Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[ClH:5].C([NH:13][C@H:14]([C:23]([NH:25][C@@H:26]([C:31]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(OC(C)(C)C)=O>O1CCOCC1>[ClH:5].[NH2:13][C@H:14]([C:23]([NH:25][C@@H:26]([C:31]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C2
Reaction time: 0.5 h

Procedure:
To a mixture of 5.0 ml acetic acid, 5.0 ml dioxane and 10.0 ml of a 6 M solution of hydrogen chloride in dioxane is added 1.0 g of methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate. The reaction mixture is allowed to stand for 30 minutes at room temperature then the solvent is removed by vacuum distillation. The residue is dissolved in a mixture of 2.0 ml methanol and 20 ml water and the solution is lyophilized to give methyl L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR20##
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:14][CH:13]=1.O>C(OCC)(=O)C>[CH:1]([NH:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:14][CH:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1cccc(N)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: CCOC(=O)Cc1cccc(NC=O)n1
Reaction time: 0.5 h

Procedure:
Acetic anhydride (16.6 ml.) and 98% formic acid (7.32 ml.) were mixed at room temperature and stirred at 50° to 66° C. for 30 minutes. The solution was dropwise added to a solution of ethyl 2-(6-aminopyridin-2-yl)acetate (26.5 g.) in ethyl acetate (250 ml.) at 20° to 23° C. over 30 minutes, and stirred at the same temperature for one hour. Cool water was added to the resultant solution and shaked sufficiently. The ethyl acetate layer was separated, washed with water, an aqueous solution of sodium bicarbonate and water in turn, dried and concentrated under reduced pressure to give ethyl 2-(6-formamidopyridin-2-yl)acetate (28 g.), mp 35° to 38° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)([O-:4])=[O:3].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)Cl>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH:12]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1C1=CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC=C(c2ccccc2[N+](=O)[O-])CC1
Reaction time: 0.5 h

Procedure:
4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (0.44 g, 1.8 mmol) was dissolved in a solution of pyridine (0.4 mL) and DCM (20 mL). Acetyl chloride (0.142 mL) was added and the mixture was stirred for 0.5 hours. The mixture was diluted with DCM (20 mL) and the organic solution washed with water then 1 N hydrochloric acid. The solution was dried with magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as an orange oil (0.4 g). LCMS m/z 247.4 [M+H]+. R.T.=3.70 min (Analytical Method 4).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]4[N:25]=[CH:26][CH:27]=[N:28][C:29]=4[C:30]([C:33]4[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[CH:36]=[C:35]([O:42][CH3:43])[C:34]=4[Cl:44])=[CH:31][CH:32]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.C(Cl)Cl.O>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]4[N:25]=[CH:26][CH:27]=[N:28][C:29]=4[C:30]([C:33]4[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[CH:36]=[C:35]([O:42][CH3:43])[C:34]=4[Cl:44])=[CH:31][CH:32]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c3nccnc23)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(N4CCNCC4)cc3)c3nccnc23)c1Cl
Yield: 80.2 %

Procedure:
A mixture of 4-(4-{[8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonyl]-amino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Step 8.1) (137 mg, 0.22 mmol) and a 4 N solution of HCl in dioxane (5 mL) was stirred for 1 h at rt. The reaction mixture was diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in Et2O to afford 95 mg of the title compound as a red solid: ESI-MS: 537.9/539.9 [M+H]+; tR=4.01 min (System 1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: CC(C)(C)OC(=O)NCCCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
5.13 g (16.11 mmol) of N-[4-(tert-butoxycarbonylamino)butyl]phthalimide was dissolved in 100 ml of methylene chloride and 6.21 ml (80.56 mmol) of trifluoroacetic acid was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness, then dried by heating in vacuum at 50° C. to obtain 5.35 g (16.10 mmol) of N-(4-aminobutyl)phthalimide trifluoroacetate as a pale brown solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:31])[CH:20]=[CH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CC(C)=O>[O:11]1[CH2:10][CH:9]1[CH2:7][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:31])[CH:20]=[CH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2
Reactant: ClCC1CO1
Reactant: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1OCC1CO1

