture was heated to 100° C. and a solution of tert-butyl 4-chloropicolinate in DMA (18 mL) was slowly added dropwise, and then the mixture was stirred for 1 h. After being cooled to room temperature, ethyl acetate (500 mL) was added, and the resulted mixture was filtered to remove the undissolved material. The filtrate was washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a brown solid. The crude was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give the title compound (1.38 g, purity 98%, yield 20%) as a light brown solid.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=O)[C:4]2=[N:3][CH:2]=1.[OH-].[Na+].BrCCBr.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.C(O)(=O)C>[CH2:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][CH:9]=[C:4]2[N:3]=[CH:2]1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: BrCCBr
Solvent: O
Product: C1=NC2=CNC3=C(Cc4ccccc43)N2C1
Temperature: 18 °C
Reaction time: 8 h

Procedure:
A suspension of 1.3 g of 5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one, 2 g of sodium hydroxide pellets and 32 mg of tetrabutylammonium bromide in 10 ml of dry dimethyl sulphoxide is stirred at a temperature in the region of 18° C. A solution of 0.4 ml of 1,2-dibromoethane in 5 ml of dimethyl sulphoxide is then added and the stirring is continued overnight at a temperature in the region of 20° C. The reaction mixture is poured into a mixture of water and ice (250 ml), acidified with 8 ml of acetic acid and kept stirring for 1 hour 30 minutes. The solid formed is then filtered off and it is purified by chromatography on a column of silica (100 g) with a mixture of dichloromethane and methanol (95/5 by volume). After drying at 60° C., 0.45 g of spiro[5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-10:1'-cyclopropane]-4-one is obtained, in the form of a pink solid melting above 260° C. (Analysis % calculated C: 72.28, H: 4.45, N: 16.86, O: 6.42, % found C: 71.8, H: 4.4, N: 16.3).
Reaction SMILES: C(C1C=CC(C#C)=CC=1)(C)(C)C.C[Si]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)(C)C.[OH-].[K+]>CO>[C:25]([C:21]1[CH:20]=[C:19]([C:18]#[CH:17])[CH:24]=[CH:23][CH:22]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Agent: C#Cc1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cccc(C(C)(C)C)c1

Procedure:
Using the same general procedure as described for Compound 21), but using instead trimethylsilyl (3-tert-butyl) phenylethyne (Compound 27) and aqueous KOH in methanol, the title compound was synthesized as a colorless oil. PMR (CDCl3): δ1.29 (9H, s), 3.03 (1H, s), 7.22 (1H, t, J~7.5 Hz), 7.30 (1H, dt, J~7.5 Hz, 1.5 Hz), 7.36 (1H, dt, J~7.5 Hz, 1.5 Hz), 7.53 (1H, t, J~1.5 Hz).
Reaction SMILES: [CH2:1]1[C@@H:5]([OH:6])[C@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][CH:13]=2)[C@@H:3]([CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@H:2]1[OH:32].C([O-])([O-])=O.[K+].[K+].[CH:39](I)([CH3:41])[CH3:40].OS([O-])(=O)=O.[Na+]>CN1CCN(C)C1=O.C(OCC)(=O)C.CCCCCC.O>[CH3:40][CH:39]([O:30][C:29]([CH2:28][CH2:27][CH2:26]/[CH:25]=[CH:24]\[CH2:23][C@@H:3]1[C@@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[C@H:5]([OH:6])[CH2:1][C@@H:2]1[OH:32])=[O:31])[CH3:41]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Temperature: 45 °C

