Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][N:38]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:37]1
Reactant: CN(C)C1CCNC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CN(C)C1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)C1
Yield: 9 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of N,N-dimethylpyrrolidin-3-amine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[O:10][C:11]2[C:12]([N:18]=1)=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1[CH:21]=[C:22]2[O:28]C(=O)N(C)C2=NC=1>>[C:22]([C:15]1[CH:16]=[C:11]2[O:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:18][C:12]2=[N:13][CH:14]=1)(=[O:28])[CH3:21]
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Reactant: Brc1cnc2nc(OCc3ccccc3)oc2c1
Product: CC(=O)c1cnc2nc(OCc3ccccc3)oc2c1

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 1 (coupling with 1-ethoxy-1-(trimethylstannyl)ethylene), 2-benzyloxy-6-bromooxazolo[4,5-b]pyridine from Preparation 4 being used instead of the 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one from Preparation 2. The yield obtained is 78%. ##STR49##
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[CH3:23][O:22][CH2:21][CH2:20][N:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:38]4[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)[CH3:19]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COCCN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COCCN(C)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperidin-4-amine was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 290. NMR (CDCl3): 1.63-1.70 (m, 2H, CH2), 1.78 (m, 2H, CH2), 2.09-2.15 (m, 2H, CH2), 2.36 (s, 3H, CH3), 2.50 (m, H, CH), 2.69 (m, 2H, CH2), 3.04-3.06 (m, 2H, CH2), 3.38 (s, 3H, CH3), 3.49 (m, 2H, CH2), 3.82 (s, 2H, CH2), 389-3.91 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 5.23 (s, 2H, NH2), 7.27 (s, H, ArH), 9.30 (s, 2H, 2×ArH). MS: (ESI+): MH+=499.29
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].[H-].[Na+].Br[CH2:37][C:38]([O:40]CC)=[O:39].[OH-].[Na+]>O1CCCC1.C(O)C>[F:1][C:2]([F:32])([F:33])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:37][C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)CBr
Reactant: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)COCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product of step (c) (750 mg) in tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in mineral oil, 91 mg). The reaction was stirred at 20° C. for 30 minutes then ethyl bromoacetate (335 μl) was added and the reaction was stirred for a further 15 hours. Ethanol (1 mL) was then added and the stirring continued for 5 minutes. Sodium hydroxide solution (2M, 10 mL) was added and the resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was then partitioned between dichloromethane (40 mL) and water (40 mL). The aqueous layer was acidified to pH 1 by the addition of hydrochloric acid (2M) and then extracted with dichloromethane (2×40 mL). The combined organic layers were dried and the solvent removed in vacuo to give the title compound as a yellow oil (612 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:25]O>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:23][N:25]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)on1
Reaction time: 24 h

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)-isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-]>CO>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cnccn1
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1CNCCN1

Procedure:
Analogously to Example 4, 5 g (27 mmol) of pyrazinecarboxylic acid tert-butylamide, 127 mg (0.27 mmol) of bicyclo[2.2.1]hepta-2,5-dienerhodium(I) chloride dimer and 353 mg (0.594 mmol) of 1-[1 (R)-(dicyclohexylphosphino)ethyl]-2(S)-(diphenylphosphino)ferrocene were hydrogenated for 20 hours in 70 ml of methanol at 100° C. and 50 bar. A conversion of 85 percent was determined by NMR. The enantiomeric excess (ee) was 49 percent according to GC analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:6][CH:7]=1.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:21][C:4]1[C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(Cl)cc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(Cl)cc2N)C1
Yield: 92.9 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(5-chloro-3-nitropyridin-2-ylamino)pyrrolidine-1-carboxylate (802 mg, 2.34 mmol) in MeOH (25 mL) and water (25 mL) were added iron dust (2.00 g, 35 mmol) and NH4Cl (1.25 g, 2.4 mmol). The mixture was heated at reflux for 6 h and filtered through Celite, washing with EtOAc. The filtrate was concentrated and the residue was dissolved in CH2Cl2 (150 mL) and 1 M aq NaOH (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined CH2Cl2 layer was washed with brine (50 mL), dried over Na2SO4 and concentrated to leave (R)-tert-butyl 3-(3-amino-5-chloropyridin-2-ylamino)pyrrolidine-1-carboxylate (680 mg, 93%) as a black solid. LC-MS Method 1 tR=1.28 min, m/z=313, 257.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine (261 mg, 2.58 mmol), 4-methoxyphenylsulfonyl chloride (320 mg, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 590 mg (88%) of the product as a solid. HR-MS: m/z Calculated for C24H72N8O8S2 522.1251; Found 522.1252.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[NH4+]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1=NCCc2ccccc21
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Product: CC1=NCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Methyl-3,4-dihydroisoquinoline (4.25 g, 29.3 mmol) was dissolved in ice cold concentrated sulfuric acid (15 ml) and to this was added potassium nitrate (3.25 g, 32.2 mmol) portionwise with cooling. The mixture was stirred overnight, poured over ice, basified with concentrated ammonium hydroxide, and the precipitated solid was collected, washed with water and dried: 4.47 g (80%), MS (M+H)+ 191, 1H NMR (D2O), 8.30 (d, 1H), 8.22 (dd, 1H), 7.39 (d, 1H), 3.80-3.62 (m, 2H), 2.92-2.70 (m, 2H), 2.48 (broad s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:16][CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:32]([OH:35])[CH:33]=[CH2:34]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:16][CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:34][CH2:33][CH:32]=[O:35])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCO
Reactant: CC(C)(C)OC(=O)N(CCc1c(Cl)cccc1Cl)Cc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(CCc1c(Cl)cccc1Cl)Cc1cccc(CCC=O)c1

