Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]([CH3:12])[N:6]=1.C1(C)C=CC=CC=1>O>[Cl:4][C:5]1[N:6]=[C:7]([CH3:12])[N:8]=[C:9]([S:2][CH3:1])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1nc(C)nc(Cl)n1
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Sodium methanethiolate (0.49 g, 7.0 mmol) was added portionwise at 0° C. to a stirred cloudy solution of 2,4-dichloro-6-methyl-1,3,5-triazine (7) (1.04 g, 6.3 mmol) in toluene (10 mL, 94 mmol) over 15 min. After addition, the pale yellow mixture was stirred at the same temperature for another 1 h, and water (10 mL) was added. The separated aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography (hexanes to 70% DCM in hexanes) to give 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (0.87 g, 78% yield) as a white solid. MS (API-ES) m/z 176 (M+H)+; 1H NMR (d6-DMSO, 400 MHz) δ 2.55 (s, 3H) 2.51 (br. s., 3H).
Reaction SMILES: [C:1]([CH:4]1[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.O.C(OCC)(=O)C>C(OCC)C.O1CCCC1>[CH:4]1([C:1]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)([OH:3])[CH3:2])[CH2:6][CH2:5]1
Reactant: CC(=O)C1CC1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)(c1ccc(F)cc1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.50 g (5.94 mmol) of acetylcyclopropane was dissolved at 0° C. in 5 ml of diethyl ether, and 8.9 ml (8.91 mmol) of a 1N solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, and the reaction solution was mixed with water and ethyl acetate, and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1) to result in 0.99 g (93% of theory) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([Cl:17])=[O:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ncn(-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.00 g (10.5 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carboxylic acid in 20 mL DCM was added 10.0 mL (137 mmol) thionyl chloride and 1 drop of DMF. The reaction mixture was stirred at 40° C. for 1 h. The solvent was removed by distillation. Yield: 2.20 g (100%); ESI-MS: m/z=204 (M+H)+ (methyl ester); Rt(HPLC): 1.04 min (method 8) (methyl ester)
Reaction SMILES: C([O-])(=O)C.[Zn+2:5].C([O-])(=O)C.[NH2:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:10][C@H:11]([C:19]([O-:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Zn+2:5].[NH2:10][C@H:11]([C:19]([O-:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Product: N[C@@H](Cc1ccccc1)C(=O)[O-]

Procedure:
28.5 g of zinc acetate (0.16 M) is added to 1l of fermented broth of phenylalanine (25 g/l, 0.15 M), from which microorganisms have been removed, and stirred slowly to completely dissolve the zinc acetate. Ammonia water is gradually added to the dissolved solution so as to adjust the pH to 8 and then zinc phenylalaninate crystals are obtained (crystal wt: 31.4 g, purity: 98.4%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH:10]=2)[CH:8]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[OH:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: CNC(=O)CCc1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CNC(=O)CCc1cc(O)cc(-c2ccc3cc(O)ccc3c2)c1
Yield: 35 %

Procedure:
The compound is prepared by reaction of 3-[3-methoxy-5-(6-methoxy-naphthalene-2-yl)phenyl]-N-methylpropionamide (47.8 mg, 0.16 mmol, 1 eq) with aluminum trichloride (213.3 mg, 1.60 mmol, 10 eq) according to method F. Purification by preparative thin-layer chromatography with dichloromethane/methanol 98/2 yielded the desired product in a yield of 35%, 16 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([S:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Cl)[CH3:23]>CC(CC)=O>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][O:13][C:10]1[CH:11]=[CH:12][C:7]([S:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH3:23]
Reactant: Cc1ccc(Sc2ccc(O)cc2)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(Sc2ccc(C)cc2)cc1
Yield: 63.3 %

Procedure:
While stirring, 30 g of 4(4-methylthio-phenoxy)-phenol were dissolved in 350 ml of methylethyl-ketone. After addition of 18 g of potassium carbonate and 16 g of chloroacetic acid ethyl ester, the mixture was heated at the boil for 8 hours. Inorganic components were then separated by suction-filtration. After vaporization of the organic solvent, the residue was dissolved in 300 ml of methylene chloride and the solution was shaken several times with water. The organic phase was vaporized and the residue was distilled in vacuo. 25 g of 4(4-methylthio-phenoxy)-phenoxy-acetic acid ethyl ester were obtained, boiling point: 215°-230°/3-4 mm mercury.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]2[O:13]C(=O)[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:10]2)=[CH:4][C:3]=1[Cl:30].Cl>C1COCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:10][NH:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[OH:13])=[CH:4][C:3]=1[Cl:30]
Reactant: Nc1c(Cl)cc(C2CN(CCCCCCOCCc3ccccn3)C(=O)O2)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1Cl
Yield: 92.8 %

