Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(N)=O)ccc2c1=O
Yield: 84.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.21 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.96 g, 5 mmol) and 1-hydroxybenzotriazole ammonium salt (0.76 g, 5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (1.02 g, 85.0%) as crystals.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N([CH2:13][CH3:14])CC)C.Cl[C:16](OC)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]1(=[O:17])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cl
Reactant: Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a CH2Cl2 (2 mL) solution of the phenol from Example 31 (10.5 mg, 0.03 mmol) was added triethylamine (21 μL, 5 eq), DMAP (0.5 M dichloromethane solution, 6 μL, 0.1 eq) and methyl chloroformate (4.6 μL, 2 eq). The mixture was stirred at room temperature for 1.5 h, concentrated and purified by reverse-phase HPLC (70 to 100% solvent B) to give Example 32 (12 mg, 99%). MS Found: (M+H)+=409.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]([NH:13][C:14]2[S:15][C:16](SC)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[O:28][S:29]([O-:31])=O.[K+].Cl[CH2:34]Cl>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:29]([CH3:34])(=[O:31])=[O:28])=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CSc1cnc(NC(=O)N(C2CCCCC2)C2CCN(C(C)=O)CC2)s1
Reactant: O=S([O-])OO
Reactant: ClCCl
Agent: [K+]
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(S(C)(=O)=O)s2)C2CCCCC2)CC1

Procedure:
Prepared by oxidising 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-urea (Example 339) using montmorillonite clay, oxone (2.5 equivalents) for 16 h at room temperature in dichloromethane. The title compound was purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:6]=1)(=[O:27])=[O:26]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1

Procedure:
The title compound was prepared from 2-amino-4-(-3-nitrophenyl)thiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (27.3 mg) with purity >90%. MS (pos) m/z 444.0, 446.0.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Br.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>O1CCCC1.O>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[PH:2][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1ccccc1[Mg]Br
Reactant: Br[Mg]c1ccccc1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1ccccc1Pc1ccccc1-c1ccccc1O
Temperature: 25 °C
Yield: 98.9 %

Procedure:
23.5 g (100 mmol) of 6-chloro-6H-dibenz[c,e][1,2]oxa-phosphorine in 50 ml of anhydrous tetrahydrofuran are introduced, in an argon atmosphere with stirring, and a solution of 100 mmol of 2-methoxyphenylmagnesium bromide in tetrahydrofuran is added dropwise at -10° C. The mixture is slowly heated to 25° C. and stirred for 3 hours. A solution of 100 mmol of phenylmagnesium bromide in 150 ml of tetrahydrofuran is added dropwise and the mixture is then stirred for 5 hours at 65° C. The mixture is cooled to room temperature and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 38.0 g of colorless oil are obtained. By crystallization with methanol/water, 10:1, 32.7 g (86%) of colorless crystals having melting point 137° to 139° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)=[N:9][CH:8]=[N:7]1)=[O:4].[CH3:38][O:39][C:40]([CH2:42][N:43]1[CH:47]=[N:46][C:45](/[CH:48]=[C:49]2\[CH2:50][N:51]([C:56]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:52][CH2:53][CH:54]\2O)=[N:44]1)=[O:41].[C:75]([OH:78])(=[S:77])[CH3:76]>ClCCl.C1(C)C=CC=CC=1.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>[C:75]([S:77][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:10]1[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=[CH:8][N:9]=1)(=[O:78])[CH3:76].[C:75]([S:77][CH:54]1[CH2:53][CH2:52][N:51]([C:56]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH2:50]/[C:49]/1=[CH:48]\[C:45]1[N:46]=[CH:47][N:43]([CH2:42][C:40]([O:39][CH3:38])=[O:41])[N:44]=1)(=[O:78])[CH3:76]
Reactant: COC(=O)Cn1cnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Reactant: COC(=O)Cn1ncnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)Cn1cnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Product: COC(=O)Cn1ncnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %
Yield: 62 %

