Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH:29](O)([OH:33])[C:30]#[C:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:32][C:31]#[C:30][CH2:29][OH:33])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC#CC(O)O
Product: O=C1c2ccccc2C(OCC#CCO)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 58 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and butynediol (435 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (271 mg, 58%). 1H NMR (300 MHz, CDCl3): 8.05-7.93 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.61-7.54 (m, 2H, Ar—H), 7.36-7.33 (m, 2H, Ar—H), 7.24-7.16 (m, 5H, Ar—H), 4.60 and 4.52 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.20-4.18 (m, 2H, HO—CH2), 3.83 and 3.52 (dt: AB, J=1.8, 15.3 Hz, 2H, O—CH2), 2.42 (t, J=6.0 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 169.24, 148.20, 145.18, 137.24, 135.88, 133.78, 132.49, 131.29, 130.78, 129.43, 128.79, 124.81, 124.43, 124.14, 95.88, 86.01, 81.28, 54.04, 52.97, 51.55, 43.60. m/z (ES): 463 [M+H]+. calc. for C25H19ClN2O5+0.2 H2O: C, 64.36; H, 4.20; N, 6.01. Found: C, 64.11; H, 3.72; N, 5.53.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]1.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]#[CH:23].C(N([CH2:36][CH3:37])CC)C>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]([C:23]#[C:22][CH2:21][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:37]2[CH:36]=[CH:16][CH:15]=[CH:14][CH:19]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]1
Reactant: C#CCOc1ccccc1
Reactant: CCN(CC)CC
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Nc1nc(C#CCOc2ccccc2-c2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 6 h
Yield: 38.1 %

Procedure:
To a solution of (4S,2R,3R,5R)-2-(6-amino-2-iodopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol (compound 1) (50 mg, 0.126 mmol) and prop-2-ynyloxybenzene (22 δ, 0.1605 mmol) in N,N-dimethylformamide (1 ml) and triethylamine (21 δ, 16.065 mmol) at 23° C. was added copper iodide (5 mg, 0.026 mmol) and dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) catalyst. After being stirred in a sealed reacti-vial at 80 C for 6 hours, the reaction was concentrated in vacuo, the residue purified by preparatory thin layer chromatography (methylene chloride:methanol 9:1) to afford compound 10 (9.6 mg, 0.024 mmol) in 20% yield. 1H NMR(CDCl3:CD3OD 9:1) δ 3.02-3.04 (m, 1H), 3.07 (s, 1H), 3.55, 3.74 (dd, 2H), 4.02 (s, 1H), 4.11-4.13 (m, 1H), 4.48-4.52 (m, 1H), 4.72 (s, 2H), 5.65 (d, 1H), 6.75-6.82 (m, 3H), 7.08-7.12 (m, 2H), 7.94 (s, 1H).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1.Br[CH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[S:23][C:22]=1[C:34]([O:36][CH3:37])=[O:35]>CO.C(Cl)Cl>[C:26]([C:25]1[C:21]([CH2:20][N:10]2[C:9](=[O:8])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11]2)=[C:22]([C:34]([O:36][CH3:37])=[O:35])[S:23][C:24]=1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)#[N:27]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1CBr
Reactant: Oc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Cn1cnc2ccccc2c1=O
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
Under N2 atmosphere Sodium hydride (23.0 mg, 0.910 mmol) was suspended in anhydrous N,N-Dimethylformamide (3.0 mL, 39 mmol), cooled with ice bath and stirred for 10 min. 4-hydroxyquinazoline (0.120 g, 0.821 mmol) was added and the clear solution was stirred at r.t. for 10 min, cooled with ice bath. Methyl 3-(bromomethyl)-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylate (0.203 g, 0.588 mmol) was added and the reddish-brown solution was stirred with cooling for 40 min. The mixture was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc. The EtOAc solution was washed with water (3×) then brine, dried over Na2SO4, filtered, rotavaped to give a crude solid. Chromatograph in a silica gel column using MeOH/DCM (0/100 to 5/95) afforded a solid product (0.211 g, yield 87.4%). LC/MS: (FA) ES+ 411. 1H NMR (400 MHz, d-chloroform) δ 8.30 (m, 1H), 8.26 (s, 1H), 7.68-7.76 (m, 2H), 7.45-7.49 (m, 1H), 5.43 (s, 2H), 3.83-3.85 (m, 4H), 3.82 (s, 3H), 3.59-3.62 (m, 4H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])=[CH:26][CH:25]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(F)cc2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 89 %