Procedure:
A solution of 5-(4-amino-3,5-dichlorophenyl)-3-[6-[2-(2-pyridinyl) ethoxy]hexyl]-2-oxazolidinone (80 mg) and 2N hydrochloric acid (1 ml) in THF (5 ml) was heated at 80° for 2 h. The solvent was evaporated and the aqueous residue extracted with ethyl acetate (2×25 ml). The aqueous layer was basified with 2N sodium hydroxide solution to pH10 and extracted with ethyl acetate (3×25 ml). The combined extracts were dried and evaporated to leave a pale yellow gum (70 mg). Crystallisation from ethyl acetate/n-hexane gave the title compound as a white crystalline solid m.p. 97.5°-100°, t.l.c. (System A 39:10:1) Rf 0.44.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][C:23]1=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]1[S:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:20][CH2:21][N:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[NH:24][C:23]3=[O:31])[N:7]=2)=[CH:12][CH:11]=1
Reactant: Clc1nccc(-c2ccc(-c3cccs3)s2)n1
Reactant: NCCn1c(=O)[nH]c2ccccc21
Agent: CN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Product: O=c1[nH]c2ccccc2n1CCNc1nccc(-c2ccc(-c3cccs3)s2)n1
Temperature: 160 °C

Procedure:
A mixture of 2-chloro-4-(5-(thiophen-2-yl)thiophen-2-yl)pyrimidine (20 mg, 0.072 mmol), 1-(2-aminoethyl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride salt (15 mg, 0.072 mmol) and potassium carbonate (20 mg, excess) in N-methylpyrrolidine (1 mL) was heated at 160° C. for 35 min in a Personal Chemistry microwave reactor. The solvent was removed in vacuo and the product was purified by HPLC to give the title compound (trifluoroacetate salt) as a yellow solid. MS (M+H)+ 420.
Reaction SMILES: CC[C:3](C)=[O:4].[C:6]([O:10][C:11]12[CH2:20]C3CC(CC(O)(C3)C1)[CH2:18]2)(=[O:9])[CH:7]=C.CC(N=NC(C#N)(C)C)(C#N)C>CO>[CH3:20][CH:11]([O:10][C:6]([CH3:7])=[O:9])[CH2:18][O:4][CH3:3]
Reactant: CCC(C)=O
Reactant: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Product: COCC(C)OC(C)=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A monomer solution was prepared by placing 8000 g of MEK in a tank kept at a nitrogen atmosphere and dissolving 2080 g of (B) NLA, 2480 g of (A) EAM and 2220 g of 3-hydroxy-1-adamantyl acrylate (hereinafter inscribed as “HAA”). Also, a polymerization initiator was prepared by placing and dissolving 1000 g of MEK and 110 g of AIBN in another container kept at the nitrogen atmosphere. Into a polymerization tank kept at the nitrogen atmosphere, 5000 g of MEK was put and the temperature was raised to 80° C. with stirring. Subsequently, the monomer solution and the polymerization initiator solution kept at the temperature of 25 to 30° C. were fed into the polymerization tank kept at 80° C. over 4 hours, respectively. After the completion of feed, the polymerized solution was matured for 2 hours with keeping the polymerization temperature at 80° C., then cooled to room temperature and taken out. Polymer was precipitated from the resulting polymerized solution by dropping in 100 kg of aqueous methanol and filtrated. The resultant wet cake was washed with 100 kg of methanol, filtrated subsequently dissolved in MEK again, and passed through a filter 40QSH supplied from Cuno Incorporated to remove a trace amount of metals. Then, the solvent was replaced by PGMEA with removing MEK by heating under reduced pressure to pre-pare PGMEA solution containing 15% polymer. The features of the resultant polymer, the content of high polymer and the evaluation results of storage stability of PGMEA solution are shown in Table 1.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(S(C)(=O)=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (735.3 mg, 1.421 mmol) in DCM (14.2 mL) at 0° C. was treated with triethylamine (0.594 mL, 4.26 mmol), followed by methanesulfonyl chloride (0.221 mL, 2.84 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered through a Millipore® 0.45 μm syringe filter, and purified by HPLC Method A. The corresponding fractions were collected and concentrated under reduced pressure. The resulting residue was taken up in DCM and washed with saturated aqueous K2CO3 to generate the free base. The organic layer was separated, dried over Na2SO4, and filtered. Evaporation of the filtrate and lyophilization gave the title compound as an off-white solid (229.6 mg, 33.6%). 1H NMR (500 MHz, DMSO-d6) 1.18 (d, J=6.3 Hz, 6H), 1.88 (m, 2H), 2.07 (m, 2H), 2.75 (t, J=5.9 Hz, 2H), 2.89 (m, 2H), 2.97 (s, 3H), 3.29 (m, 2H), 3.45 (t, J=5.9 Hz, 2H), 4.09 (m, 1H), 4.16 (s, 2H), 4.52 (tt, J=8.1, 3.9 Hz, 1H), 5.57 (d, J=8.3 Hz, 1H), 7.01 (m, 1H), 7.30 (m, 2H); ESI-MS m/z [M+H]+ 481.90.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH:25]1[CH2:34][CH2:33][CH2:32][C@H:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([N:25]2[CH2:34][CH2:33][CH2:32][C@H:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H]1CCCN1C(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl L-prolinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-prolinate (oil), saponification of which and processing of the reaction product yields N-[N-p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-proline (M.P. 129° to 131°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].C(Cl)CCl.C1[CH:37]=[CH:38][C:39]2N(O)N=[N:42][C:40]=2C=1.C1(CN)CC1>C(Cl)Cl>[CH:39]1([CH2:40][NH:42][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH2:12][NH:11][C:10](=[O:31])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([S:29][CH3:30])[N:17]=3)[CH:20]=2)[CH2:37][CH2:38]1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: On1nnc2ccccc21
Agent: NCC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CSc1nc(-c2cc(C(=O)NCC3CC3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (500 mg) in methylenechloride (100 mL) were added EDC (260 mg), HOBt (160 mg) and cyclopropylmethylamine (260 uL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified via column chromatography to provide the title compound as a white solid. LC-MS m/z 496 (M+H)+, 2.62 min (ret. time).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:30][C@H:29]([NH2:31])[CH2:28]1)([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>CC(O)C>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:30][C@H:29]([NH:31][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 70 °C