Procedure:
The mixture (2.98 g) of (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol and (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-3-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol obtained in Example 166-(b) was dissolved in a mixed solvent of dichloromethane (40 ml) and toluene (40 ml), and thioacetic acid (1.3 ml) and N,N-dimethylformamide dineopentyl acetal (5.0 ml) were added thereto. After the mixture was stirred at room temperature for 2 hours, it was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure gave a residue, which was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:1:1) to afford (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (containing impurities, 1.52 g, gross yield: 46%) as the less polar isomer, and (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-3-yl]methylidene}-1-(triphenylmethyl)piperidine (2.08 g, yield: 62%) as the polar isomer, respectively.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:14]=1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
Ethylsulfonyl chloride (15 uL, 0.16 mmol) was added dropwise to a stirred solution of 3-bromo-5-(2,4-difluorophenoxy)aniline (48 mg, 0.16 mmol) and pyridine (40 uL, 0.48 mmol) in DCM (320 uL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 60%) in hexanes to afford the title compound (60 mg, 95%) as a tan solid. LCMS (M+H)+=393.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[O:19]>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[O:19]1
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of tert.-butyl dichloroacetate in 15 ml of tetrahydrofuran and 2.6 ml of picolinaldehyde were mixed together and cooled to -20° C. to -25° C. Over 15 minutes at this temperature, 28 ml of potassium tert.-butylate in tetrahydrofuran at 0.9M/l were introduced and the mixture was allowed to warm up to ambient temperature. After 1 hour and 25 minutes, 25 ml of water were added, and extraction was effected with tetrahydrofuran. The organic phase was washed with water saturated with sodium chloride and then dried. The resulting solution containing 1,1-dimethylethyl 2-chloro-3-(2-pyridyl)oxirane carboxylate was held at -25° C. and used for the following step of the synthesis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:6]=O.[C:15]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:22]([O:21][C:15](=[O:20])[C:16]([C:17](=[O:18])[CH3:19])=[CH:6][C:5]1[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(=O)CC(=O)OCCC(C)C
Reactant: COc1cc(C=O)cc(C(C)C)c1O
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C=C(C(C)=O)C(=O)OCCC(C)C)cc(C(C)C)c1O

Procedure:
Condensation of 3-methoxy-4-hydroxy-5-isopropyl benzaldehyde with isoamyl acetoacetate in the presence of piperidine-acetic acid and benzene as the reaction medium at reflux temperature under continuous azeotropic water removal yields the title product. The reaction takes about 4 hrs for completion. The yield obtained is typically 90–95%.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.O.CN(C=O)C>[NH:1]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
Boc-Ala-Ala-OH (7.23 g, 27.8 mmol) was dissolved in a mixture of 200 ml MeOH and 20 ml H2O.Cs2CO3 solution (20% aqueous) was added until the pH reached 7.0 (~30 ml) and the resultant neutral solution evaporated to dryness. The residue was re-evaporated twice with DMF (150 ml) and the gelatenous solid that remained was stirred in 120 ml DMF with benzyl bromide (7.2 g, 42 mmol) for 15 hours. The solvent was then removed by evaporation and the residue treated with 500 ml water. The product precipitated as an oil which gradually solidified on standing. It was taken up in EtOAc (400 ml), washed with H2O (3 times), dried (Na2SO4), and evaporated to a syrup which on treatment with petroleum ether began to crystallize. The product was recrystallized from EtOAc and petroleum ether to yield, 7.2 g (73.8%); mp 71°-73° (lit. mp 73°-74°; D. A. Laufer et al., J. Amer. Chem. Soc., 90, 2696 (1968)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[O:14]C=CC=3)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)=[CH:4][C:3]=1[C:22]#[N:23].C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=[O:30].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:30])=[O:14])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)ccc1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-(2-furyl)pyrazole (4.0 g, 12.5 mmol) in acetonitrile (30 mL) was added carbon tetrachloride (30 mL), ruthenium chloride (0.4 g) and a solution of sodium periodate (11.9 g, 56.1 mmol) in water (45 mL). The reaction is stirred at room temperature overnight. The next day the reaction mixture was filtered through celite. The filtrate was concentrated and partitioned between ethyl acetate and HCl (1N). The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated to give 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxycarbonyl pyrazole (2.4 g, 64% yield) as pure compound. MS (ES−): 298 (M−H)− (40%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24])([OH:16])=[O:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:24][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:14]([OH:16])=[O:15])=[O:25])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccccc1C(=O)O
Product: O=C(O)c1ccccc1C(=O)C=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 8 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.64 g of 2'-carboxyacetophenone. Yield 0.36 g (11%), m.p. 178-180° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J10) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) according to the general procedure M. Obtained as a yellow foam (228 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH3:3].[H-].[Na+].Cl[CH2:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:32]([F:43])[CH:31]=2)=[CH:26][CH:25]=1.Cl>CN(C)C=O>[F:43][C:32]1[CH:31]=[C:30]([O:29][CH2:28][C:27]2[CH:44]=[CH:45][C:24]([CH2:23][N:4]([CH2:1][CH2:2][CH3:3])[C:5]3[S:6][CH:7]=[C:8]([C:10]4[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=4)[N:9]=3)=[CH:25][CH:26]=2)[CH:35]=[CH:34][C:33]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(Cc1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-propyl-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (700 mg, 2.44 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (100 mg, in oil, 2.5 mmol) at room temperature and the mixture was stirred at room temperature for 1 hr. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (700 mg, 2.0 mmol) was added and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by preparative HPLC. The obtained fraction was concentrated, neutralized with 10% aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was filtered with a Presep Dehydration tube (Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.C[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CNCCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 43.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 4-methylamino-butan-1-ol (44.5 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide (30.5 mg, 43.4%). HRMS (ES+) m/z Calcd for C27H33Cl2N3O2+H [(M+H)+]: 502,2023. found: 502.2020.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=[O:9].[In+3].S([O-])([O-])(=O)=[O:15].S([O-])([O-])(=O)=O.[In+3]>>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:9])[OH:7].[C:1]1([CH:6]=[CH:5][C:4]([OH:15])=[CH:3][CH:2]=1)[OH:7]
Reactant: O=S(=O)([O-])[O-]
Reactant: Oc1ccccc1
Agent: [In+3]
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O

