Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 82.8 %

Procedure:
N-t-butyloxycarbonyl-L-phenylalanine (36.54 g, 137.7 mmole), L-proline benzylester hydrochloride (33.84 g, 140 mmole) and HOBT (18.91 g, 140 mmole) were dissolved in methylene chloride (500 ml), and triethylamine (14.17 g, 140 mmole) and WSC hydrochloride (26.40 g, 137.7 mmole) were added thereto at -30° C. The solution was stirred for 2 hours at less than 0° C. and then overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oily residue thus obtained was crystallized from ethyl acetate and n-hexane to give N-t-butyloxycarbonyl-L-phenylalanyl-L-proline benzylester (yield: 51.61 g, 82.8%).
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26](O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl.C(O)(=O)C.C1COCC1.C(N(CC)CC)C>[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26]([N:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 75.1 %

Procedure:
To 121 g of H-Pro-OBzl·HCl, 400 ml of THF was added and 70 ml of triethylamine was added dropwise thereto under cooling with stirring. Further, 100 ml of THF and 50 ml of chloroform were added thereto. To the resultant mixture, 132 g of BOC-Phe-OH was added and 113 g of DCC dissolved in 100 ml of chloroform was added dropwise under cooling with stirring over a period of 1 hour. The mixture was stirred at a temperaturebelow 10° C. and after 16 hours, 5 ml of acetic acid was added thereto under cooling. After stirring for an additional 2 hours, the insoluble materials were removed by filtration and the filtrate was washedwith THF and concentrated in vacuo. The resultant oily residue was dissolved in 1 liter of ethyl acetate and the insoluble materials were removed by filtration. The filtrate was washed with water, 1 N hydrochloric acid, water, a 5% sodium bicarbonate aqueous solution and water, dried over magnesium sulfate and concentrated in vacuo. The resultant oily residue was dissolved in diethyl ether and crystallized by addition of n-hexane. The crystals were recrystallized from ethyl acetate-n-hexane to obtain 169 g (yield: 74.8%) of the desired material having a melting point of 104°-106° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl>C(O)C.O>[OH:5][CH:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
Sodium borohydride (2.1 g) was added to a solution of 1-acetylnaphthalene (18.86 g) in ethanol (200 ml) at room temperature and the mixture was stirred at the same temperature for 2 hours. The mixture was diluted with water (50 ml), acidified to pH 3 with 1N hydrochloric acid and concentrated to about 70 ml. The concentrate was extracted with ethyl acetate (100 ml×2). The extract was dried over magnesium sulfate and evaporated to give 1-(1-hydroxyethyl)naphthalene as an oil which was used in a next reaction without further purification. Hydrogen bromide was bubbled into a solution of 1-(1-hydroxyethyl)naphthalene (18.96 g) in ether (180 ml) for 2 hours under ice-bath cooling. The reaction mixture was washed with water (50 ml×2), 2.5% sodium bicarbonate (50 ml×2) and water (50 ml×2), dried over magnesium sulfate and evaporated to give 1-(1-bromoethyl)naphthalene (22.63 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.C(O)(=O)C.Br>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(O)c(F)c2)cc1
Yield: 92.2 %