Procedure:
N-(4-Fluorophenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 4-fluoroaniline. Yield: 89% of theory; m.p. 284°-285° C (decomp.; from xylene).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](OCC)=[O:15])=[C:10]([OH:19])[C:9]3[CH2:20][O:21][CH2:22][C:8]2=3)=[CH:4][CH:3]=1.C([NH:29][CH2:30][C:31]([OH:33])=[O:32])(C)(C)C.C(Cl)Cl>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:29][CH2:30][C:31]([O:33][CH2:24][CH2:2][CH2:3][CH3:4])=[O:32])=[O:15])=[C:10]([OH:19])[C:9]3[CH2:20][O:21][CH2:22][C:8]2=3)=[CH:23][CH:24]=1
Reactant: CC(C)(C)NCC(=O)O
Reactant: CCOC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)COC2
Solvent: COCCOC
Solvent: ClCCl
Product: CCCCOC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)COC2
Temperature: 120 °C

Procedure:
To a solution of the ester from Step C (563 mg, 1.43 mmol) in 1,2-dimethoxyethane (12 mL) was added tert-butyl glycine (0.390 mL, 2.86 mmol). The mixture was heated in the microwave at 120° C. for 1.5 h. The mixture was concentrated in vacuo to give a yellow oil which was taken up in the minimum amount of CH2Cl2 and chromatographed on a Biotage 40S+ column with a 10, 20, 30, EtOAc/hexanes gradient elution to give compound, 28-4, as a white solid, 494 mg: 1H NMR (500 MHz, CDCl3): δ 1.49 (s, 9 H), 4.09 (d, 2 H, J=5.2 Hz), 4.91 (t, 2 H, J=3.2 Hz), 5.01 (s, 2 H), 5.05 (t, 2 H, J=3.2 Hz), 7.09 (d, 2 H, 8.3 Hz), 7.46 (d, 2 H, J=8.2 Hz), 10.44 (m, 1 H); HPLC/MS: 1.28 min, 480.0 (M+H)+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.S[C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].[CH2:19]([C:26](=[CH2:37])[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[S:38]([O:42]OS([O-])(=O)=O)([O-])(=O)=[O:39].[K+].[K+]>O>[CH2:30]([O:29][C:27]([CH:26]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:37][S:38]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])(=[O:42])=[O:39])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CC(C)(S)C(=O)O
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.4 g (55.4 mm01) of DBU were added dropwise to a solution of 3.3 g (27.7 mmol) of 2-mercaptoisobutyric acid [Can. J. Chem. 61(8), 1872]and 6.9 g (27.7 mmol) of benzyl 2-benzylacrylate (EPA 0117429), whereby the temperature of the reaction mixture was held between 5 and 10°. After completion of the addition the mixture was stirred at 10° for a further 5 hours. Subsequently, the reaction mixture was treated dropwise with 22.5 g (36.6 mmol) of potassium monopersulphate triple salt suspended in 450 ml of water while cooling with ice, whereby the temperature was held below 10°. Thereafter, the mixture was stirred at the same temperature for a further hour, then cooled to 0° and a further 22.5 g (36.6 mmol) of potassium monopersulphate triple salt were added spatula-wise. The mixture was left to warm slowly to room temperature and was stirred for a further 15 hours. For the working-up, the mixture was diluted with 200 ml of water and extracted four times with 60 ml of ethyl acetate each time. The combined organic extracts were dried over sodium sulphate and evaporated under reduced pressure until the product began to crystallize. Then, 30 ml of hexane and 20 ml of ether were added while stirring, the separated product was subsequently filtered off under suction and dried. There were obtained 9.7 g of (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionic acid as a colourless solid; MS: 422 (M+NH4)+.
Reaction SMILES: [C:1]([C@H:4]1[CH2:13][C@H:12]([NH:14][C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:11]2[C:6](=[CH:7][C:8]([Cl:25])=[CH:9][C:10]=2[Cl:24])[NH:5]1)([OH:3])=[O:2].[CH2:26](N(CC)CC)C.IC[CH2:35][C:36]([CH3:41])([CH3:40])[C:37]([O-:39])=[O:38]>O1CCCC1>[C:36]([C:37]([O:39][CH2:26][O:2][C:1]([C@H:4]1[CH2:13][C@H:12]([NH:14][C:15]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[C:11]2[C:6](=[CH:7][C:8]([Cl:25])=[CH:9][C:10]=2[Cl:24])[NH:5]1)=[O:3])=[O:38])([CH3:41])([CH3:40])[CH3:35]
Reactant: O=C(Cc1ccccc1)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Reactant: CC(C)(CCI)C(=O)[O-]
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCOC(=O)[C@H]1C[C@H](NC(=O)Cc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
To a solution of trans-2-carboxy-5,7-dichloro-4-phenylmethylcarbonylamino-1,2,3,4-tetrahydroquinoline (0.06 g, 0.16 mmol, Example 34) in tetrahydrofuran (5 ml) was added triethylamine (0.027 ml, 0.19 mmol) followed by a solution of iodomethylpivalate (0.06 g, 0.24 mmol) in tetrahydrofuran (2 ml). This mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum and the residue obtained was purified by flash chromatography (using ethyl acetate in hexane as eluent) to give the title compound (0.044 g), m.p. 162.4°-163° C. δ (360 MHz, DMSO) 1.41 (9H, s, C(CH3)3, 1.66 (1H, ddd, J=13.4, 12.6 and 3.8 Hz, CHACHBHCCHD), 2.12 (1H, dm, J=13.4 Hz, CHACHBHCCHD), 3.41 (2H, NHCOCH2Ph), 3.97 (1H, dd, J=12.6 and 3.8 Hz, CHACHBHCCHD), 5.02 (1H, m, CHACHBHCCHD), 5.81 (2H, 2d, J=5.9 Hz, CO2CH2CO), 6.71 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.86 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.97 (1H, bs, ArNH), 7.26 (5H, m, ArH), 8.45 (1H, d, J=7.1 Hz, CHDNHCO); m/e (CI+) 493 (M+1). Found C, 58.37; H, 5.33; N, 5.69; C24H26Cl2N2O5 requires C, 58.43; H, 5.31; N, 5.68%.
Reaction SMILES: CO.[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C.[OH-].[Na+]>[C].[Pd].C(Cl)Cl>[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Yield: 66 %