Procedure:
With 10 g. (106 m.moles) of phenol was admixed the ketone peroxide as listed in Table 3 so that a peroxide amount (P) may be 5.30. To the mixture was added 0.70 g. of indium sulfate (In2 (SO4)3.9H2O) and then the reaction was carried out at 100° C. for 30 minutes. Yields of catechol and hydroquinone are shown in Table 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]=1[F:24])[O:6][CH2:7][CH3:8])[CH3:2].[CH3:26][Si:27]([CH3:32])([CH3:31])[CH2:28][CH2:29][OH:30].C(N(CC)CC)C.C[CH2:41][O:42]C(C)=O>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:26][Si:27]([CH3:32])([CH3:31])[CH2:28][CH2:29][O:30][C:41](=[O:42])[C:12]1[CH:11]=[C:10]([F:24])[C:9]([CH:5]([O:6][CH2:7][CH3:8])[C:4]([O:3][CH2:1][CH3:2])=[O:25])=[C:14]([F:15])[CH:13]=1
Reactant: CCOC(=O)C(OCC)c1c(F)cc(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: C[Si](C)(C)CCO
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(OCC)c1c(F)cc(C(=O)OCC[Si](C)(C)C)cc1F
Temperature: 70 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of (RS)-(2,6-difluoro-4-trifluoromethanesulfonyloxy-phenyl)-ethoxy-acetic acid ethyl ester (200 mg) and 2-(trimethylsilyl)ethanol (603 mg) in DMSO (2.5 ml) was added triethylamine (1.8 ml) followed by Pd(OAc)2 (6 mg) and 1,3-bis(diphenylphosphino)propane (11 mg). The flask was put under carbon monoxide and the reaction mixture was stirred 2 h at 70° C. AcOEt (30 ml) was added and it was washed with 1 N HCl (2×40 ml), water (2×40 ml) and brine (30 ml). After drying (MgSO4) the solvent was evaporated. CC (Hept/AcOEt 98:2) afforded 151 mg (76%) of (RS)-4-(ethoxy-ethoxycarbonyl-methyl)-3,5-difluoro-benzoic acid 2-trimethylsilanyl-ethyl ester. Colorless oil. MS 406.6 ([M+NH4]+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:5]=1[F:14].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22](C)[C:23](=O)OC(C)(C)C)[CH:21]=1>CN(C)C=O>[CH3:23][NH:22][C:20]1[CH:21]=[C:16]([O:10][C:9]2[C:4]([F:3])=[C:5]([F:14])[C:6]([F:13])=[C:7]([F:12])[C:8]=2[F:11])[CH:17]=[CH:18][C:19]=1[N+:31]([O-:33])=[O:32]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(Oc2c(F)c(F)c(F)c(F)c2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 19 %

Procedure:
To a suspension of sodium hydride (55 wt. %, 1.66 g) in anhydrous N,N-dimethylformamide (50 ml) was added pentafluorophenol (6.38 g). The mixture was stirred at ambient temperature for several minutes. To this mixture was added t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (10 g) in small portions and the mixture was stirred at 150° C. for 15 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/toluene=4/1 as the eluant to give the title compound (2.2 g).