Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19]>CC(C)=O>[CH2:18]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:19]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CC)CCCC1=O
Yield: 96.7 %

Procedure:
Under vigorously agitation, 31.2 g (purity of 90%,) of ethyl 2-oxocyclopentane carboxylate was added to 76.04 g (purity of 98%) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then to the mixture was dropwise added 29.51 ml (purity of 98.5%) of ethyl iodide. Upon the completion of the addition, the reaction mixture was heated for reflux for 5 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 32.03 g of colorless liquid as a distillate cut of 130-134° C./18 mmHg was collected. Yield-96.7%. MS: m/e 184(M+′), 156(M+″—C2H5), 140(M+′—OCH2CH3), 139, 101(M+′—CO2CH2CH3), 127(155—CH2CH2), 111(156-OCH2CH3), 55(base).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH3:37])[C:25](=[O:27])[CH2:24][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C@H:19]3[CH2:23][CH2:22][O:21][CH2:20]3)[N:12]=2)[C:3]=1[NH2:24].[N:25]([O-])=O.[Na+]>CCO.C(O)(=O)C.O>[Cl:1][C:2]1[C:3]2[N:24]=[N:25][N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[N:12]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=N[O-]
Reactant: Nc1nc(Cl)c(N)c(NCc2cccc(CO[C@H]3CCOC3)n2)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)c2nnn(Cc3cccc(CO[C@H]4CCOC4)n3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of 6-chloro-N4-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}pyrimidine-2,4,5-triamine (8.09 g, 23.06 mmol) in EtOH (85 mL) and glacial acetic acid (21 mL) at 0° C., was treated with a solution of sodium nitrite (2.07 g, 29.979 mmol) in water (5.3 mL), stirred at 0° C. for 1 h and the resulting precipitate was filtered, washed with EtOH (85 mL) and dried to give the title compound (5.82 g, 70%) as an off-white solid; LC-MS retention time 1.94 min, (M+H)+ 362.
Reaction SMILES: NC1C=C(C(C)C)C=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:21][C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[S:31]([NH:34][C:35]([NH:37][CH:38]([CH3:40])[CH3:39])=S)(=[O:33])=[O:32]>>[CH:28]([C:26]1[CH:25]=[CH:24][C:23]2[S:31](=[O:33])(=[O:32])[N:34]=[C:35]([NH:37][CH:38]([CH3:40])[CH3:39])[NH:21][C:22]=2[CH:27]=1)([CH3:30])[CH3:29]
Reactant: CC(C)NC(=S)NS(=O)(=O)c1ccc(C(C)C)cc1N
Agent: CC(C)N=C=S
Agent: CC(C)c1ccc(S(N)(=O)=O)c(N)c1
Product: CC(C)NC1=NS(=O)(=O)c2ccc(C(C)C)cc2N1

Procedure:
Starting from 2-amino-4-isopropylbenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4-isopropylbenzenesulfonyl)-N′-isopropylthiourea was prepared. The crude product containing approx. 16% starting material (by 1H-nmr) was used without purification for the next step. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 237-239° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[C:28]([S:32]([CH2:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:40][C:41]=1[Cl:42])(=[O:34])=[O:33])([CH3:31])([CH3:30])[CH3:29].[F-].[Cs+]>COCCOC.C(O)C>[C:28]([S:32]([CH2:35][C:36]1[CH:37]=[C:38]([C:12]2[CH:11]=[CH:10][C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:39]=[CH:40][C:41]=1[Cl:42])(=[O:34])=[O:33])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC1(C)OB(c2ccc(Cl)c(CS(=O)(=O)C(C)(C)C)c2)OC1(C)C
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(-c2ccc(Cl)c(CS(=O)(=O)C(C)(C)C)c2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.1 g, 2.65 mmol) was dissolved in 1,2-dimethoxyethane (15.7 ml) and ethanol (1.5 ml). 2-{3-[(tert-butylsulfonyl)methyl]-4-chlorophenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.09 g, 2.92 mmol) was added and argon was bubbled in the solution for 10 minutes. Cesium fluoride (0.89 g, 5.84 mmol) and palladium tetrakistriphenylphosphine (0.153 g, 0.13 mmol) were: added for 2.5 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate and water. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) giving 0.53 g (39%) of the desired product.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:16][O:15][N:14]([CH3:13])[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)=[O:11]
Reactant: CNOC
Reactant: CSc1nccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccnc(SC)n1
Reaction time: 20 h