Procedure:
[2-(2,6-Dichloro-phenyl)-ethyl]-(3-iodo-benzyl)-carbamic acid tert-butyl ester (506 mg), tetrabutylammonium chloride (280 mg), sodium bicarbonate (210 mg), allyl alcohol (100 μL) and toluene (20 mL) were charged to a flask, followed by palladium acetate (10 mg) and the resultant mixture heated to 80° C., under nitrogen for 5 hours. On cooling, the reaction was filtered, the filtrate diluted with toluene and extracted sequentially, twice with water, once with brine, dried (magnesium sulfate) and evaporated. Purification on silica, eluting with a gradient of iso-hexane/ethyl acetate [4:1 to 2:1], gave the subtitle product as an oil (300 mg).
Reaction SMILES: [CH2:1]([O:3]CCO)C.[C:7]([O:10][C:11]1[CH:18]=CC(C=C)=C[CH:12]=1)(=[O:9])[CH3:8]>C(OC1C=CC(C=C)=CC=1)(C)(C)C.COC(=O)C(N=NC(C)(C)C(OC)=O)(C)C.[OH-].C[N+](C)(C)C>[C:7]([O:10][CH:11]([CH3:18])[CH2:12][O:3][CH3:1])(=[O:9])[CH3:8]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CCOCCO
Agent: C=Cc1ccc(OC(C)(C)C)cc1
Agent: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Agent: C[N+](C)(C)C
Product: COCC(C)OC(C)=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 624.5 %

Procedure:
In a separable flask, 100 g of ethylene glycol monoethyl ether, 78.6 g of 4-acetoxystyrene, 21.4 g of 4-tert-butoxystyrene, and 3.7 g of dimethyl-2,2′-azobis(2-methylpropionate) as a polymerization initiator were charged and, after replacing the atmosphere in the separable flask with nitrogen, the reaction was conducted at 80° C. for 16 hours. To this reaction solution, 5 g of 25% tetramethylammonium hydroxide was added, followed by heating at 70° C. for 5 hours. To remove low-molecular weight oligomers and residual monomers, this solution was washed several times with methanol/deionized water mixed in arbitrary rate. After washing, the solvent in the solution was replaced with propylene glycol monomethyl ether acetate to obtain 400 g of a propylene glycol monomethyl ether acetate solution (solid content: 20%) of a 4-hydroxystyrene/4-tert-butoxystyrene polymer.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)CCn1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4.64 g (0.03 mol) of 6-chloropurine, 12.9 g (0.15 mol) of methyl acrylate, 0.3 g (0.002 mol) of finely ground potassium carbonate and 50 mL of dimethylsulfoxide was stirred at room temperature for 48 h. The solvent was removed by distillation (0.1 mm) and the residue was extracted with methanol. The insoluble salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was then dissolved in methanol, and petroleum ether was added to effect crystallization. Yield 3.71 g (51%); m.p. 93.5°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[O:17])[CH:6]([CH3:16])[C:7]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[N:8]O)[CH3:2].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[O:17][N:8]=[C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]=1[CH3:16])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C)C(=NO)C1CCCCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(C2CCCCC2)c1C
Temperature: 25 °C
Yield: 91.2 %

Procedure:
4-Cyclohexyl-4-hydroxyimino-3-methyl-2-oxo-butyric acid ethyl ester (3.1 g, 12.2 mmol) and concentrated sulfuric acid (3 mL) were added to 50 mL of absolute ethanol and the mixture was refluxed for 16 hours. After the mixture cooled to room temperature, saturated sodium bicarbonate solution was added to neutralize the mixture. The product was extracted with CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated to give 2.64 g of the title compound. MS: (+) m/z 238.38 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:24][CH3:25])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCO
Reactant: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (80 g) in ethanol (3.2 () was added dropwise conc. sulfuric acid (160 ml) over a period of 0.5 hour and the mixture was stirred for 2.5 hours at ambient temperature. Evaporation of ethanol gave a residue which was poured into ice-cold water (2.4 () and extracted with chloroform. The extract was washed with water and brine successively and evaporated to dryness to give ethyl 3-(4-hydroxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionate which was recrystallized from diisopropyl ether (87.05 g).
Reaction SMILES: [OH-].[Li+].[Si]([O:10][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.C(N)C(C)C.N(O)=[N+]=[N-].O1CCCCC1[O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.C1C=C(S(O)(=O)=O)C=C(N)C=1>CC(O)C.O>[OH:33][C:34]1[CH:35]=[C:36]([S:40]([OH:41])(=[O:42])=[O:10])[CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)(Cl)c1cccc(OC2CCCCO2)c1
Reactant: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: Nc1cccc(S(=O)(=O)O)c1
Agent: [Li+]
Agent: [N-]=[N+]=NO
Solvent: CC(C)CN
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)(O)c1cccc(O)c1