Procedure:
First 3.46 g of potassium carbonate and then 10.5 ml of epichlorohydrin were added to a solution of 4 g of 1-[2-hydroxyphenyl]-3-(1H-indol-4-yl)-2-propen-1-one in 80 ml of acetone and the mixture was refluxed for 50 hours under an inert atmosphere and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica. Elution with a 95-5 dichloromethane-ethyl acetate mixture yielded 2.26 g of 1-[2-[(2-oxiranyl)-methoxy]-phenyl]-3-(1H-indol-4-yl)-2-propen-1-one.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8])[CH3:2].[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=[O:11].C1(C=CC(O)=CC=1)O>C(Cl)Cl>[CH2:14]([O:13][C:9]([CH:10]1[CH:7]([CH3:8])[CH:6]=[CH:5][CH:4]([O:3][CH2:1][CH3:2])[O:11]1)=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: CC=CC=COCC
Reactant: CCCCOC(=O)C=O
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Product: CCCCOC(=O)C1OC(OCC)C=CC1C

Procedure:
Following the procedure of Example 12, a solution of 26.7 g. (0.226 mol) of 1-ethoxy-1,3-pentadiene (purity, 95%), 32.5 g. (0.25 mol) of butyl glyoxylate and 0.250 g. of hydroquinone in 250 ml. of methylene chloride was refluxed for 48 hours to give 28.0 g. of a mixture of 1-ethoxy-1,3-pentadiene and butyl glyoxylate and 20.32 g. of distilled 2H-pyran butyl ester (b1.0 = 100°-110°) as an oil. Yield based on 1-ethoxy-1,3-pentadiene, 34%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][CH2:25][OH:26].CCCCCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]2[O:26][CH2:25][CH2:24][CH2:23][O:7]2)=[C:8]([CH3:10])[CH:9]=1
Reactant: OCCCO
Reactant: Cc1cc(Br)cc(C)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Br)cc(C)c1C1OCCCO1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-bromo-2,6-dimethylbenzaldehyde (2.51 g, 12 mmol), 4-methyl-benzenesulfonic acid (0.20 g, 1.2 mmol), and propane-1,3-diol (1.2 mL, 16 mmol) in toluene (200 mL) was heated under nitrogen at 140° C. for 16 h, using a Dean-Stark trap to remove water. The reaction solution was then cooled to 25° C., diluted with EtOAc (200 mL), and sequentially washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to provide a yellow-brown oil. Hexane (200 mL) was added to the oil, and the resulting mixture was stirred vigorously for 10 min, resulting in the precipitation of a solid. This solid was collected by vacuum filtration, washed with hexanes (100 mL), and dried in vacuo to provide 2-(4-bromo-2,6-dimethylphenyl)-1,3-dioxane as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:7][CH2:6][C:5]2C=CC=C[C:4]=2O1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH:2]([NH:7][C:6]1[CH:5]=[CH:4][CH:21]=[CH:20][C:19]=1[CH2:23][OH:22])([CH3:12])[CH3:1]
Reactant: CC1(C)NCc2ccccc2O1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)Nc1ccccc1CO
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 2,2,-dimethyl-1,4-dihydro-2H-benzo[1,3]oxazine (125 g, 0.77 mol) in THF (1 L) was filtered through a scintillation funnel and then added dropwise via an addition funnel, over a period of 2.5 h, to a stirred solution of 1.0 M LiAlH4 in THF (800 mL) at 0° C. The reaction was quenched by slow portionwise addition of Na2SO4.10H2O (110 g), over a period of 1.5 h, at 0° C. The reaction mixture was stirred overnight, filtered and the solid salts were washed thoroughly with THF. The filtrate was concentrated under reduced pressure to yield 2-isopropylaminophenylmethanol (120 g, 95%) as a yellow oil. 1H NMR (CDCl3; 300 MHz): 1.24 (d, 6H, CH(CH3)2), 3.15 (bs, 1H, OH), 3.61 (sept, 1H, CH(CH3)2), 4.57 (s, 2H, CH2), 6.59 (t, 1H, ArH), 6.65 (d, 1H, ArH), 6.99 (d, 1H, ArH), 7.15 (t, 1H, ArH).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1.[C:10]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1>[CH3:1][N:2]1[C:6]([C:10]2([OH:17])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1
Reactant: Cn1cc([N+](=O)[O-])cn1
Reactant: O=C1CCC=CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1(O)CCC=CCC1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 48.9 %