Procedure:
To 42 g (0.17 mol) of the above 3'-fluoro-4'-methoxybiphenyl-4-carboxylic acid were added 1.7 l of acetic acid and 300 ml of 48% hydrogen bromide solution, which was refluxed for 20 hours, poured into 3.5 l of water and air cooled. The precipitated crystal was filtered to obtain 36.4 g (yield: 92%) of 3'-fluoro-4'-hydroxybiphenyl-4-carboxylic acid.
Reaction SMILES: CN(C)C=O.[OH:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:23][O:22][C:20]([CH2:19][O:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])=[O:21]
Reactant: COC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 50 ml of dry N,N-dimethylformamide are added 10 g of N-hydroxyphthalimide and 9.38 g of methyl bromoacetate, followed by addition of 8.5 g of potassium carbonate. The mixture is stirred at room temperature for 2 days and, then, poured into 400 ml of water. The resulting crystalline precipitate is recovered by filtration, washed with water, hexane and ether in this order to give cololess needles of N-methoxycarbonylmethyloxyphthalimide, m.p. 137°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO.C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1Nc2c(F)cccc2C1=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 7-fluoroindoline-2,3-dione (12.22 g, 74 mmol) in THF (40 mL) at 0° C. was added phenylmagnesium bromide (148 mL, 148 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 15 min after the addition was completed. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford Intermediate A-7A (18.84 g, 88%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.37-7.25 (m, 5H), 7.19 (ddd, J=10.4, 8.1, 1.3 Hz, 1H), 7.04-6.92 (m, 2H); HPLC: RT=1.810 min (CHROMOLITH® SpeedROD column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=599 [M+H−H2O]+.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[CH2:6]([S:13]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][S:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)(=[O:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O:35][C:36](=[O:42])[C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1)C1C=CC=CC=1>C1COCC1.[Pd]>[CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[CH2:6]([S:13]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][S:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)(=[O:14])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[NH:38]1[CH2:39][CH2:40][CH2:41][C@H:37]1[C:36]([OH:42])=[O:35]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: [Pd]
Agent: CS(C)(=O)=O
Agent: O=C(O)[C@H](CSc1nnn[nH]1)NS(=O)(=O)Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1
Reaction time: 18 h

Procedure:
The compound of Example 75 (2.77 g, 4.81 mmole) is dissolved in THF (50 mL), 0.5 g of 10% palladium on carbon is added and the mixture is stirred under hydrogen gas at atmospheric pressure for 18 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.C(N(CC)CC)C>>[OH:16][CH:14]1[CH2:15][N:12]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:13]1
Reactant: OC1CNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Yield: 95.7 %

Procedure:
The process is carried out according to the method described in step 5.1, using 7 g (42.83 mmol) of 2-chloro-5-nitropyridine and 5.75 g (51.4 mmol) of 3-azetidinol hydrochloride. In this case, 13 g (128.45 mmol) of triethylamine are also added. 8 g of the expected product are thus isolated.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.C[O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C(O)(C)C>C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:1]([CH3:6])[CH3:2])[C:22]([OH:21])=[O:31]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Yield: 73.1 %

