Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C2N=NNC=2C=CC=1.[CH2:39]([S:46][CH:47]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49](=[O:55])[CH2:48]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:52](=[O:53])[CH2:51][N:50]2[CH:47]([S:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:48][C:49]2=[O:55])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCc1ccccc1
Reactant: O=C(O)CN1C(=O)CC1SCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CC1SCc1ccccc1)NCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research, 1991, 1846), (7.0 g, 40 mmol) in DMF (20 ml) was added to DCC (8.2 g, 40 mmol), hydroxybenzotriazole (5.3 g, 39 mmol) and (4-benzylthio-2-oxoazetidin-1-yl)acetic acid (10 g, 39 mmol) and the mixture stirred for 2 hours at room temperature. Ethyl acetate (250 ml) was added, the precipitate filtered, the filtrate washed with dil NaHCO3, water (×2), dried (MgSO4) and evaporated to an oil which was purified by flash chromatography on silica gel using hexane/ethyl acetate (1:1). Evaporation of the appropriate fractions followed by treatment with hexane gave a white solid (11.2 g, 70%), mp 65-70° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1.C(O)C>CN(C)C=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]3=[O:21])[CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=c1c2ccccc2n(-c2ccccc2)c(=O)n1CCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)c3ccccc3n(-c3ccccc3)c2=O)CC1
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 6 parts of 3-(2-chloroethyl)-1-phenyl-2,4(1H,3H)-quinazolinedione, 8.3 parts of (4-fluorophenyl) (4-piperidinyl)methanone and 48 parts of ethanol is stirred and refluxed. N,N-dimethylformamide is added at reflux temperature till all solid enters solution. Stirring is continued overnight at reflux. The reaction mixture is evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 2.2 parts (23%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-1-phenyl-2,4(1H,3H)-quinazolinedione; mp. 166.1° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].CO.C([BH3-])#[N:13].[Na+].[OH-].[Na+]>N.C(O)(=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([NH2:13])[CH3:2])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cccnc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
3-Acetylpyridine (2.4 g, 20 mmol, Aldrich) was dissolved in 2M ammonia solution in methyl alcohol (50 mL, 100 mmol, Aldrich) and acetic acid (15 mL, J. T. Baker) was slowly added at 0 C. After stirring for 3 h at room temperature, the sodium cyanoborohydride (5.0 g, 80 mmol, Aldrich) was added to the solution at 0 C. The mixture was stirred under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with aqueous 5 N sodium hydroxide (30 mL, 150 mmol, J. T. Baker). The methyl alcohol was removed from the mixture via vacuo. The residue was extracted by diethyl ether (30 mL×4). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated via vacuo to give crude 1-pyridin-3-yl-ethylamine as light yellow oil in 44% yield (1.07 g, 8.8 mmol).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].[P:13]([Cl:17])(Cl)(Cl)=[S:14]>C1(C)C=CC=CC=1>[P:13]([Cl:17])([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:3]([CH3:5])[CH3:4])([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:3]([CH3:5])[CH3:4])=[S:14]
Reactant: S=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1OP(=S)(Cl)Oc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (38.0 g of 80% suspension in mineral oil) was added to a stirred solution of 2-isopropylphenol (139.2 g) and thiophosphoryl chloride (84.5 g) in toluene (500 cm3) at such a rate that the reaction temperature did not rise above 65° C. After stirring for a further 0.5 hr at ambient temperature, the solution was extracted twice with water (250 cm3 portions), separated, dried (MgSO4) and concentrated by distillation of solvents under reduced pressure yielding crude bis(2-isopropylphenyl) chlorothiophosphate, a brown oil (164.2 g); 31P NMR in CDCl3, singlet 53.0 ppm downfield of H3PO4). Of this material, 54.0 g were reacted with ammonia by the procedure of Example 9 yielding crude bis(2-isopropylphenyl)thiophosphoramide) (50.0 g; 31PNmr, singlet δ=58.8 ppm).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[OH:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([O:25][C@H:23]3[CH2:24][C@H:21]([CH2:20][OH:19])[CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CC(O)C1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: OC[C@H]1C[C@H](Oc2ncc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, yellow solid, MS: m/e=281.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and 3-(hydroxymethyl)cyclobutanol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C. and by separation of the received isomers-mixture using a chiral column (Lux2 Cellulose with heptane:isopropanol 85:15 as solvent).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 33.6 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-(methanesulfonyl)phenylboronic acid 86 mg, sodium carbonate 69 mg and polymer-carried bis(acetato)triphenylphosphine palladium(II) 31 mg at room temperature, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. 2.0 mol/L Sodium hydroxide aqueous solution 1.0 mL and ethanol 6.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour. 0.5 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 40-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(4-(methanesulfonyl)phenyl)benzoic acid 28 mg of pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:7]2[C:8]([O:10][C:11](=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=[O:9].[NH:17]([CH2:19]C(O)=O)[CH3:18].O>CS(C)=O>[CH3:18][N:17]1[C:8](=[O:9])[C:7]2[CH:14]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=[CH:5][C:6]=2[NH:12][C:11](=[O:10])[CH2:19]1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(=O)o1
Solvent: CS(C)=O
Solvent: O
Product: CN1CC(=O)Nc2ccc(C(F)(F)F)cc2C1=O
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A suspension of 5.76 g (24.9 mmole) of 5-(trifluoromethyl)isatoic acid anhydride and 2.44 g (27.4 mmol) of sarcosine in 8 ml of dimethyl sulphoxide is stirred at 110° C. for 4 hours, subsequently poured into 70 ml of water and evaporated to dryness in vacuo. After column chromatography on silica gel using ethyl acetate/n-hexane (9:1) for the elution and recrystallisation of the product from ethanol, there is obtained 3,4-dihydro-4-methyl-7-(trifluoromethyl)-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 203°-206° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].C([O-])(=O)C.[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([F:22])=[C:15]([Cl:14])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cc(I)ccc2n1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(Nc2nc(Cl)nc3ccc(I)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 144 h
Yield: 73.4 %