Procedure:
A mixture of 2-(methylthio)pyrimidine-4-carboxylic acid (1-1, prepared according to Kim, C.-H., et al J. Med. Chem. 1986, 29, 1374–1380 and McOmie, W. J. Chem. Soc. 1953, 3129, 2.00 g, 11.8 mmol, 1 equiv), N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.3 mmol, 3.00 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.38 g, 17.6 mmol, 1.50 equiv), 1-hydroxy-7-azabenzotriazole (2.40 g, 17.6 mmol, 1.50 equiv), and triethylamine (6.55 mL, 47.0 mmol, 4.00 equiv) in DMF (40 mL) was stirred for 20 hours. The reaction mixture was partitioned between a 1:1 mixture of brine and saturated aqueous sodium carbonate solution (100 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexane initially, grading to 40% hexane in ethyl acetate) to give N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (1-2) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H, J=4.9 Hz), 7.13 (br s, 1H), 3.74 (br s, 3H), 3.36 (br s, 3H), 2.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ccccn2)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2ccccn2)c(F)cc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a suspension of methyl 2-chloro-4-fluoro-5-(pyridin-2-yl)benzoate (Preparation 40A, 37.6 g, 142 mmol) in methanol (300 mL) was added aqueous sodium hydroxide solution (300 mL, 2 M). The reaction mixture was stirred at 40° C. for 2 hours. The mixture was filtered and the filtrate acidified to pH 6-7 with aqueous HCl solution (300 mL, 2 M). The resulting solid was collected by filtration, washed with water (20 mL) and dried under vacuum over potassium hydroxide at 50° C. for 48 h to afford the title compound as a white solid (36.2 g, 100%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:12]([O:15][CH2:16][CH2:17][CH2:18]Br)(=[O:14])[CH3:13]>CN(C=O)C>[C:12]([O:15][CH2:16][CH2:17][CH2:18][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)(=[O:14])[CH3:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1ccc2ccccc21
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a stirred 0° C. DMF (400 mL) suspension of NaH (60% in mineral oil, 0.705 moles, 28.2 g, 1.5 eq.) in a three-neck flask fitted with a reflux condenser and an addition funnel was added a DMF (150 mL) solution of indole (55 g, 0.47 moles) dropwise. After 30-60 minutes, a DMF (50 mL) solution of the alkyl halide, 3-bromopropyl acetate (170 g, 0.94 moles) was added. The reaction was heated at 50° C. for 6 hours and then allowed to stir at room temperature for 5-15 hours.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[SH:9][C:10]1[NH:11][C:12]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[N:15]=[CH:14][C:13]=2[N:30]=1>ClCCl.CO>[CH3:1][S:9][C:10]1[NH:11][C:12]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[N:15]=[CH:14][C:13]=2[N:30]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c2[nH]c(S)nc2cnn1Cc1cccc2ccccc12
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CO
Product: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.38 g (17.2 mmol) of potassium carbonate and 1.07 ml (17.20 mmol) of iodomethane were added to a suspension of 5.3 g (17.19 mmol) of 2-mercapto-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 100 ml of dichloromethane and 100 ml of methanol and stirred overnight at ambient temperature. Then the solvent was evaporated off, the residue was combined with approx. 30 ml of water, acidified with 2N hydrochloric acid, the product thus obtained was suction filtered, washed again with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[C:10]1([CH2:16][O:17][CH2:18][C@@H:19](O)[C@H:20](O)[CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OC(C)C)(C)C.O>[F:1][C:2]1[C:3]2[O:9][C@@H:19]([CH2:18][O:17][CH2:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:20]([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1O
Reactant: O[C@H](COCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: Fc1cccc2c1O[C@@H](COCc1ccccc1)[C@H](COCc1ccccc1)O2