Procedure:
To a mixture of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (342 mg, 1.07 mmol), as prepared in Example 2, step 1, and tert-butyl((trans)-3-aminocyclobutyl)carbamate (200 mg, 1.07 mmol) in iPrOH (4 mL) was added DIPEA (0.5 mL). A stir bar was added to the reaction vessel and it was capped and heated in a reaction block at 70° C. for 2 hrs. The solvent was removed and the product was purified via flash chromatography eluting with a gradient of 12%-100% EtOAc in heptanes to afford the title compound (260 mg, 52% yield) as a pink solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH:7]([CH2:11][C:12]1([C:18](=[O:34])[NH:19][CH:20]([C:30](=[O:33])[NH:31][CH3:32])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].[O:36]=[C:37]1[C:45]2[CH:44]=[C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]3=[CH:41][C:40]=2[C:39](=[O:50])[NH:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:35])[CH:7]([CH2:11][C:12]1([C:18](=[O:34])[NH:19][CH:20]([C:30](=[O:33])[NH:31][CH3:32])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][CH2:9][N:38]1[C:39](=[O:50])[C:40]2[CH:41]=[C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]3=[CH:44][C:45]=2[C:37]1=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCO)C(=O)OC(C)(C)C)CCCCC1
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCCC1
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)-ethylcarbamoyl]cyclohexylmethyl}butyric acid tert-butyl ester (490 mg, 1.0 mmol) in dry tetrahydrofuran (20 mL) was added 1,3-dioxo-1,3-dihydrobenzo[f]isoindole (394 mg, 2.0 mmol), triphenylphosphine (524 mg, 2.0 mmol) and diethylazodicarboxylate (0.31 mL, 2.0 mmol). The resulting mixture was stirred for 3 days. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel eluting with 40% ethyl acetate in hexane. Fractions containing the two diastereomeric products were combined and evaporated to leave a white solid which was recrystallized from ethyl acetate to afford 4-(1,3-dioxo-1,3-dihydrobenzo [f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)-ethylcarbamoyl]cyclohexylmethyl}butyric acid tert-butyl ester (diastereomer A) as a white solid, 105 mg (16%). The mother liquor from the recrystallization was concentrated under vacuum to afford an oil highly enriched in diastereomer B, 140 mg (21%).
Reaction SMILES: P(OCC)(OCC)OCC.[CH2:11]([O:14][C:15](=[O:39])[C:16]([N:18]1[C@H:21]([C@H:22]([C:24]([S:26][CH3:27])=S)[CH3:23])[C@@H:20]([C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])[C:19]1=[O:38])=O)[CH:12]=[CH2:13].C(OC(=O)C(N1[C@H]([C@@H](C(SC)=S)C)[C@@H]([C@H](O[Si](C(C)(C)C)(C)C)C)C1=O)=O)C=C>C1(C)C=CC=CC=1>[Si:31]([O:30][C@@H:28]([C@H:20]1[C:19](=[O:38])[N:18]2[C@@H:21]1[C@@H:22]([CH3:23])[C:24]([S:26][CH3:27])=[C:16]2[C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:39])[CH3:29])([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33]
Reactant: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)SC
Agent: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@H](C)C(=S)SC
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Yield: 13.2 %