Procedure:
Into a round bottom flask was added triphenylphosphine (62 g, 0.263 mol), 3-chloro-4-hydroxy-benzoic acid methyl ester (10 g, 0.0535 mol) and anhydrous THF (500 mL). The mixture was briefly stirred under nitrogen, then DBAD (19.75 g, 0.0858 mol) was added. The mixture was stirred for a few minutes before adding anhydrous isopropanol (5.125 mL, 0.067 mol). After the reaction mixture was stirred at room temperature under an atmosphere of nitrogen for about 3 hours, DBAD (19.75 g, 0.0858 mol) and anhydrous isopropanol (5.125 mL, 0.067 mol) were added and the mixture was left to stir at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in minimum amount of ethyl acetate. Heptane was added and the precipitate was removed by filtration. The filtrate was brought up in methanol. Water was added until cloudy. Precipitate was filtered off. The methanol/water precipitation procedure was repeated two more times. The filtrate was taken up in THF (200 mL) and 5 M NaOH (200 mL). The mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure. The aqueous layer was extracted three times with ethyl acetate. The aqueous layer was further acidified to pH 1-2 with 2 M HCl. The cloudy suspension was then extracted with ethyl acetate three times. The organic layers were combined, dried over magnesium sulfate, and concentrated to dryness to give 3-chloro-4-isopropoxy-benzoic acid (8.4 g, 71.4%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.[O-][CH2:26][CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:21][C:27]2[CH:26]=[CH:4][CH:3]=[CH:2][CH:14]=2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1
Reactant: CC[O-]
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC)c(Cl)c1Cl)C2
Solvent: ClCCl
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (Example 20, Step C) (5.8 g., 0.016 mole) is dissolved in a mixture of dry benzyl alsohol (50 ml) and methylene chloride (40 ml.) containing amberlite IRA 400 (ethoxide) (5-6 g.). The mixture is stirred magnetically at reflux for four hours and then filtered. The filtrate is concentrated in vacuo to give a yellow solid (5.3 g.) which upon trituration with ethanol and washing with ether yields the product.
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.Br[C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.CN([CH:24]=[O:25])C>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[Br:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([OH:20])[CH:16]=1)[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Oc1cc(Br)cc(Br)c1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=Cc1cc(O)cc(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (1.6 M) of n-butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at −10° C. n-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at −10° C. for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at −10° C. over a period of 35 min. After stirring at −10° C. for a further 30 min, the reaction mixture was cooled to −40° C. before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to rt and allowed to stir at rt for 1 h. The reaction was carefully quenched at 0° C. with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4. Concentration of the filtrate in vacuo afforded a yellow solid. Recystallization of the crude product in ether/hexane afforded the title compound as a beige powder.
Reaction SMILES: [CH2:1]([CH:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BrH:18].BrBr>O>[Br:18][C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17]
Reactant: CCCCCCCCC1C(=O)NC(=O)NC1=O
Reactant: Br
Agent: BrBr
Solvent: O
Product: CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-octylbarbituric Acid (20 g) in 120 ml of water, cooled at 0-5° C., are added 12 ml of 48% hydrobromic acid and successively are dropped 4.72 ml of bromine. Ater 2 hours under stirring, the white solid which separated is recovered by filtration, washed with water and partitioned between 200 ml of diethyl ether and 100 ml of water. The aqueous phase is extracted with additional 50 ml of diethyl ether. The pooled organic phases are washed with 75 ml of saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. 25.8 g of the product as white solid are obtained.
Reaction SMILES: [C:1](O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:8]([C:10](=[S:12])[NH2:11])[NH2:9].[OH-].[NH4+]>S(=O)(=O)(O)O>[C:2]([C:1]1[S:12][C:10]([NH2:11])=[N:8][N:9]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: NNC(N)=S
Reactant: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nnc(N)s1
Temperature: 2 °C

Procedure:
To a solution of pivalic acid (85.1 g, 0.833 mol) in concentrated sulfuric acid (280 ml) was slowly added hydrazinecarbothioamide (76.0 g, 0.833 mol) such that the internal temperature was maintained at 0-4° C. After addition was complete, the resulting mixture was heated to 80° C. and monitored by TLC. After the reaction was complete, the resulting yellow solution was cooled to room temperature, poured into ice, and then adjusted the pH to 7 by the addition of aqueous ammonium hydroxide. The resulting precipitate was filtered to obtain 5-tert-butyl-1,3,4-thiadiazol-2-amine which was used directly without purification.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CS(C)=O>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCn1c2ccccc2c2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 10.85 g (65.0 mmol) of carbazole, 2.60 g (65.0 mmol) of sodium hydroxide and 6.1 mL (72.0 mmol) of allylbromide in 100 mL dimethylsulfoxide was heated to 60° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then concentrated. The crude product was purified using column chromatography (silica, 1:4 dichloromethane:hexane). Yield: 9.85 g (73%).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.[Na+].[I-:20].C(O)(=O)C>C(#N)C>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([OH:17])=[O:16])[C:3]([OH:18])=[C:2]([I:20])[CH:1]=1
Reactant: [I-]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 864.1 %

Procedure:
20 mg (0.08 mmol) of diflunisal, 14 mg (0.093 mmol) of NaI and 30 mg (0.13 mmol) of CAT dissolved in 1040 μl of acetonitrile and 52 μl of acetic acid are placed in a 25 ml flask. It was stirred for 1.5 hr at room temperature. The reaction was monitored by HPLC until the consumption of starting product was observed and 96% of iodinated product was detected. The solution was then acidified to pH=1.0 with a 5% solution of HCl and extracted with ethyl acetate. The organic phases were combined and washed with a solution of sodium thiosulphate and then dried over anhydrous magnesium sulphate. The solvent was removed at low pressure and a crude of 98% purity was obtained and then purified by chromatography on silica gel. 260 mg (86% yield) of the desired product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1F
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1F
Temperature: 80 °C