Procedure:
A mixture of 3-fluorobenzene-1,2-diol (5.12 g) and (R*,R*)-(±)-1,4-bis(phenylmethoxy)-2,3-butanediol, bis(4-methylbenzenesulphonate) (24.4 g) was stirred with dimethylformamide (D.M.F.) (160 ml) under a nitrogen stream for 45 min. Anhydrous cesium carbonate (13.0 g) was added and the mixture was heated to 150° under reflux for 18 hours. The dark brown mixture was cooled to 30° and diluted with di-isopropyl ether (370 ml) and water (320 ml). The layers were separated and the aqueous layer was re-extracted with di-isopropyl ether (150 ml then 100 ml). The extracts were sequentially washed with M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) and were combined and evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in light petroleum-dichloromethane (3:1) (40 ml) and chromatographed over Sorbsil (126 g) using light petroleum-dichloromethane mixtures of gradually increasing polarity. Combination of appropriate fractions and evaporation of the solvents gave the title compound as a yellow oil (7.0 g), NMR τ (CDCl3) 2.6-2.8 (10H, m, Ph), 3.18-3.38 (3H, m, 6-H, 7-H, 8-H), 5.32-5.58 (4H, m, CH2Ph), 5.64 (2H, m, 2-H, 3-H), 6.06-6.32 (4H, m, CH2O).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([C:20](=[O:42])[C@@H:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:22])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:20](=[O:42])[C@@H:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:22])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Yield: 86.6 %

Procedure:
0.6 g of tert.-butyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-2-phenylethyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 20 ml of a 20% hydrogen chloride-dioxane solution are treated in the same manner as described in Example 10-(3), whereby 0.47 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-2-phenylethyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless viscous oil. This oil (0.47 g) and 30 mg of palladium black are treated in the same manner as described in Example 10-(5), whereby 0.32 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-2-phenylethyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless crystals. Yield: 71.1%
Reaction SMILES: N1(CC(O)=O)C2C(=CC=CC=2)C=C1.COC(=O)[C@@H](NC(OC(C)(C)C)=O)CSCC1C=CC(N)=CC=1.C(Cl)CCl.C(N(CC)CC)C.C[O:49][C:50](=[O:82])[C@@H:51]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:52][S:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:62](=[O:73])[CH2:63][N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH:66]=[CH:65]2)=[CH:57][CH:56]=1.[OH-].[Na+].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.C1COCC1>[C:78]([O:77][C:75]([NH:74][C@@H:51]([CH2:52][S:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:62](=[O:73])[CH2:63][N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH:66]=[CH:65]2)=[CH:57][CH:56]=1)[C:50]([OH:82])=[O:49])=[O:76])([CH3:81])([CH3:79])[CH3:80]
Reactant: COC(=O)[C@H](CSCc1ccc(NC(=O)Cn2ccc3ccccc32)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@H](CSCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(NC(=O)Cn2ccc3ccccc32)cc1)C(=O)O

Procedure:
A solution of indol-1-yl-acetic acid (1.25 g, 7.14 mmol), (2R)-3-(4-amino-benzylsulfanyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (2.67 g, 7.85 mmol), EDC (1.71 g, 8.93 mmol), triethylamine (2.48 mL, 17.85 mmol) and DMAP (87 mg, 0.714 mmol) in DCM (50 mL) was stirred at ambient temperature. Upon completion (TLC: 2% methanol in dichloromethane), the reaction was quenched with water (75 mL) and extracted with ethyl acetate (3×50 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash chromatography (SiO2; 30-40% ethyl acetate/heptane as eluent). To a stirred solution of (2R)-2-tert-butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionic acid methyl ester (0.470 g, 0.945 mmol) in methanol (3 mL) and THF (12 mL) was added 2N NaOH solution (2.5 mL, 5.3 mmol). Upon completion (TLC 10% methanol in dichloromethane), the mixture was acidified to pH 2 with 2N HCl solution and extracted with ethyl acetate (3×20 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the titled compound as a light yellow solid. Rf=0.40 (20% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 7.71 (1H, d, J=7 Hz, Ar—H), 7.37-7.20 (6H, m, Ar—H), 7.16 (1H, d, J=3 Hz, Ar—H), 7.00 (1H, m, Ar—H), 6.69 (1H, d, J=3 Hz, Ar—H), 4.95 (2H, s, NCH2CO), 4.38 (1H, m, CHN), 3.66 (2H, s, PhCH2S), 2.85 (2H, m, CH2CHN), 1.45 (9H, s, CMe3); ESI-LCMS e/z calculated for C25H29N3O5S 483.183, found 484 (M+H)+, 506 (M+Na)+.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([O:17][CH2:23][C:22]#[CH:21])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)c1nn(-c2cc(O)c(Cl)cc2F)c(=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(-n2nc(C(C)(C)C)oc2=O)c(F)cc1Cl
Yield: 96.4 %