Procedure:
To an 100 ml methanol solution of 3.51 g of the 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine synthesized in Step B was added a 200 mg of palladium carbon and 1 ml of acetic acid. The resultant mixture was hydrogenated under atmospheric pressure at room temperature. After completion of the reaction, the insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in-methylene chloride, adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10, then shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (methylene chloride:methanol=20:1) to give the above-referenced compound, 4-(4-phenoxyphenyl)piperidine in an amount of 2.32 g (yield 66%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][Mg]Br.C([O:40][CH2:41][CH3:42])C>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[C:41]([OH:40])([CH3:42])[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(=O)OC)n2Cc1ccccc1
Reactant: CCOCC
Solvent: C1CCOC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(C)(C)O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Compound 47 (100 mg, 0.218 mmol) obtained in Example 47 was dissolved in tetrahydrofuran (5 mL), to the solution was added a 3.0 mol/L solution (500 μL) of methyl magnesium bromide (1.50 mmol, 6.8 equivalents) in diethyl ether, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then the residue was directly purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound (60 mg, 60%).
Reaction SMILES: O.Br[CH2:3][C:4](=O)[CH:5](C)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:7].[C:18]([NH:23][C:24]([NH2:26])=[S:25])(=[O:22])[CH:19]([CH3:21])[CH3:20].N1C=CC=C[CH:28]=1>C(O)C>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]([CH2:5][CH:4]=[C:3]2[CH2:28][S:25][C:24]([NH:23][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[N:26]2)=[O:7])=[CH:14][CH:13]=1
Reactant: CC(C(=O)CBr)C(=O)Nc1ccc(Cl)cc1
Reactant: CC(C)C(=O)NC(N)=S
Reactant: c1ccncc1
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)NC1=NC(=CCC(=O)Nc2ccc(Cl)cc2)CS1
Yield: 69.3 %

