Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:19](=[O:31])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:3][C:4](=[O:7])[O:5][N:46]=3)=[CH:37][CH:38]=2)[C:19](=[O:31])[C:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A mixture of hydroxylammonium chloride (2.62 g), sodium hydrogen carbonate (3.72 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-(4-fluorophenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.54 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.81 g, 72%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
Under a nitrogen atmosphere, 4.5 mL (0.043 mole) of t-butylamine was added to a solution of 7.7 grams (0.035 mole) of 4-bromobenzoyl chloride in 75 mL of tetrahydrofuran. To this was added dropwise 6.7 mL (0.048 mole) of triethylamine. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours, after which it was poured into 50 mL of water, and the organic layer was separated. The aqueous layer was extracted with one 50 mL portion of diethyl ether. The combined organic layer and extract were washed with two 25 mL portions of water, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 8.4 grams of N-t-butyl-4-bromobenzamide, mp 126-128° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Temperature: 4 °C
Yield: 55.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (4.6 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-chloro-1,8-naphthyridine (3.6 g). The product produced by precipitation in water (4.3 g; m.p. 208° C.) is dissolved in boiling acetonitrile (660 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-4-methoxybenzamide (3.5 g) is produced, m.p. 208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]1[N:22]=[C:21]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH2:30][OH:31])[CH2:25]2)[O:20][N:19]=1.[CH3:32][NH:33][C:34](=[O:37])[CH2:35]Cl.C(N(CC)C(C)C)(C)C.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:8]=[C:7]2[C:18]1[N:22]=[C:21]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH2:35][C:34](=[O:37])[NH:33][CH3:32])[C@H:26]([CH2:30][OH:31])[CH2:25]2)[O:20][N:19]=1
Reactant: CNC(=O)CCl
Reactant: OC[C@@H]1CN(Cc2nc(-c3cn(CC4CCOCC4)c4c(Cl)cccc34)no2)CCN1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCN(Cc2nc(-c3cn(CC4CCOCC4)c4c(Cl)cccc34)no2)C[C@H]1CO
Yield: 93.9 %

Procedure:
A mixture of (S)-7-chloro-3-[5-(3-hydroxymethylpiperazin-1-ylmethyl)-[1,2,4]-oxadiazol-3-yl]-1-[(tetrahydropyran-4-yl)methyl]-1H-indole (22 mg, 0.049 mmol), N-methyl-2-chloroacetamide (11 mg, 0.098 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol) and sodium iodide (7 mg, 0.049 mmol) in dimethylformamide (2.0 ml) was subjected to microwave irradiation at 160° C. for 5 minutes. The mixture was filtered through a 5 g Strata™ SCX giga tube, eluting with dichloromethane, methanol and then 2 M ammonia in methanol, and purified by flash column chromatography eluting with ethyl acetate to 33% (v/v) methanol in ethyl acetate to afford the title compound (23.9 mg, 0.046 mmol). EsIMS: m/z 539.8, 517.5 [M+H]+, 503.1, 200.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)=[CH:12][C:11]([C:25](O)=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:23])([F:22])[F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=[O:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OC(F)(F)F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 78A in analogy to the synthesis of the compound of Example 1. 53 mg (91% of theory) of the title compound are obtained.
Reaction SMILES: C([N-][CH:5]([CH3:7])C)(C)C.[Li+].[Si:9]([N:16]1[CH:19]([CH2:20][CH2:21][O:22]C(=O)C)[CH2:18][C:17]1=[O:26])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[OH2:27].[Cl-].[Na+]>O1CCCC1>[Si:9]([N:16]1[CH:19]([CH2:20][CH2:21][OH:22])[CH:18]([C:5](=[O:27])[CH3:7])[C:17]1=[O:26])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: O
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1CCO

Procedure:
To a solution of 1.1 equivalents of freshly prepared lithium diisopropylamide in 3 ml anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° is added a solution of 1-(t-butyldimethylsilyl)-4-(2'-acetoxyethyl)-2-azetidinone (61 mg, 0.225 mmole) in 1 ml anhydrous tetrahydrofuran which has been cooled to -78°. After 12 minutes the reaction mixture is poured into 5 ml water. The solution is saturated with sodium chloride and extracted with methylene chloride. The combined methylene chloride solutions are washed with brine, dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives 50 mg of crude product. Purification by preparative thick-layer chromatography on silica gel developing with ethyl acetate gives 1-(t-butyldimethylsilyl)-3-acetyl-4-(2'-hydroxyethyl)-2-azetidinone (19 mg).
Reaction SMILES: O.[C:2](=[O:5])([O-])[O-:3].[K+].[K+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([N:25]4C(=O)[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]4=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]#[N:48])=[CH:12][CH:11]=1)#[N:9].Cl>C(O)C>[C:47]([C:17]1[CH:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=2)[N:21]2[N:22]=[C:23]([NH:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:2]([OH:3])=[O:5])=[O:35])[N:24]=[C:20]2[N:19]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:43])[F:45])[CH:37]=2)[C:18]=1[CH3:46])#[N:48]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(NC(=O)c3ccccc3C(=O)O)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 55 °C
Yield: 96.1 %