Procedure:
In a 50 mL round-bottomed flask was added 2,4-dichloro-6-iodoquinazoline (0.52 g, 1.6 mmol), 3-chloro-4-fluoroaniline (0.30 g, 2.1 mmol), and sodium acetate (0.20 g, 2.4 mmol) in THF (6 mL) and water (2 mL) to give a brown suspension. After being stirred at room temperature for 6 days, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), dried over Na2SO4, filtered and concentrated. The resulting product, was washed with CH2Cl2 and dried to give 0.51 g of 2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine as a tight brown solid in a 73% yield, 1H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 8.95 (s, 1H), 8.14 (dd, J=1.5, 9.0 Hz, 1H), 8.06 (dd, J=2.7, 6.6 Hz, 1H), 7.81-7.76 (m, 1H), 7.52-7.46 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])=[CH:6][CH:5]=1)[CH3:3])(=[O:30])=[O:29]
Reactant: CC(O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reaction time: 4 h

Procedure:
tert-Butyl [2-[4-(1-hydroxyethyl)phenyl]ethyl]carbamate (606 mg) was dissolved in dichloromethane (20 ml), triethylamine (0.38 ml) and then methanesulfonyl chloride (0.195 ml) were added at 0° C., and the mixture was stirred for 4 hr. The reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-[4-[2-[(tert-butoxycarbonyl)amino]ethyl]phenyl]ethyl methanesulfonate. The obtained compound, (3S)-3-fluoropyrrolidine hydrochloride (287 mg) and N,N-diisopropylethylamine (1.18 g) were mixed with DMF (10 ml), and the mixture was stirred at 50° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, and washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 (volume ratio)→ethyl acetate→ethyl acetate:methanol=9:1 (volume ratio)) to give tert-butyl [2-[4-[1-[(3S)-3-fluoropyrrolidin-1-yl]ethyl]phenyl]ethyl]carbamate (133 mg) as a crude oil.
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:11]=[CH:10]C=C[C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[N+:48]([C:51]1C=CC(CS)=C[CH:52]=1)([O-:50])=[O:49]>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:14]([S:12][CH2:7][C:6]3[CH:4]=[CH:52][C:51]([N+:48]([O-:50])=[O:49])=[CH:10][CH:11]=3)[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:38])[CH3:39]
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 81 %

Procedure:
Following a procedure similar to that described in Example 1, but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 4-nitrobenzylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 81%. Recrystallization of this product from a mixture of ethyl acetate and diisopropyl ether the title compound in the form of crystals, melting at 150.5° to 151° C.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH:19]=[CH:18][NH:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C)C=O>[CH3:29][NH:30][C:31]([N:17]1[C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH:19]=[CH:18]1)=[O:32]
Reactant: CN=C=O
Reactant: O=c1c2c[nH]c3[nH]ccc3c-2nn1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c21
Reaction time: 8 h

