Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:20])=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(N)=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.79 mmol) in 5 mL of dry tetrahydrofuran is added 1,1'-carbonyldiimidazole (167 mg, 1.03 mmol). The reaction solution is heated at reflux for 1 hour then cooled to room temperature. Aqueous ammonium hydroxide (3 mL) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with 1N HCl, saturated aqueous sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxamide in 84% yield; mp=154°-155° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:18])([F:17])[C:7]([NH:9][C@@H:10]1[C:15](=[O:16])[O:14][C:12](=[O:13])[CH2:11]1)=[O:8].[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1>ClCCl>[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[C:12](=[O:13])[CH2:11][C@H:10]([NH:9][C:7](=[O:8])[C:6]([F:5])([F:18])[F:17])[C:15]([OH:16])=[O:14]
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
To a dichloromethane (50 mL) suspension of aluminum chloride (3.19 g, 0.024 mol) at 0° C., under an inert nitrogen atmosphere was added via a solid addition funnel an intimate mixture of N-trifluoroacetyl-L-aspartic acid anhydride (3.01 g, 0.0142 mol) and dibenzofuran (2 g, 0.0119 mol). The resulting brick-red suspension was allowed to warm to room temperature over 12 hours. The reaction mixture was poured into ice water (250 mL), and the resulting colorless biphasic mixture was extracted with ethyl acetate (4×100 mL). The combined organic extracts were washed with water (2×100 mL), brine (2×100 mL) and dried over magnesium sulfate. The mixture was filtered, and the organic solution was concentrated by evaporation of the solvent in vacuo to yield a white solid. The solid was recrystallized from 10% ethyl acetate/hexane (v/v) to give (S)-4-dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid (2.16 g, 48%) as a while solid; mp 174-176° C.
Reaction SMILES: [C:1]1([C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])=[N:2]O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:2][C:1]1[C:4]([OH:5])=[N:6][C:7]([OH:8])=[N:9][C:10]=1[OH:11]
Reactant: O=C1NC(=O)C(=NO)C(=O)N1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1c(O)nc(O)nc1O
Temperature: 70 °C
Yield: 82.3 %

Procedure:
100 g of violuric acid was added to 1 liter of water with vigorous overhead stirring and heated to 70° C. 200 g sodium hydrosulfite was added in portions over 15 minutes. After 2.5 hours the reaction was filtered and the precipitate rinsed with water. The solid was dried under vacuum at 98° C. for 3 hours to yield 75 g of 5-amino-2,4,6-trihydroxy-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH:11]2[O:22][CH:10]2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12]
Reactant: CC1(C)C=Cc2ccccc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C(=O)c2ccccc2C2OC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3 g (17.4 mmol) of 2,2-dimethyl-1-oxo-1,2-dihydronaphthalene (L. H. Klemm, J. Shabtai, D. R. Taylor, J. Org. Chem., 1968, 33, 1480) in 30 ml of CH2Cl2, were added 6.00 g (19.1 mmol) of m-chloroperbenzoic acid dissolved in 90 ml CH2Cl2 and the resulting mixture was stirred overnight at room temperature. The resulting solution was washed successively with Na2S2O5 and NaHCO3 solutions and dried over MgSO4. The solvent was removed to yield 3.27 g of a crude that was chromatographed on silica gel eluting with hexane-CH2Cl2 mixtures of increasing polarity. 2.09 of the title compound of this preparation were obtained as a colorless oil (yield: 64%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].S(=O)(=O)(O)O>>[C:12]([O:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(Br)cc1O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cc(Br)ccc1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-hydroxy-benzoic acid (12.35 g, 56.91 mmol), acetic anhydride (35.6 mL) and conc sulfuric acid (0.93 mL) was heated at 100° C. for 1 h; then cooled, poured into 400 g ice/water, stirred for several minutes, the white precipitates were collected with filtration, washed with water, then the white solids were oven vacuum dried at 50° C. for 3 days to give the desired product (11.62 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.95 (d, 1H, J=8.5 Hz), 7.48 (dd, 1H, J=2.0 Hz, 8.5 Hz), 7.32 (d, 1H, J=2.