Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[O:4][CH2:3]1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:1]=[C:2]1[CH2:3][O:4][C@@H:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[C@H:6]([N+:8]([O-:10])=[O:9])[CH2:7]1
Reactant: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: C=C1CO[C@@H](c2cc(F)c(F)cc2F)[C@H]([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran (798 mg, 2.94 mmol) in chloroform (42 mL) and isopropyl alcohol (7.8 mL) was added silica gel (5.1 g), and sodium borohydride (420 mg, 11.1 mmol), and the reaction mixture stirred for 30 minutes at room temperature. The reaction mixture was then quenched by dropwise addition of hydrochloric acid (6 mL, 2/V) and filtered. The resulting solid residue was washed with ethyl acetate (100 mL). The combined filtrate was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The resultant amber oil (802 mg) was dissolved in tetrahydrofuran (15 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 40 μL) was added. The solution was stirred for 105 minutes and then transferred to a separatory funnel containing ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was washed with brine and the aqueous layer extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield a crude product which was purified by flash chromatography (silica, 8-10% ether in hexane) to yield trans-5-methylene-3-nitro-2-(2,4,5 trifluorophenyl)tetrahydro-2H-pyran. A portion of this product (388 mg) was resolved by HPLC (ChiralCel OD, 1.5% isopropyl alcohol in heptane) to yield the slower-moving enantiomer, (2R,3S)-5-methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([NH2:25])=O)=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23](=[S:36])[NH2:25])=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=S
Temperature: 55 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a solution (10 mL) of 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carboxamide (135 mg) in tetrahydrofuran was added Lawesson's reagent (156 mg), and the mixture was stirred for 3 hr at 55° C. After cooling to room temperature, the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and the title compound (120 mg, yield 86%) was m obtained as yellow amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 391 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:38][C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: ClCc1ccncc1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccncc5)cc4)cc3)n(C)c(=O)c12
Yield: 22.2 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (369 mg), 4-picolyl chloride hydrochloride (144 mg) and potassium carbonate (350 mg) in DMF (5 ml) was stirred at room temperature for 3 days. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate-chloroform to provide the title compound as colorless solid (99 mg).
Reaction SMILES: [Li].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=CC=1.C1([O:18]CC=C)C=CC=CC=1.C([Li])C=C.C1(=O)CCC=C1.CN(C)CCN(C)C.ICC#CCC>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.[Cu](I)I.CO>[CH2:10]([CH:9]1[CH2:8][CH2:7][C:6](=[O:18])[CH2:5]1)[CH:11]=[CH2:2]
Reactant: C=CCOc1ccccc1
Reactant: c1ccc2ccccc2c1
Agent: I[Cu]I
Agent: CCC#CCI
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Product: C=CCC1CCC(=O)C1
Reaction time: 0.75 h
Yield: 57 %

Procedure:
Lithium wire (2.1 g, 303 mmol) in small pieces in 26 ml of dry tetrahydrofuran containing a trace of naphthalene under argon was cooled to -15° and was treated with 3.32 g (24.8 mmol) of allyl phenyl ether in 14 ml of tetrahydrofuran containing a trace of naphthalene, with rapid stirring for 45 minutes. After an additional 1.25 hours at room temperature, 14.7 ml (ca. 6.6 mmol) of the allyllithium solution was added at -15° over 2 minutes to 635 mg (3.3 mmol) of copper iodide in 10 ml of tetrahydrofuran under argon with rapid stirring. After 5 minutes, the dark solution was of lithium diallylcuprate cooled to -78° and 245 mg (3.0 mmol) of cyclopentenone in 2 ml of tetrahydrofuran was added over 2 minutes. After 40 minutes at -78°, 1 ml of tetramethylethylenediamine was added followed 5 minutes later by 3.0 g (15.5 mmol) of 1-iodo-2-pentyne in 10 ml of hexamethylphosphoramide. After 2 additional hours at -78°, 1 ml of methanol was added and the mixture was poured into aqueous ammonium chloride-ammonium hydroxide-ether. After rapidly stirring for 15 minutes, the organic phase was separated and washed successively with aqueous sodium hydroxide, aqueous hydrochloric acid, aqueous sodium thiosulfate, and aqueous sodium chloride. After drying over potassium carbonate, the solvent was removed under reduced pressure and the resulting oil was chromatographed on silica gel using chloroform-hexane to afford 325 mg of 2-pentynyl, 3-allylcyclopentanone (57%).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:31]([O:33]CC)=[O:32])=[C:23]([C:25](=[O:30])[NH:26][CH2:27][CH2:28][F:29])[N:24]=3)[CH2:16][C@H:15]2[O:36][CH2:37][CH3:38])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]>CO>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:31]([OH:33])=[O:32])=[C:23]([C:25](=[O:30])[NH:26][CH2:27][CH2:28][F:29])[N:24]=3)[CH2:16][C@H:15]2[O:36][CH2:37][CH3:38])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCCF
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCO[C@@H]1CN(c2nc(C(=O)NCCF)c(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reaction time: 4.5 h
Yield: 41.7 %