Procedure:
A solution of pyrrolo-pyridine 16 in dimethylformamide under an atmosphere of nitrogen and 3 equivalents of di-iso-propylethylamine (3 eq.) was added 3 equivalents of methylisocyanate and stirred overnight. The crude reaction mixture was concentrated to dryness and purification by column chromatography afforded the title compound 17a. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83-3.11 (m, 3H) 6.64-6.92 (m, 1H) 7.21-7.43 (m, 1H) 7.44-7.63 (m, 2H) 7.77-8.05 (m, 3H) 8.57-8.81 (m, 1H) 9.48-9.76 (m, 1H).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]([OH:6])=O.[CH2:7]([C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([C@H:14]1[CH2:18][N:17]([C:4](=[O:6])[CH2:3][OH:2])[C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CO
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CO
Yield: 33.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-hydroxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 120, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (9.1 mg, 33.8%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.55-7.59 (m, 2H), 7.28-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.94-7.02 (m, 4H), 4.50-4.52 (m, 1H), 4.02 (s, 2H), 3.50-3.59 (m, 1H), 3.15 (m, 1H), 2.63-2.73 (m, 3H), 1.89-1.93 (m, 2H). MS (EI) for C26H25FN2O4. found 449.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].CO[C:29]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:34][CH2:33][CH:32]([NH:35][CH2:36][CH2:37][NH2:38])[C:31](=C=O)[CH2:30]1>ClCCl>[C:41]1([C:29]2([C:11]([O:12][CH3:13])=[O:14])[CH2:30][CH2:31][CH:32]([NH:35][CH2:36][CH2:37][NH:38][C:15]([N:10]3[CH:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH2:13][O:12][C:11]3=[O:14])=[O:17])[CH2:33][CH2:34]2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC1(c2ccccc2)CCC(NCCN)C(=C=O)C1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COC(=O)C1(c2ccccc2)CCC(NCCNC(=O)N2C(=O)OCC2c2ccc(F)c(F)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(3,4-difluorophenyl)-3-(4-nitrophenyloxy-carbonyl)-2-oxo-oxazolidine (50 mg, 0.123 mmol) and 2-[4-methoxy-carbonyl-4-phenylcyclohex-1-yl]aminoethylamine (75 mg) in dichloromethane (6 mL) was stirred at room temperature and the product formed was purified by preparative TLC on silica gel using ethyl acetate as the eluent. There were two bands for the two isomers, the higher band was the minor product (1H-NMR confirmed it to be the cis isomer with respect to methoxycarbonyl and amine groups) and the lower band was the major product (1H-NMR confirmed it to be the trans isomer with respect to methoxycarbonyl and amine groups). The HCl salt was made by treatment with 1N HCl in ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH:8]([C:12](O)=O)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>O>[CH2:12]=[C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccc(CC(C(=O)O)C(=O)O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=C(Cc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxybenzylmalonic acid, (20.2 g., 0.09 mol) was suspended in N,N,N1,N1 -tetramethylmethanediamine (45 ml). Acetic anhydride (45 ml) was added dropwise, keeping the temperature below 45° C. by cooling in an ice-bath as necessary. The resulting clear solution was stirred for 11/2 hour at ambient temperature and then was poured into ice and water. The white solid product was collected, combined with comparable product from a second 0.083 mol run, and dried at 0.1 mm at room temperature to give 22.4 g. (68%) of product, m.p. 88°-91° C. A sample recrystallized from ether-petroleum ether melted at 90°-93° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([OH:19])[CH2:8][C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][CH2:6][C@@H:7]([OH:19])[CH2:8][C@@H:9]([OH:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
In a 100 ml-volume egg plant type flask equipped with a three-way cock whose atmosphere had been displaced with nitrogen was charged 15 mg (0.009 mmole) of Ru2Cl4 ((R)-BINAP)2 (NEt3), and 500 mg (1.75 mmole) of t-butyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate as synthesized in Example 4 and 60 ml of methanol were added thereto to form a solution. The solution was transferred to a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen and stirred at 30° C. for 16 hours under a hydrogen pressure of 50 kg/cm2 to conduct hydrogenation. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography to obtain 340 mg (yield: 68%) of t-butyl (3R,5S)-6-t-butoxy-3,5-dihydroxyhexanoate.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(OC(C)C)(C)C.[C:16]([O:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26])(=[O:20])[C:17]([CH3:19])=[CH2:18].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCCCCC>[C:16]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:8][C:2]1([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: CC1(O)CCOCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: C=C(C)C(=O)OCCNC(=O)OC1(C)CCOCC1
Temperature: 5.5 °C
Reaction time: 10 h
Yield: 46.2 %

Procedure:
In a three-necked flask having an inner volume of 50 mL equipped with a thermometer and a stirring apparatus were charged 1.00 g (8.51 mmol) of 4-methyltetrahydropyran-4-ol, 1.0 mg of 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl, 4.0 g of isopropyl ether, and 1.42 g (8.94 mmol) of 2-methacryloyloxyethyl isocyanate. After the mixture was cooled by ice water to an inner temperature of 5° C., 250 mg (2.55 mmol) of methanesulfonic acid was added dropwise. After stirring the reaction mixture for 10 hours with the reaction temperature maintained at 5 to 6° C., 4.0 g of a saturated aqueous NaHCO3 solution was added dropwise with the inner temperature maintained at 10° C. or less and, after completion of the dropwise addition, the mixture was allowed to stand still for 30 minutes. The organic layer (upper layer) formed was separated and the aqueous layer (lower layer) was extracted twice with 4.0 g of isopropyl ether. All the separated organic layers were combined, washed with 4.0 g of distilled water, and the organic layer was concentrated under reduced pressure to obtain 2.29 g of a concentrate. The concentrate was dissolved in 10 g of hexane at 30° C. and the solution was cooled to −10° C. at a rate of 10° C./hour. The crystals which precipitated were separated by filtration and the crystals obtained were dried under vacuum (26.7 Pa) at 30° C. for 2 hours to obtain 1.10 g (purity 97.0%, 3.93 mmol, yield: 46.2%) of 4-methyltetrahydropyran-4-yl (2-methacryloyloxyethyl)carbamate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (319 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (370 mg, 68%).