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(O)C.[Ni]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 5-chloro-2-nitrobenzoic acid (20 g, 110 mmol) in ethanol was added freshly activated raney nickel (2 g). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The solution was filtered through celite and evaporated under reduced pressure to yield 16 g (96%) of white solids. 1H NMR (DMSO-d6): δ 6.77 (d, J=8.9 Hz, 1H), 7.24 (dd, J=2.9, 8.9 Hz, 1H), 7.62 (d, J=2.9 Hz, 1H), 8.7 (b, 3H); EIMS: 170 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:40][CH:37]3[CH2:38][CH2:39][CH:34]([C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=4)[CH2:35][CH2:36]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NC1CCC(c2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccc(Cl)cc5)CC4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), N,N-dimethylpyridin-4-amine (0.0016 g, 0.013 mmol), and 4-(4-chlorophenyl)cyclohexanamine (0.042 g, 0.20 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.031 g, 0.16 mmol), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 65 mg of the title compound (86% yield).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:28]([O-:30])=[O:29])=[C:12]([CH2:15][O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[CH2:39](O)[CH3:40]>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:28]([O:30][CH:17]([C:40]3[CH:39]=[CH:5][CH:4]=[CH:33][CH:37]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:29])=[C:12]([CH2:15][O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CCO
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(=O)c3ccc([N+](=O)[O-])cc3)CS[C@H]12)c1csc(N)n1
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)c3ccc(N)cc3)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h

Procedure:
Platinic oxide (0.4 g.) was added to a solution of benzyhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-nitrobenzoyloxymethyl)-3-cephem-4-carboxylate (syn isomer) (4.3 g.) in a mixture of ethanol (50 ml.) and tetrahydrofuran (50 ml.), and the suspension was subjected to catalytic reduction at ambient temperature under ordinary pressure for 3 hours. After removing the catalyst from the resultant mixture by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-aminobenzoyl-oxymethyl)-3-cephem-4-carboxylate (syn isomer) (3.0 g.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH2:7][CH2:8][CH3:9])[NH2:6].[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([F:22])[CH:21]=1)[CH2:18][C:17](=O)[CH2:16][CH2:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[C:20]([F:22])[CH:21]=[C:12]([F:11])[CH:13]=2)[CH2:18]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](N)C(=O)OC
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine L-norvaline methyl ester-hydrochloride (1 equiv) with 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (1 equiv) in methylene chloride and stir 30 min. and add sodium triacetoxy borohydride (1.1 equiv) and stir at rt overnight. The reaction is quenched with aqueous sodium bicarbonate, extracted with methylene chloride, dried, and concentrated. The resultant material is purified by silica gel chromatography to afford the separated diastereomers of 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid methyl ester: Diastereomer 1; 13C NMR (100 MHz, CDCl3) 14.0, 19.4, 27.7, 28.2, 29.5, 29.6, 36.3, 51.1, 58.7, 100.7, 100.9, 101.2, 110.5, 110.7, 110.8, 118.5, 118.6, 141.1, 159.7, 159.8, 162.1, 176.7; MS m/z 298.3 (M+1). Diastereomer 2; Diagnostic 13C NMR (100 MHz, CDCl3) 14.0, 19.3, 28.3, 28.4, 28.5, 30.3, 36.4, 51.1, 52.0, 58.5, 100.7, 100.9, 101.2, 110.5, 110.7, 176.8; MS m/z 298.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][C:9]([Cl:16])=[O:10])[CH:7]=1
Reactant: O=C(O)Cc1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-chlorophenylacetic acid (2.0 g) obtained in Reference Example 125-(3) was dissolved in dichloromethane (40 ml), and thereto were added oxalyl chloride (0.77 ml) and N,N-dimethylformamide (one drop) at 0° C. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetyl chloride, which was used in the subsequent step without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31][CH3:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31][CH3:32])=[CH:26][C:23]=1[CH:24]([OH:25])[C:9]#[C:8][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1cc(C=O)c(OC)cc1C