Procedure:
A 2 N aqueous lithium hydroxide solution (1.92 mL, 3.83 mmol) was added to a solution of ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-4-[(2-fluoroethyl)carbamoyl]-1,3-thiazole-5-carboxylate obtained in Example (250a) (209 mg, 0.38 mmol) in methanol (4 mL) at room temperature, followed by stirring for 4.5 hours. The reaction solution was concentrated under reduced pressure, and then a 1 N aqueous hydrochloric acid solution was added to the resulting residue. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 82 mg of the title compound as a milk white solid (41%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1
Yield: 50 %

Procedure:
To 4-aminophenylacetic acid (Aldrich, 5 g, 33 mmol) in 50 mL of anhydrous methanol was added 2.5 mL of concentrated sulfuric acid cautiously. The mixture was heated to reflux for 4 h. The reaction was cooled to room temperature and neutralized with sodium carbonate. The volatiles were evaporated on a rotoevaporator and the residue triturated with chloroform (80 mL) and saturated sodium bicarbonate (100 mL). The chloroform layer was separated and filtered through a small pack of silica gel. The solvent was evaporated and the residue purified through vacuum distillation at 130°-150° C. to give 2.7 g (50%) of methyl 4-aminophenylacetate as a light brown syrup.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1)[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-])=O)[CH:11]=2)[N:6]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:3]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][CH:21]=1)[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:15])[CH:11]=2)[N:6]=1)[CH3:2]
Reactant: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc(N)ccc2n1
Reaction time: 3 h
Yield: 99.7 %

Procedure:
The product of part (A) (0.55 g) was catalytically hydrogenated similarly to Preparation 1(C) but using H2 over 5% Pd on C in ethyl acetate at 15 p.s.i. (103.4 kPa) for 3 hours, giving the title compound (0.51 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8].Br.CC(O)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:17][C:16]=1O.C([O-])([O-])=O.[Cs+].[Cs+]>CCCCC.CC(C)=O.CCOC(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:19][C:20]=1[O:8][CH2:7][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[CH3:1]
Reactant: CC1CCCC1CO
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1=C(COc2cc(Nc3nccs3)ccc2Cl)CCC1
Reaction time: 0.5 h
Yield: 3.6 %

Procedure:
To a solution of (2-methylcyclopent-1-yl)methanol (29 mg, 0.26 mmol) in pentane (0.7 mL) at 0° C. was added 45% HBr in AcOH (0.07 mL, 0.52 mmol). After having been stirred for 30 min, the reaction mixture was washed with brine, saturated aqueous NaHCO3, dried over MgSO4 and filtered with Et2O. This solution was added to a solution of 2-chloro-5-(thiazol-2-ylamino)phenol (59 mg, 0.26 mmol) and Cs2CO3 (85 mg, 0.26 mmol) in acetone (1 mL). After 4 h, the reaction mixture was diluted with AcOEt and washed with 5% aqueous NaOH solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel (hexane:EtOAc 8/2) to give the product (3 mg, 3% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[CH2:16]([O:15][C:11](=[O:14])[CH2:12][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:17]
Reactant: CCOC(=O)C=O
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNCCCN1CCOCC1
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
A solution of 4-(3-aminopropyl)morpholine (10.0 mL, 68.4 mmol) in MeOH (180 mL) was cooled in an ice bath and treated with ethyl glyoxylate (50% solution in toluene, 20.0 mL, 98.0 mmol) and HOAc (12 mL). After stirring for 15 min, NaBH3CN (4.81 g, 76.5 mmol) was added and the mixture was allowed to stir at 0° C. for 2 h. The mixture was diluted with saturated aqueous NaHCO3 (500 mL) and then extracted with EtOAc (5×300 mL) followed by CH2Cl2 (9×200 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (7.44 g, 47%) as a colorless oil: MS (ESI) m/e 231 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH:4]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:26][NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31]>>[CH3:26][N:27]([C:20]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:4]([C:5]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9]=2[CH3:10])[CH2:3][CH:2]([CH3:25])[CH3:1])=[CH:24][CH:23]=1)=[O:21])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)sc2ccccc12
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)sc2ccccc12