Procedure:
A 300 ml reaction flask fitted with a magnetic stirrer, heating mantle, thermometer and water-cooled condenser was charged with 5.0 g (0.016 mole) of 4-bromo-4'-chloro-2-methylacetoacetanilide [M.P. 103°-105°; prepared as described by Hodgkinson and Staskun in The Journal of Organic Chemistry, vol. 34, p. 1710 (1969)], 100 ml of ethanol, 2.5 g (0.017 mole) of N-isobutyrylthiourea [M.P. 112°-114°; prepared as described by Moore and Crossley in The Journal of the American Chemical Society, vol. 62, p. 3273 (1940)] and 1.6 g (0.02 mole) of pyridine. The solution was stirred and refluxed for three hours. The solvent was removed under reduced pressure and the residual solid was stirred with water-toluene. There was obtained 3.9 g (69%) of white solid, M.P. 202°-204°. N.M.R. (dimethyl-d6 sulfoxide)∂ 1.1-1.3 (2×CH3), 1.4- 1.6 (CH3, doublet), 3.5-4.0 (2×CH), 6.8 (hetero-aromatic), 7.2-7.7 (aromatic).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[NH:15][N:14]=[N:13]1.[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-n2nn[nH]c2=O)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(-n2nnn(C)c2=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2-methyl-3-trifluoromethylphenyl)-1,4-dihydrotetrazole-5-one, potassium carbonate 11.20 g, dimethyl sulfate 3.71 g and N,N-dimethylformamide 150 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(2-methyl-3-trifluoromethylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 5.13 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](O)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[NH:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[Li+]>C1COCC1.C(OCC)(=O)C>[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[N:46]1[C:21]([C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:22])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (described herein above) (13.39 g, 0.038 mol) in THF (200 mL) at −20° C. were added triethylamine (13.32 mL, 0.096 mol) and pivaloyl chloride (11.76 mL, 0.096 mol) subsequently. Stirring was continued for two hours at the same temperature, and to this mixture were added (S)-4-benzyl-oxazolidin-2-one (8.13 g, 0.046 mol) and lithium chloride (1.94 g, 0.046 mol). The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water two times and saturated sodiumbicarbonate. The separated organic phase was dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:2) to yield (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one 9.47 g (49%) as a white solid ES-MS m/e: 509.3 (M+H+) and (S)-4-benzyl-3-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one 9.40 g (48%) as a white solid ES-MS m/e: 509.3 (M+H+).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:30](=[O:42])[NH:31][C@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][CH2:34][CH2:33]2)[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O.COC(C)(C)C>C1COCC1>[NH2:1][C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH3:18])[C:11]([CH3:13])([CH3:14])[CH3:12])[C@H:6]([C:30](=[O:42])[NH:31][C@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][CH2:34][CH2:33]2)[CH2:5]1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the title compound of Example 3 (1.7 g, 2.9 mmol) in 10.6 mL dry THF was added Ph3P (765 mg, 2.9 mmol) at room temperature. Water (78.3 μL, 4.35 mmol) was added drop wise and the reaction mixture was allowed to stir for 16 hours at room temperature. A 1:1 mixture of water/MeOtBu was added to quench the reaction. The two phases were separated. The aqueous phase was extracted by EtOAc twice, and then the combined organic phase was washed by brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with EtOAc, the 5% to 15% MeOH/methylene chloride to give the title compound as a white foam-like solid. 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[Br:12][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCc1ccsc1Br

Procedure:
3-hexylthiophene and N-bromosuccinimide (hereinafter, referred to as ‘NBS’) in the same amount were reacted in DMF at room temperature for 15 hours to obtain 2-bromo-3-hexylthiophene (d). 12.4 g (50 mmol) of the 2-bromo-3-hexylthiophene (d) was added to a solution of 28 mL (56 mmol) of lithium diisopropylamine (hereinafter, referred to as ‘LDA’, 2.0M in THF/Hexane) in 40 mL of anhydrous THF at about −80˜−90° C. with stirring. At this temperature, the reaction was allowed to proceed for 20˜30 minutes. A solution of 10.0 g (50 mmol) of Me3SnCl in THF was added to the mixture, and was then stirred at −50° C. for 1 hour. After completion of the reaction, the reaction mixture was extracted with ether and water. The obtained organic layer was concentrated, and distilled to afford the title compound (yield: 78%) as a colorless oil. The 1H-NMR spectrum (CDCl3) of the monomer (3) is shown in FIG. 2.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2)=O.[OH-].[Na+].O>CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2
Reactant: COC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Reaction time: 18 h

Procedure:
A mixture of 25.8 g. o 6-methoxycarbonyl-2-naphthyl-α-methylacetic acid, 4 g. of sodium hydroxide, 10 ml. of water, and 500 ml. of methanol are heated to 50° C, cooled, and evaporated. The residue is taken up in 500 ml. of diethylene glycol dimethyl ether and diborane is bubbled through. The resulting mixture is saturated with diborane and then is allowed to stand for 18 hours. The reaction mixture is acidified by the addition of aqueous 1n hydrochloric acid. The mixture is extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-hydroxymethyl-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:24]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)=[O:25])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)c1ccsc1
Product: Cc1noc(-c2sc(NC(=O)c3ccsc3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and thiophene-3-carbonyl chloride.