Procedure:
463 g of Travoprost acid is dissolved in 2.3 L of 1,3-dimethylimidazolidinone (DMI), and 420 g of K2CO3 and 300 ml of isopropyl iodide are added. The reaction mixture is stirred at 45° C. After the completion of the reaction NaHSO4 solution, water, hexane and ethyl acetate are added. The mixture is shaken, then the phases are separated and the lower, aqueous phase is extracted with hexane:ethyl acetate mixture. The united organic phase is washed with water, dried over Na2SO4, the drying material is filtered off and the solution is evaporated. The product is purified by chromatography on silica gel, using diisopropyl ether, acetone, dichloromethane, isopropanol mixture as eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][N:15]1C(=O)C2=CC=CC=C2C1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CN>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CN
Solvent: C1CCOC1
Solvent: CCO
Product: NOCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of N-[2-(benzyloxycarbonylamino)ethoxy]phthalimide (1.36 g, 4.00 mmol), as prepared in the preceding step, in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2.0 mL, 25 mmol) and the reaction was stirred at ambient temperature for 1 h. After evaporating the solvent, the residue was purified by flash column chromatography (75-100% ethyl acetate in hexanes) to give the title compound as a white solid (0.80 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 5.47 (bs, 2H), 5.21 (bs, 1H), 5.10 (s, 2H), 3.72 (t, J=5.0 Hz, 2H), 3.44 (q, J=5.0 Hz, 2H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].FC1C(OC)=C(F)C=C2C=1C=CN2C.CCN(CC)CC>C(Cl)Cl>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: COc1c(F)cc2c(ccn2C)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
Combine phenyl boronic acid (7.32 g, 60 mmol), 4-methyl-3-nitrophenol (4.5 g, 30 mmol), and Cu(oAC)2—H2O (6 g, 30 mmol) in 30 mL CH2Cl2 and treat with 6 g 4 A molecular sieves powder. Add Et3N (15.18 g, 150 mmol) dropwise, and stir the reaction at ambient temperature for 8 days. Dilute with 100 mL CH2Cl2 and filter through celite and concentrate to dryness. Purification by chromatography using 2% EtOAc in hexanes gave the desired product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[N:18]O)[CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)/C=C\C(O)=O.[OH-].[Na+]>O1CCCC1.CCOCC.O>[NH2:18][CH:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][C:14]([CH3:16])([OH:17])[CH3:15]
Reactant: CC(C)(O)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)CC(N)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-hydroxy-3-methylbutan-1-one oxime (3 g prepared as described in Example 84 above) in dry tetrahydrofuran (20 ml) was added under nitrogen to lithium aluminium hydride (2 g). The mixture was heated under reflux for 3 hours and then left without further heating for 16 hours. Water (100 ml) was added dropwise and the organic layer was separated. The aqueous layer was extracted with ether and the extracts combined with the organic layer and dried. The solvents were evaporated to give an oil which was dissolved in ether. Addition of a solution of maleic acid in ether gave a gum which slowly solidified. The solid was added to an aqueous solution of sodium hydroxide and the mixture extracted with ether. Removal of the ether gave an oil which was purified by high performance liquid chromatography to give 4-amino-4-[1-(4-chlorophenyl)cyclobutyl]-2-methylbutan-2-ol (m.p. 60°-62° C. shrinks 50° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(N(CCC)C1C=CC=CC=1)CC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: CCCN(CCC)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 827 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added dipropylaniline (2.76 g) and 325 mg (5.51 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 230 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 46%) and 2.7 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.5%) were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.N1C2C(=CC=CC=2)C=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 63.7 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 833 mg (5.53 mmol) of 2-cyclopropyl-6-methylphenol were added quinoline (2.76 g) and 327 mg (5.55 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 321 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 64%) and 3.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.7%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:11][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.35 g, 6.28 mmol) in anhydrous DMF (16 mL) was treated in several portions with sodium hydride (377 mg of 60% in oil, 226 mg, 9.42 mmol) followed by stirring at room temperature for 30 min. The mixture was then treated with methyl bromo-acetate (871 μL, 1.45 g, 9.48 mmol) dropwise (solution became warm after addition was complete) followed by stirring at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (4×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a nearly colorless solid, which was purified by column chromatography on silica gel, eluting with 20-100% ethyl acetate in hexanes. These procedures afforded the title compound as a colorless solid (1.47 g, 82%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:27][C:28](=[O:30])[CH3:29])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1)[C:6](OCC)=[O:7])C.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>O.C(O)C>[OH:3][CH2:4][C:5]([NH:27][C:28](=[O:30])[CH3:29])([CH2:6][OH:7])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1
Reactant: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(CO)(CO)NC(C)=O)cc1
Reaction time: 8 h
Yield: 101.9 %