Procedure:
To a solution of 1-methyl-4-nitro-1H-pyrazole (1.5 g, 11.8 mmol) and (Z)-cyclohept-4-enone (1.4 g, 13.0 mmol) in dry THF (30 mL) under nitrogen cooled to −78° C. was added dropwise a solution of lithium hexamethyldisilazide (1.0 M in THF, 30 mL, 29.5 mmol). The reaction mixture was allowed to warm to −40° C. and stirred for 90 min. Saturated aqueous ammonium chloride solution (30 mL) was added (dropwise initially) and the mixture was allowed to warm to room temperature and extracted with EtOAc (150 mL). The organic layer was washed with water (30 mL), washed with brine (20 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (20-25% EtOAc) gave (Z)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-4-enol as a tan oil (1.37 g, 49%).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1ON=C(C(C2C=CC=CC=2)C(O)=O)C=1)CCCCCCCCCCC.[CH3:55][CH:56]([C:58]1[CH:64]=[CH:63][CH:62]=[C:61]([CH:65]([CH3:67])[CH3:66])[C:59]=1[NH2:60])[CH3:57]>>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:60][C:59]2[C:61]([CH:65]([CH3:66])[CH3:67])=[CH:62][CH:63]=[CH:64][C:58]=2[CH:56]([CH3:57])[CH3:55])=[O:21])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)on1
Agent: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)no1
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)on1

Procedure:
In a manner similar to Example 128, a mixture of 3-dodecyl-α-phenyl-5-isoxazole acetic acid and 5-dodecyl-α-phenyl-3-isoxazole acetic acid was condensed with 2,6-bis(1-methylethyl)aniline to give after chromatography pure title compound; mp 115°-117° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[CH2:8][CH2:9][C:10]([O:12]C)=[O:11].O>O1CCCC1.C(O)C.[OH-].[Na+]>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Methyl 4-(1,3-dithian-2-ylidene)-4-(4-phenoxyphenyl)-butyrate, 1.29 g, was dissolved in a solvent mixture of 30 ml of tetrahydrofuran and 30 ml of ethanol and, 10 ml of 1 N sodium hydroxide aqueous solution was added to the solution followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture. After washing with ethyl acetate, the aqueous phase was rendered acidic with conc. hydrochloric acid and extracted with ethyl acetate. After drying the ethyl acetate phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was crystallized from ether to give 1.21 g of white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1([CH3:24])[CH3:23]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1([CH3:23])[CH3:24]
Reactant: COCCOCCO
Reactant: CC1(C)NC(C)(C)N(CCCI)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCCN1C(=O)C(C)(C)NC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
Neat diethylene glycol monomethyl ether (1.30 mL, 11.0 mmol, 1.5 equiv.) was added dropwise to a suspension of sodium hydride (400 mg, 60% disp., 10 mmol, 1.35 equiv.) in N,N-dimethylformamide (10 mL) over 5 minutes. The mixture was stirred at room temperature for 15 minutes, before a solution of 3-(3-iodopropyl)-2,2,5,5-tetramethylimidazolidin-4-one (2.29 g, 7.38 mmol) in N,N-dimethylformamide (10 mL) was added via cannula over 15 minutes. The mixture was then stirred overnight at room temperature. After 23 hours, the mixture was concentrated to a yellow oil which was absorbed on silica (5 g). Chromatography on silica (0-6% methanol in dichloromethane) afforded the title compound (190 mg, 8.5%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.68-3.64 (m, 4H), 3.63-3.59 (m, 2H), 3.57-3.54 (m, 2H), 3.53 (t, J=6.1 Hz, 2H), 3.39 (s, 3H), 3.29-3.24 (m, 2H), 1.96-1.89 (m, 2H), 1.82 (br s, 1H), 1.41 (s, 6H), 1.32 (s, 6H); LRMS (ESI/APCI) m/z 303 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>P([O-])([O-])([O-])=O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
In another experiment, ethyl (2R/S) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (5 g) was added to an aqueous 0.1 M phosphate buffer pH 7 (10 ml). 100 mg of the lyophilised hydrolytic enzyme mixture from Aspergillus oryzae was added and the mixture was stirred for 18 hours at room temperature. During that time, the pH of the reaction mixture was kept constant at pH=6-8 by addition of NaOH. Most of the water was evaporated in vacuo. Methanol was added to the remaining slurry in order to stop the hydrolysis. The precipitate, which formed was filtered off and the methanol was evaporated in vacuo. The remaining oil was dissolved in water followed by extraction of unreacted ester with TBME (CCE method 2: eeester=87%). The water phase was acidified to pH=3 and the acid extracted with TBME. After drying over Na2SO4 and evaporation of the TBME, 1.8 g (2S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid was obtained as an oil, which crystallized on standing (m.p.=105° C., CCE method 2: eeacid=>99%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:38])[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH2:37][C:32]([F:38])([F:31])[CH2:33]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: FC1(F)CCCNC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCCC(F)(F)C2)c1OCCC(C)c1ccc(F)cc1
Yield: 33 %