Procedure:
A mixture of 3-fluoro-anisaldehyde (1.5g) and malonic acid (2.08g) in 5 ml pyridine was warmed until clear solution was obtained. To this mixture piperidine (0.4ml) was added and then the content of the flask was heated at 80° C. for 1 hour. It was further refluxed for 3 hours. At the end of this period the mixture was poured into 50ml of cold water. It was then acidified by adding 5ml of concentrated hydrochloric acid. Upon addition of acid, the solid separated, which was filtered and washed with cold water. The material was dried. Yield 1.7 g. The crude material was crystallized from a mixture of tetrahydrofuran and water. m.p. 227°-230° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.[CH3:24][CH:25]([CH3:31])[CH2:26][CH2:27][C:28](Cl)=[O:29].C([O-])(O)=O.[Na+]>CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([CH3:31])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
(S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g).
Reaction SMILES: C([NH:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9])(=O)C>[Co](Cl)Cl>[NH2:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9]
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: Cl[Co]Cl
Product: CSCC[C@H](N)C(=O)O
Temperature: 37 °C
Reaction time: 0.5 h

Procedure:
The enzymatic activity of the complex is determined by contacting 500 mg. of complex with 50 ml. of an 0.4 weight percent solution of N-acetyl-DL-methionine in 0.1 M TRIS buffer, of pH 8, containing 5·10-4M of cobalt chloride, at 37° C., and agitated for 30 minutes. The complex is filtered and the L-methionine formed is determined in the filtrate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11]>ClCCl>[CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: O=CO
Reactant: c1ccc2c(c1)CCN2
Solvent: ClCCl
Product: O=CN1CCc2ccccc21
Reaction time: 2.5 h

Procedure:
A solution of indoline (10 g, 840 mmol) in dichloromethane (400 mL) was treated with 88% formic acid (48.8 g, 924 mmol), heated to reflux, and stirred for 2.5 hours. The mixture was concentrated to 2/3 of the original volume, diluted with 1,2-dichloroethane (200 mL), and again concentrated to 2/3 of the original volume to provide a solution of N-formylindoline in 1,2-dichloroethane, which was used without further purification.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[PH4+].[BH4-].[Na+].CC(N=NC(C#N)(C)C)(C#N)C>CC#N.C(Cl)(Cl)Cl>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C1C2CC3CC1CC(C2)C3

Procedure:
A solution of 1-bromoadamantane (108 mg, 0.5 mmol, 1.0 equiv), the phosphonium supported chlorostanne (15) (82 mg, 0.1 mmol, 0.2 equiv), NaBH4 (28 mg, 0.75 mmol, 1.5 equiv) in CH3CN (2.5 mL, 0.2 M) was heated to reflux under Ar for 10 min. Then AIBN (8 mg, 0.05 mmol, 0.1 equiv) was added and the solution was heated to reflux for an additional 2 h. CHCl3 (5 mL) was added and the solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was diluted with CHCl3(1 ml) and the tin residues were precipitated by adding Et2O (10 mL). The mixture was filtered through Celite and the filtrate was evaporated to afford pure adamantane in quantitative yield. No traces (<1%) of stannane impurities could be detected by NMR.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OCC1C=CC=CC=1)(OCC1C=CC=CC=1)OCC1C=CC=CC=1.[CH2:37]([NH2:39])[CH3:38]>O>[CH2:37]([NH:39][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:38]
Reactant: CCN
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(COP(OCc2ccccc2)OCc2ccccc2)cc1
Solvent: O
Product: CCNc1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
288 parts of β-naphthol, 5 parts of tribenzyl phosphite and 115 parts of ethylamine gas are heated at 230° C in a pressure autoclave for 10 hours. The pressure is 35 atmospheres. The mixture is added to 2,000 parts of water and the batch is stirred for 30 minutes at 70° - 80° C. The lower oily phase is separated off and distilled. 321 parts of N-ethyl-β-naphthylamine, boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 94% of theory.