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cc(C(O)C#Cc2ccccc2)c(OC)cc1C
Yield: 98 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,5-dimethoxy-4-methyl-benzaldehyde (1.00 g, 5.55 mmol) was reacted to give the title compound (1.54 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.34 (m, 5H), 7.16 (s, 1H), 6.86 (s, 1H), 5.98-5.94 (d, 1H), 5.77-5.74 (d, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9].[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[CH2:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([CH3:1])[C@@H:3]1[C:8]([OH:10])=[O:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CCCN[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1CCCN(C(=O)OCc2ccccc2)[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(+/−)—Cis-3-methylpiperidine-2-carboxylic acid (10.4 g, 72.9 mmol) in 1,4-dioxane (200 mL) and 1 N NaOH (218 mL, 219 mmol) was treated with CBzCl (15.4 mL, 109 mmol) and stirred for 18 h. The mixture concentrated and the resulting solid was suspended in EtOAc (200 mL) and the mixture was filtered. The solids were washed with EtOAc (3 50 mL) and the solution was dried over MgSO4. The solution was concentrated to afford (+/−)-cis-1-(benzyloxycarbonyl)-3-methylpiperidine-2-carboxylic acid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:39])[N:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]([CH2:30][CH2:31]O)[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[O:45]=[C:43]1[C:42]2[C:41](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40](=[O:50])[N:44]1[CH2:31][CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22]([NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)=[O:23])[C:25](=[O:39])[N:26]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCO)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCN5C(=O)c6ccccc6C5=O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.20 g, 0.38 mmol) and phthalimide (0.11 g, 0.76 mmol) in 10 mL of CH2Cl2 was added triphenyl phosphine (0.13 ml, 0.57 mmol), followed by diethyl azodicarboxylate (0.089 ml, 0.57 mmol) via a syringe. The reaction mixture was stirred at RT for 16 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc to 10% MeOH/EtOAc) to give the title compound as a light yellow solid (0.22 g, 88% yield). MS (ESI pos. ion) m/z: 658 (MH+). Calc'd exact mass for C37H28FN5O6: 657. 1H NMR (300 MHz, MeOH) 8.53 (1H, d, J=5.5 Hz), 8.28 (1H, d, J=9.0 Hz), 7.80-7.91 (5H, m), 7.50 (1 H, s), 7.48 (2H, d, J=3.0 Hz), 7.26-7.36 (6H, m), 6.49 (1H, dd, J=5.4, 1.0 Hz), 4.27 (2H, t, J=5.5 Hz), 3.97 (3H, s), 3.74 (2H, t, J=5.5 Hz), 2.68 (3H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=O)[CH2:10][CH:11]([C:16]([CH3:18])=O)[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(O)(=O)C>[F:22][C:23]1[CH:29]=[CH:28][C:26]([N:27]2[C:16]([CH3:18])=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]2[C:8]2[CH:20]=[CH:21][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Yield: 92 %

Procedure:
3.00 g (9.6 mmol) of methyl 2-(4-methylsulfonylphenacyl)acetoacetate [prepared as described in step (ii) above] were dissolved in 100 ml of acetic acid and 0.97 g (8.7 mmol) of 4-fluoroaniline was added to the resulting solution. The resulting mixture was then heated under reflux for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 1:2 by volume mixture of ethyl acetate and hexane, to give 3.10 g of the title compound as a white powder (yield 92%), melting at 154-155° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[K+].[Br-]>>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[C:16]([F:15])([F:25])[F:26])([CH3:10])([CH3:11])[CH3:12]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)Nc1c(NCc2ccccc2C(F)(F)F)c(=O)c1=O
Yield: 73 %

Procedure:
The title compound was prepared according to the procedure for example 1-step 2 except that 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione was used in place of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione and 2-trifluoromethyl-benzylamine was used in place of 4-fluoro-benzylamine. Yield: 73%; mp: 237-239° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.37 (m, 9H), 4.81-4.88 (m 2H), 7.56-7.61 (m, 2H), 7.63-7.83 (m, 4H); IR (KBr, cm-1 ): 3299m, 3224m, 3040w, 2976w, 2940w, 1796m, 1670m, 1650m, 1576s, 1534s, 1468s, 1315s, 1216-1127brm; MS (ES) m/z (relative intensity): 349 (M+ +Na, 20), 327 (M+ +H, 100); Anal. Calcd. for C16H17F3N2O2 : C, 58.89; H, 5.25; N, 8.58. Found: C, 58.84; H, 5.28; N, 8.54.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:31]5[C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]=[CH:29][CH:30]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (104 mg, 86%), MS (ISP) m/z=486.5 [(M+H)+], mp 210° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[Br:13]C1C=CC(O)=CC=1.C(O)(C)(C)C.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl>[Br:13][C:3]1[CH:2]=[CH:7][C:6]([OH:8])=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Using the same general procedure as for the preparation of 5-bromo-2t-butylphenol (Compound D), but instead using 50.00 g (289.0 mmol) of 4-bromophenol, 21.40 g (27.25 ml, 289.0 mmol) of t-butanol, 14.0 ml of conc. sulfuric acid (added slowly) and 140 ml of distilled carbon tetrachloride, stirred at room temperature for 24 hours produced a dull green-colored solution and a white precipitate. At this time an additional 3.5 ml of conc. sulfuric acid was added and the solution was allowed to stir for 4 days at room temperature. After aqueous workup, a dark yellow oil was isolated. Purification by flash chromatography (silica, 2% ethyl acetate in hexane) yielded the title compound as a clear, light yellow oil. PMR (CDCl3): d 1.38 (9H, s), 4.79 (1H, s), 6.54 (1H, d, J=8.5 Hz), 7.16 (1H, dd, J=8.5, 2.5 Hz), 7.35 (1H, d, J=2.5 Hz).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:9]([OH:10])[CH2:8]1.[OH-].[K+].[Br:39][C:40]1[S:41][C:42]([CH2:47]Cl)=[C:43]([Br:46])[C:44]=1[Br:45]>O1CCOCC1>[F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][OH:13])[C@@H:9]([O:10][CH2:47][C:42]2[S:41][C:40]([Br:39])=[C:44]([Br:45])[C:43]=2[Br:46])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: ClCc1sc(Br)c(Br)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3sc(Br)c(Br)c3Br)[C@@H](CO)O2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 5.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 100 ml of dioxane were added 5.74 g of fine powder of potassium hydroxide and 5.65 g of 2,3,4- tribromo-5-chloromethylthiophene, and the mixture was stirred at a temperature of 80° C. for 2 hours. The reaction mixture was concentrated and the residue was dissolved in 100 ml of ethyl acetate. The solution was washed with aqueous solution of acetic acid, dried and concentrated. To the residue was added 100 ml of 80% acetic acid and the mixture was left to stand at a temperature of 80° C. for one hour. The solvent was distilled off and the residue was placed on silica gel column and eluted with 2% methanol-chloroform for purification, giving 1.07 g (18%) of the desired 2'-deoxy 5-fluoro-3'-O-(3,4,5-tribromo-2-thenyl)uridine.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].O=[CH:8][C@@H:9]([C@H:11]([C@@H]([C@@H](CO)O)O)O)O>>[C:1]([O:4][CH2:5][CH2:6][CH:9]([CH3:11])[CH3:8])(=[O:3])[CH3:2]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCOC(C)=O
Product: CC(=O)OCCC(C)C
Reaction time: 120 h

Procedure:
Liquid rich medium high in glucose content (10 ml PS-medium in 25 ml tube) was inoculated with the appropriate yeast strain and grown overnight at 30° C. 1-2 ml of this culture containing 107 cells was used to inoculate 50 ml fresh medium in a 250 ml conical flask. The culture was incubated at room temperature for 5 days with agitation (90 rpm.). Yeast cells were sedimented overnight at 4° C. and the supernatant discarded. 50 ml fresh medium was added to the cells and 2. generation fermentation performed as above. 25 ml supernatant from the fermentation was delivered for GC-headspace analysis (see below) to determine the content of esters and alcohols. The results are shown in Table 5.5. The yeast strains carrying inactive alcohol acetyltransferase genes produced a reduced amount of acetate esters such as ethyl acetate and isoamyl acetate in comparison to the MBP94-21 strain.