Procedure:
Using 4-{[3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}benzoic acid (300 mg) synthesized above and ethyl 3-(methylamino)propanoate (134 mg) and in the same manner as in Example A1(4), the title object compound (218 mg, 59%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[Li].C(O[C:12](=[O:18])[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])C.O>C(OCC)C>[CH3:17][N:15]([CH2:14][CH2:13][C:12]([C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)([C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)[OH:18])[CH3:16]
Reactant: ClC1=CCCCC1
Reactant: CCOC(=O)CCN(C)C
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCC(O)(C1=CCCCC1)C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-chloro-1-cyclohexene (5.8 g; 0.049 mol) was added to lithium (1.1 g; 0.049 mol) in diethyl ether (50 ml) in a single portion. After stirring overnight at room temperature, stirring was continued for 7 more hours with reflux. After cooling, ethyl-3-(N,N-dimethylamino)propionate (3.0 g; 0.021 mol) was added and as a result of the exothermic reaction refluxing occurred. After cooling to room temperature and stirring for another 30 minutes 100 ml of water was added. The water layer was separated off and extracted with diethyl ether. The combined ether layer was dried (K2CO3), filtered and evaporated. The yield was 4.5 g (83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH:6]=O)[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=1.C(#N)C.C(O)C>C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C:5]1[N:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]2=[N:9][CH:6]=1)=[O:8])[CH3:2]
Reactant: Nc1ccc(I)cn1
Reactant: CCOC(=O)CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)c1cnc2ccc(I)cn12
Yield: 78 %

Procedure:
Reflux a solution of 3-oxo-propionic acid ethyl ester (J. Med. Chem. 2001, 44(12), 1193-2003; 3.4 g, 23.7 mmol) and 2-amino-5-iodopyridine in 1:1 acetonitrile/ethanol (100 mL) overnight. Dilute with saturated aqueous sodium bicarbonate, extract into dichloromethane (4×100 mL), combine organics, and concentrate. Flash chromatography using appropriate ethyl acetate/hexane mixtures gives 3.7 g (78%) of the subtitled compound as an off-white solid. ES+ m/e 316.7 (M+1).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH2:13]>>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 1.5 h

Procedure:
To 200 g of Chinese milk vetch honey was added 300 g of water followed by addition of 0.5 g of an enzyme preparation containing glucose oxidase (60 units/mg) and catalase (390 units/mg) activities and the reaction was carried out at 23° C. under aerobic conditions for 90 minutes to provide a gluconic acid-containing honey. The result of assay of gluconic acid in this reaction mixture by high performance liquid chromatography is shown in Table 10. This product has a refreshing gustatory quality possessing both a sour taste and a sweet taste.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].O.CCOC(C)=O>[O:7]1[CH2:10][CH2:11][O:12][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[N:3][CH:4]=1
Reactant: OCCO
Reactant: O=Cc1ccc(F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(C2OCCO2)cn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
6-Fluoronicotinaldehyde (Asymchem Laboratories, Inc., Morrisville, N.C., 3.035 g, 24.26 mmol) was suspended in toluene (80 mL) and ethylene glycol (1.40 mL, 25.1 mmol) and p-toluenesulfonic acid (Acros Organics, Geel, Belgium, 12% in acetic acid, 0.15 mL) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (120° C.) and stirred under nitrogen for 20 minutes. At this time, the reflux condenser was replaced with a Dean-Stark trap, and stirring was continued at 120° C. for 25 minutes. Then, the reaction was cooled and diluted with saturated sodium bicarbonate solution (20 mL) (before it had cooled to room temperature). The reaction was then diluted with water (20 mL) and EtOAc (30 mL). The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (about 3 inches, 40:1 DCM/MeOH to 30:1 DCM/MeOH) to afford 5-(1,3-dioxolan-2-yl)-2-fluoropyridine (3.858 g), which was taken on to the next step. MS (ESI pos. ion) m/z 170 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[CH2:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:18]=[O:19])[CH:13]=[CH2:14]>CC(C)=O>[CH2:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:4][CH2:3][CH2:2][Br:1])[CH:18]=[O:19])[CH:13]=[CH2:14]
Reactant: BrCCCBr
Reactant: C=CCc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C=O)ccc1OCCCBr
Temperature: 25 °C