Procedure:
28 g (64.57 mmole) 2-(acetylamino)-2-[2(4-octylphenyl)ethyl]propanedioic acid diethylester (=compound according to formula (III)) was added to 450 ml ethanol. A solution of 17.91 g calcium chloride in 125 ml water was added in one lot. 12.21 g (322.7 mmole) sodium borohydride was added to the reaction mixture at 0° C. in 1 hr 20 min. The reaction mixture was left overnight for stirring. 100 ml of 1 N HCl was added to neutralize the reaction mixture and inorganic solids were filtered and washed with 200 ml ethanol. Filtrate was evaporated under vacuum. 300 ml water was added to the residue obtained and was extracted with 2×250 ml EtOAC. The organic extract was washed with brine, dried over sodium sulphate and evaporated to give 23 g semisolid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][C:20]=1[CH3:21].O>CN1CCCC1=O>[N+:22]([C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[CH:8]=2)=[CH:16][C:17]=1[CH3:25])([O-:24])=[O:23]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: CC(C)(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (0.4 g of 60% in oil) in dry N-methylpyrrolidinone (10 ml) was slowly added 3-tert-butylphenol (1.62 g). When effervescence had ceased, 3-chloro-6-nitro-p-xylene (1.85 g) was added and the mixture stirred at 120-40° C. for 5 hours. On cooling, the mixture was poured into water and the mixture extracted with diethyl ether (×3). The combined ether extracts were dried over magnesium sulphate, filtered and evaporated to give the title compound as a solid.
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([O:14]C(NC)=O)[CH:12]=[CH:13][C:8]=3[N:7]([CH3:19])[C@H:6]1[N:5]([CH3:20])[CH2:4][CH2:3]2.[OH-].[Na+].[OH-].[K+].Cl>C(O)C>[CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:19])[C@H:6]1[N:5]([CH3:20])[CH2:4][CH2:3]2
Reactant: CNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12

Procedure:
hydrolyzing physostigmine in absolute ethanol under a nitrogen atmosphere at ambient temperature by treatment with aqueous 5-30% w/w NaOH or KOH solutions, followed by treatment with 1N HCl to obtain eseroline (II) ##STR10## which is purified by crystallization from a 1:1 benzene/petroleum ether mixture;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][NH:26][C:25]2=O)=[CH:20][CH:19]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(OC(F)(F)F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:25]2[N:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:31])([F:15])[F:30])=[CH:23][CH:22]=3)[CH:28]=[CH:27][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1ccn(-c2ccc(OC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nccn1-c1ccc(OC(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 20 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.32 g of 1-(4-trifluoromethoxyphenyl)-2(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethoxyphenyl)-2(1H,3H)-imidazolone (0.60 g) and 0.46 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethoxyphenyl)-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: C(O)(=O)C.NC1C=CC=CC=1S.[CH3:13][C:14]1([CH3:36])[S:18]C(C(NC(CC2C=CC=CC=2)=O)C(O)=O)[NH:16][CH:15]1[C:33]([OH:35])=[O:34]>O>[NH2:16][C@@H:15]([C:33]([OH:35])=[O:34])[C:14]([SH:18])([CH3:36])[CH3:13]
Reactant: CC1(C)SC(C(NC(=O)Cc2ccccc2)C(=O)O)NC1C(=O)O
Agent: Nc1ccccc1S
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(S)[C@@H](N)C(=O)O
Reaction time: 2.5 h

Procedure:
To a solution of 2.4 g (0.04 mole) of acetic acid in 20 ml of water, were added 1.38 g (0.011 mole) of o-aminothiophenol and 3.52 g (0.01 mole) of benzylpenicilloic acid. The mixture was heated under reflux, with stirring, for 2.5 hours in a nitrogen atmosphere. The reaction mixture was then treated as described in Example 6 to give D-penicillamine as colorless crystals: yield 1.03 g (69.1%), m.p. 202°-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: Oc1cccc(Br)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1cccc(Br)c1

Procedure:
3-Bromophenol (0.870 g, 5.00 mmol), (2-chloro-ethyl)-dimethylamine hydrochloride (0.792 g, 5.50 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O (20 mL) was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO and concentrated to a brown oil which was then purified by flash chromatography (eluent: 20% EtOAc in hexanes).
Reaction SMILES: F[B-](F)(F)F.C(=O)([O-])[O-].[Na+].[Na+].[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:21](OC=C)(=[O:23])[CH3:22].C(OCCCCCCCC)=C>C1(C)C=CC=CC=1>[C:21]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:23])[CH3:22]
Reactant: CCCCCCCCO
Reactant: C=COC(C)=O
Agent: C=COCCCCCCCC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of bis(1,5-cyclooctadiene)iridium tetrafluoroborate [Ir(cod)2]+BF4− (0.01 mmol) and sodium carbonate (0.6 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and vinyl acetate (2 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 2 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl vinyl ether and octyl acetate were produced in yields of 70% and 2%, respectively, with a conversion from 1-octanol of 72%.