Procedure:
The synthesis of HIV protease inhibitor UIC-98-056 with hydroxyethylene and hydroxyethylamine isosteres is outlined in FIG. 3. The known lactone 1 was converted to acid 2 by lithium hydroxide mediated hydrolysis followed by protection of the alcohol functionality as tert-butyldimethylsilyl ether (Ghosh et al., 1998, Synthesis, 937 (Review); Ghosh et al., 1991, J. Org. Chem. 56:6500; Evens et al., 1985). The previously described (Ghosh et al., 1992, J. Chem. Soc., Chem. Co., 273; Ghosh et al., 1998, Synthesis, 937 (Review)) azido epoxide 3 was reacted with isobutylamine in 2-propanol at 80° C. for 4 h and the resulting azidoalcohol was treated with m-tetrahydropyranyloxybenzenesulfonyl chloride 4 (Metanilic acid was diazotized at 0° C. and the resulting salt was boiled with water to obtain 3-hydroxybenzene sulfonic acid which was then treated with thionyl chloride/catalytic DMF/reflux to obtain sulfonyl chloride. The hydroxy group of the resulting 3-hydroxybenzene sulfonyl chloride was protected as THP ether by treating with DHP/catalytic PPTS in methylene chloride to get 4 as an oil.) in the presence of aqueous NaHCO3 to provide the sulfonamide derivative 5. The azide functionality of 5 was hydrogenated over 10% Pd—C in methanol to afford the corresponding amine which was coupled with the acid 2 in the presence of 1-[3-dimethylaminopropyl]-3-ethylcarodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) to afford the amide 6. Removal of the BOC group by treatment with aqueous hydrochloric acid and alkoxycarbonylation of the resulting amine with the known (Ghosh et al., 1993a) mixed active carbonate 7 in methylene chloride in the presence of 3 equivalents of triethylamine (Et3N) 23° C. for 12 h afforded the inhibitor 8 (UIC-98-056).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[CH2:33][CH3:34]>ClCCl>[Cl:25][C:26]1[N:31]=[C:30]([NH:32][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:29]=[CH:28][C:27]=1[CH2:33][CH3:34]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CCc1ccc(N)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reaction time: 16 h
Yield: 69 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.08 g, 4.15 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Dichloromethane (10 mL), triethylamine (1.75 mL, 12.5 mmol), and 6-chloro-5-ethylpyridin-2-amine (4.15 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction mixture was then washed with a saturated aqueous solution of sodium chloride, evaporated to near dryness, and then purified on 40 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-chloro-5-ethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.09 g, 69%). ESI-MS m/z calc. 380.1, found; 381.0 (M+1)+Retention time 2.24 minutes.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][C:18](=[O:23])[NH:19][C:20]([CH3:22])([CH3:21])[C:13]2=[N:12][C:11]=1[C:24]([O:26]CC)=O)(=O)C1C=CC=CC=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:24]([C:11]2[N:12]=[C:13]3[C:20]([CH3:21])([CH3:22])[NH:19][C:18](=[O:23])[CH2:17][N:14]3[C:15](=[O:16])[C:10]=2[OH:9])=[O:26])=[CH:32][CH:31]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC(=O)NC2(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Intermediate 30, ethyl 3-(benzoyloxy)-9,9-dimethyl-4,7-dioxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxylate, (1 mmol), was dissolved in 4 mL of DMF. To this was added 4-fluorobenzylamine (0.457 mL, 4 mmol) and triethylamine (0.139 mL, 1 mmol). The mixture was warmed to 80° C. and allowed to stir overnight, after which it was allowed to cool to room temperature and transferred to a seperatory funnel. The mixture was diluted with ethyl acetate, washed with 1N HCl, dried over Na2SO4 then concentrated in vacuo. Methanol and ether were added to the residue and the resulting precipitate isolated by filtration. 1H NMR (500 MHz, DMSO) δ: 1.56 (s, 3H), 4.50 (m, 4H), 7.17 (m, 2H), 7.38 (m, 2H), 8.72 (brs, 1H), 9.37 (brm, 1H), 12.37 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=2)[NH:18][C:17]([C:29]([NH2:31])=O)=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:21]=2)[NH:18][C:17]([C:29](=[S:41])[NH2:31])=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 72.7 %

Procedure:
To a solution of 5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (3.0 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (3.0 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (2.26 g, yield 73%) as a yellow amorphous solid.