Procedure:
1,3-Dibromopropane (15.76 ml) and potassium carbonate (4.69 g) were added to a solution of 3-allyl-4-hydroxybenzaldehyde (5 g) in acetone and the reaction mixture heated at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue purified by flash column chromatography on silica gel (Merck Art No 9385) using a 10:90 (v/v) mixture of ethyl acetate/hexane as eluent to give 3-allyl-4-(3-bromopropoxy)benzaldehyde (4.86 g) as an oil which slowly solidified. NMR([CD3 ]2SO): 2.2-2.4(2H,m), 3.35-3.50(2H,m), 3.65-3.80(2H,t), 4.2-4.3(2H,t), 5.0-5.15(2H,m), 5.8-6.1(1H,m), 7.15-7.25(1H,d), 7.7(1H,d), 7.75-7.85(1H,q) and 9,85(1H,s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:5]([NH:13]C(=O)C(F)(F)F)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[OH-].[Na+]>O1CCOCC1.CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:5]([NH2:13])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: O=C(Nc1c(C2CCCO2)cc(Br)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: Nc1c(C2CCCO2)cc(Br)cc1[N+](=O)[O-]
Yield: 101.3 %

Procedure:
N-(4-bromo-2-nitro-6-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide (6) (54.00 g, 140.9 mmol) was dissolved in 1,4-dioxane (162 mL) and added aqueous 6 M NaOH (70.45 mL, 422.7 mmol, JT-Baker 567202). The reaction mixture was stirred at reflux for 2 days (HPLC showed complete conversion). The mixture was allowed to cool, diluted with MTBE (800 mL), and washed with water (2×200 mL), saturated aqueous NH4Cl, water, and brine. The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure to give (6a) as a dark amber oil (40.96 g, 93% yield; overall 92% HPLC plus NMR purity). LCMS (C18 column eluting with 10-90% MeOH/water gradient from 3-minutes with formic acid modifier) M+1: 287.28 (3.44 min). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 6.91 (s, 2H), 4.80 (t, J=7.2 Hz, 1H), 4.14-4.05 (m, 1H), 3.98-3.90 (m, 1H), 2.36-2.19 (m, 1H), 2.15-2.01 (m, 3H) ppm.
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:13][C@:14]([CH3:50])([CH2:48][OH:49])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([S:9]([O:49][CH2:48][C@:14]([OH:13])([CH3:50])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: CCCCCCCCS(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COC)NC(=O)[C@H](COC)NC(=O)c1cnc(C)s1

Procedure:
Prepared according to procedures described above, by reacting octanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C33H50N4O10S2 m/z: 727 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: Brc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4ccc(Br)cc4C3)c(F)cc2c1=O
Yield: 16.5 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 119 mg of 5-bromoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 44 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:8]([OH:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:14]([O-])([OH:16])=[O:15]>C[N+]([O-])=O>[Cl:12][C:9]1[C:10]([CH3:11])=[C:2]([Cl:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([N+:14]([O-:16])=[O:15])[C:8]=1[OH:13]
Reactant: Cc1c(Cl)c(O)cc(C(=O)O)c1Cl
Reactant: O=[N+]([O-])O
Solvent: C[N+](=O)[O-]
Product: Cc1c(Cl)c(O)c([N+](=O)[O-])c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
2,4-Dichloro-5-hydroxy-3-methylbenzoic acid (90 mg, 0.41 mmol) was mixed with CH3NO2 (9 mL) and heated to 40 --C. To the solution was added HNO3 (20 μL, 90%, 0.43 mmol) and the reaction mixture was stirred at room temperature for 4 h. Evaporation of the solvent followed by vacuum-drying over KOH gave 112 mg of a crude product. Purification by flash column chromatography (SiO2, EtOAc-HOAc 30:1) afforded 79 mg of the title compound. Mp: 199° C. (dec); 1H NMR (DMSO-d6): δ 2.45 (s, 3H); 13C NMR (DMSO-d6): δ 164.27, 147.05, 139.61, 136.27, 128.35, 126.46, 118.87, 18.62; MS (EI, 70 eV): m/z (rel.int.) 267/265 (M+, 66/100), 249/248 (67/85), 205/203 (28/54).