Procedure:
A mixture of triethyl phosphite (1.43 g), toluene (3 ml) and a mixture (1.0 g) of (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1S)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine was heated at 80° C. for 26 hours and then refluxed for 16 hours. After removal of the solvent, the residue was dissolved in hexane, washed with water, dried, and concentrated in vacuo. The oily residue was purified by silica gel column chromatography [diethyl ether-hexane (1:3, V/V)] to afford a mixture (118 mg) of allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and allyl (4S,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3 -methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](O)=O.C=O.O>CC(C)=O>[CH2:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NCc1ccccc1)C(=O)O
Reactant: O=CO
Agent: C=O
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H](C)[C@@H](C(=O)O)N(C)Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To 110.7 g of above described N-benzyl-isoleucine (0.50 mol) were added 69.0 g formic acid (1.50 mol) and 49.4 g formaldehyde 36.5% in water (0.60 mol) and the clear, colorless reaction mixture was heated under stirring to ˜90° C. for 2 h. The reaction mixture was concentrated by rotary evaporation (60° C./25 mbar) and the residue was triturated under stirring (˜15 min) with 250 ml acetone. After evaporation of the solvent, triturating was repeated twice using a total of 500 ml acetone. Evaporation of the solvent (50° C./10 mbar) gave 129.9 g white, crystalline residue which was stirred with 200 ml acetone for 1 h at RT and 3 h at −20° C. The crystal suspension was filtered, washed with cold acetone and dried (16 h/50° C./10 mbar) affording 103.9 g (88.3%) product as a white, crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(CCN(C)C)C.[Li]C(CC)C.[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](OC)=[O:29]>C1COCC1.C1(C)C=CC=CC=1>[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([C:10]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])=[O:29]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1ccccc1F
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
4-(Methoxy)benzoic acid (5.00 g, 32.9 mmol) was azeotroped with toluene thrice, then dissolved in 80 mL of dry THF. TMEDA (10.9 mL, 72.3 mmol) was added, and the mixture was cooled to −78° C. sec-BuLi (51.6 mL of 1.40 M in cyclohexane, 72.3 mmol) was added dropwise over a period of 30 minutes, and the solution was stirred for 15 minutes. Methyl 2-fluorobenzoate (5.02 mL, 39.4 mmol) was added in 1 portion and, after stirring for 15 minutes, the reaction was quenched with 20 mL of water. The mixture was warmed to ambient temperature and poured into 1.5 L of water. 30 mL 1N NaOH was added and the aqueous layer was extracted 1× with EtOAc; after which the organic layer was discarded. The aqueous layer was acidified with conc. HCl until pH=1 and then extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chomatography through SiO2 (40-100% EtOAc/hexane) to provide the desired product (4.72 g, 52% yield) as a white solid. ESI+MS: 275.2 [M+H+].
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH3:18])[CH2:3]1.OC1C(O)C2C(=CC=CC=2)CC1C1CCN(C)C1>>[OH:1][CH:2]1[CH2:11][C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH3:18])[CH2:3]1
Reactant: CN1CCCCC1C1CC(O)Cc2ccccc21
Agent: CN1CCC(C2Cc3ccccc3C(O)C2O)C1
Product: CN1CCCCC1C1CC(O)CC2=C1CC=CC2

Procedure:
Following the procedure of Example 6, part D, but substituting the 2-(3-hydroxy-1,2,3,4-tetrahydronaphthalenyl)-1-methylpiperidine for the 3-(3,4-dihydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1-methyl pyrrolidine, the title C compound is obtained.