Procedure:
Reacted at 80° C. for 6 hours with stirring were 1.2 g of 5-t-butyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,3,4-oxadiazol-2-one, 0.76 g of 3-bromopropyne, 40 ml of acetonitrile, and 0.3 g of potassium carbonate. After cooling, the reaction product was filtered and the filtrate was subjected to vacuum distillation to remove the solvent. To the residue was added 30 ml of methylene chloride, and the solution was washed with a 5% aqueous solution of sodium hydroxide and then with water. Upon removal of the solvent by distillation, 1.31 g of 5-t-butyl-3-(4-chloro-2-fluoro-5-propargyloxyphenyl)-1,3,4-oxadiazol-2-one was obtained. Upon recrystallization from n-hexane, a compound having a melting point of 72°-73° C. was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].S(=O)(=O)(O)O.[O:10]=[C:11]1[O:17][C@H:16]([C@H:18]([CH2:20]O)[OH:19])[C:14]([OH:15])=[C:12]1[OH:13]>>[CH3:1][C:2]1([CH3:4])[O:19][CH:18]([CH:16]2[O:17][C:11](=[O:10])[C:12]([OH:13])=[C:14]2[OH:15])[CH2:20][O:3]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Yield: 115.4 %

Procedure:
With nitrogen substitution, 557.8 grams (9.6 moles) of acetone was cooled to −5 degrees C., 54.3 grams (0.2 moles) of 28% fuming sulfuric acid was dripped, and 176.1 grams (1.0 mole) of L-ascorbic acid was added. The mixture was then reacted at the temperature of the previous step for 17 hours, filtered and washed with cold acetone to obtain 249.5 grams of 5,6-O-isopropylidene-L-ascorbic acid (86.7% in purity) in the form of a wet cake.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6](O)[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)=[CH:15][CH:14]=1)[CH2:2][CH3:3].CN(C)C=O.S(Cl)([Cl:39])=O>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([Cl:39])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCc1nc(C)nc(O)c1Cc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Solvent: CN(C)C=O
Product: CCCc1nc(C)nc(Cl)c1Cc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g of 6-n-propyl-2-methyl-4-hydroxy-5-{[2'-(4,4-dimethyl-2-oxazolinyl)-4-biphenylyl]methyl}pyrimidine, prepared in Example 184, are dissolved in 3 ml of thionyl chloride. 0.1 ml of dimethylformamide is added and the mixture is stirred for 1 hour at room temperature. The thionyl chloride is evaporated off under vacuum without heating, and the residue is washed with ether, then alkalinised with ammonium hydroxide solution and washed with water. The ether phase is evaporated under vacuum to give 0.6 g of 6-n-propyl-2-methyl-4-chloro-5-{[2'-(4,4-dimethyl-2-oxazolinyl)-4-biphenylyl]methyl}pyrimidine in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [Br:1][C:2]([CH2:4]Br)=[CH2:3].[C:6]1([Mg]Br)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Mg].BrC1C=CC=CC=1.Cl>CC(C)=O.C(=O)=O.O.CCOCC>[Br:1][C:2]([CH2:4][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:3]
Reactant: C=C(Br)CBr
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: O=C=O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: Brc1ccccc1
Product: C=C(Br)Cc1ccccc1
Reaction time: 1 h

Procedure:
A 1000 ml 3-necked round-bottomed flask was fitted with a mechanical stirrer through a mineral oil sealed bearing, a reflux condenser and 1000 ml addition funnel. A mixture of 156 g of 2,3-dibromopropene and 150 ml of dry ethyl ether was added. The flask was cooled to 0° C. in acetone/dry-ice and a solution of phenyl magnesium bromide, prepared from 18.7 g of magnesium, 120.8 g of bromobenzene, and 350 ml of dry ether was added at such a rate so that the temperature did not exceed 15° C. The addition took about one hour. Stirring was continued and the acetone/dry-ice bath was replaced with a heating mantle. The mixture was gently refluxed for 2 hours, after which time the flask was again cooled and a solution of 15 ml 36% hydrochloric acid and 150 ml water was added dropwise by means of an addition funnel. The contents of the flask were then transferred to a separatory funnel, and the ether layer was separated and dried over anhydrous sodium sulfate.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([O:28][CH3:29])[C:17]=3[O:16][CH3:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3OC)nc2n(CC)c1=O
Yield: 57 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.3 g (13.9 mmol) of 2,3,4-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.85 g (yield 57% of Compound 79 as white crystals.