Procedure:
Example 8a (101 mg, 0.21 mmol) was reacted with 3,3-difluoropiperidine hydrochloride (2.5 eq.) as described under General Procedure K to afford the title compound (37 mg, 33%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.07 (t, J=5.4 Hz, 2H), 3.97 (td, J=6.9, 1.5 Hz, 2H), 3.83 (s, 3H), 3.05-2.83 (m, 1H), 2.75-2.68 (m, 4H), 2.50-2.46 (m, 5H), 2.18 (s, 3H), 2.13-1.94 (m, 2H), 1.90-1.74 (m, 4H), 1.29 (d, J=6.9 Hz, 3H). MS (ES+) m/z 528 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=O.F[B-](F)(F)F.C([O+](CC)CC)C.Cl.[F:26][C:27]1[CH:28]=[C:29]([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[CH:41]3[CH:37]([CH2:38][NH:39][CH2:40]3)[C:36](=[O:42])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[F:49][C:45]1[CH:44]=[C:43]([C:33]2([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=3)[CH:41]3[CH:37]([CH2:38][N:39]([C:10](=[NH:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:40]3)[C:36](=[O:42])[CH2:35][CH2:34]2)[CH:48]=[CH:47][CH:46]=1
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Reactant: COc1ccccc1CC(N)=O
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.6 %

Procedure:
A suspension of (2-methoxyphenyl)acetamide (0.9 g) in dry dichloromethane (3 cc) is treated with triethyloxonium tetrafluoroborate (1.14 g), and the solution obtained stirred for 20 hours at 25° C. After cooling to 0° C., a solution of 7,7-bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (1.5 g) and triethylamine (1.4 cc) in dichloromethane (9 cc) is added to the reaction medium. The reaction mixture is stirred for 30 minutes at 25° C., then heated to reflux for 5 hours and finally stirred for a further 16 hours at 25° C. Saturated potassium carbonate solution (50 cc) is added, the mixture is stirred and filtered and the organic phase is washed with water (2×50 cc). After drying over magnesium sulphate, filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of alumina (diameter 2.6 cm, height 24 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of 1,2 -dichloroethane and methanol (95:5 by volume) and collecting 15-cc fractions. Fractions 7 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(3-fluorophenyl)-2-[1-imino-2-(2-methoxyphenyl)ethyl]perhydro-4-isoindolone (0.54 g) in the form of a pale yellow meringue-like product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:11]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:7]=2)=[CH:2]1.II>C1(C)C=CC=CC=1.[Hg]>[CH2:17]([C:9]1[CH:10]=[C:11]2[C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[CH:7][C:8]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCc1cc(-c2ccsc2)c(-c2ccsc2)cc1CCCCCCCC
Agent: II
Agent: [Hg]
Solvent: Cc1ccccc1
Product: CCCCCCCCc1cc2c(cc1CCCCCCCC)c1ccsc1c1sccc21
Yield: 65 %

Procedure:
In a quartz tube was added a solution of 4,5-bis(3-thienyl)-1,2-dioctylbenzene (0.5 g, 1.1 mmol) and iodine (30 mg) in toluene (500 mL). The system was then irradiated by a 400 W mercury lamp equipped with an efficient cooling system for 16 hours under magnetic stirring and air bubbling. The reaction mixture was washed with a saturated aqueous solution of Na2S2O3, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (hexane as eluent), and a white solid was obtained (0.33 g, yield: 65%). mp: 62.2-63.1° C. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 2H), 7.97 (d, 2H), J=5.34 Hz), 7.47 (d, 2H, J=5.30), 2.86 (t, 4H, J=7.76 Hz), 1.74 (m, 4H), 1.32-1.50 (m, 20H), 0.92 (t, 6H), J=6.80 Hz). 13C NMR (400 MHz, CDCl3) δ 139.22, 134.12, 131.25, 126.09, 124.04, 123.34, 122.74, 33.14, 31.29, 31.52, 29.86, 29.58, 29.34, 22.70, 14.14. MS: m/z=464.4 [M]+ (Calcd.: 464.2).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:9][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Benzoic acid (2.44 g, 0.02 mole) and 2-chloro-N,N-dimethylacetamide (2.43 g, 0.02 mole) were dissolved in 10 ml of N,N-dimethylformamide. Sodium iodide (150, 2 mmol) and triethylamine (2.02 g, 0.02 mole) were added and the mixture was stirred at room temperature (20°-25° C.) overnight. After addition of 50 ml of water the reaction mixture was extracted twice with ethyl acetate. The combined extracts were washed with a diluted solution of sodium thiosulphate, a 2% aqueous solution of sodium bicarbonate, water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was crystallized from ethanol-water to give 3.5 g (85%) of the title compound. Mp 81°-82° C.