Procedure:
Water (0.5 ml) and potassium carbonate (8.1 mg, 59 mmol) were added to a solution of 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25.0 mg, 45.3 μmol; Example 3) in ethanol (3.4 ml). In a closed pressure-proof glass tube, the reaction mixture was heated at 55° C. For complete conversion, more potassium carbonate was added in two separate portions (5 mg, 36 mmol in total), and the mixture was once more heated at 55° C. 1 N hydrochloric acid (180 μl, 180 mmol) was then added, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→100:0). This gave the product as a solid (24.8 mg, 96% of theory).
Reaction SMILES: [C:1]([O:5][C:6](ON=C(C(C)=O)C(OCC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.O>[C:1]([O:5][C:6]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(=NOC(=O)OC(C)(C)C)C(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A solution of ethyl 2-tert-butoxycarbonyloxyiminoacetoacetate (646 mg.) in a mixture of tert-butyl alcohol (5 ml.) and water (5 ml.) was added at once to a solution of L-phenylalanine (330 mg.) and triethylamine (0.28 ml.) in a mixture of tert-butyl alcohol (8 ml.) and water (8 ml.) at room temperature. The mixture was stirred for 2 hours at room temperature. Water (100 ml.) was added to the reaction mixture and the mixture was adjusted to pH 7 with a 0.5M citric acid aqueous solution and washed twice with ethyl acetate (40 ml). The aqueous layer was adjusted to pH 3 with a 0.5M citric acid aqueous solution, followed by addition of a sodium chloride aqueous solution, and extracted twice with ethyl acetate (40 ml.). The extract was washed with water and dried. The solvent was distilled off under reduced pressure to give N-tert-butoxycarbonyl-L-phenylalanine (286 mg.).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[N:29]1([CH2:34][CH2:35][CH2:36][C:37](=O)[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:33]=[CH:32][N:31]=[CH:30]1>C(O)(=O)C>[CH3:28][O:27][C:22]1[CH:21]=[C:8]2[C:7](=[CH:24][C:23]=1[O:25][CH3:26])[N:6]=[C:37]([CH2:36][CH2:35][CH2:34][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: CCOC(=O)CC(=O)CCCn1ccnc1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCCn2ccnc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Conc. sulfuric acid (0.03 ml) was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (453 mg), ethyl 6-(1-imidazolyl)-3-oxohexanoate (320 mg) and acetic acid (5 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, and the mixture was made alkaline with 2N sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/methanol (50/1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[3-(1-imidazolyl)propyl]quinoline-3-carboxylate (310.0 mg, 43%) which was then recrystallized from ethyl acetate-hexane. Colorless prisms. mp. 164°-165° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C.C1(C)C=CC=CC=1.CO>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([OH:6])[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous sodium bicarbonate (1 g, 12 mmol) was added to a solution of 2,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) in 50 mL of acetonitrile and the mixture was stirred for 1 hour at RT. Benzylbromide (1.2 mL, 10 mmol) was added and the mixture was refluxed for 6 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated and it was recrystallized from methanol (ca. 40 mL) to obtain (1.82 g, 80 of P1 as a white powder: mp 78-80° C.; TLC Rf 0.88 in toluene:methanol (10:1); 1H NMR (600 MHz, acetone-d6) δ 11.41 (s, 1H, OH), 9.81 (s, 1H, CHO), 7.67 (d, 1H, J=8.4 Hz, Ar—H6), 7.45-7.35 (m, 5H, C6H5), 6.70 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5), 6.56 (d, 1H, J=1.8 Hz, Ar—H3), 5.24 (s, 2H, PhCH2).
Reaction SMILES: C([O:3][C:4]([NH:6][C@@H:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:9])=O)C.C([Li])CCC.C(O)(=O)C>C1COCC1.CCCCCC>[C:10]1([C@H:7]2[CH2:8][O:9][C:4](=[O:3])[NH:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)N[C@H](CO)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1N[C@@H](c2ccccc2)CO1
Temperature: 0 °C
Yield: 63 %

Procedure:
To a stirred, 0° C. solution of L-phenylglycine (25.3 g, 167.4 mmol) in 60 mL of 3N aqueous NaOH was added ethyl chloroformate (8 mL) in several portions. Additional 3N aqueous NaOH (35 mL) was added to redissolve the precipitated phenylglycine, followed by ethyl chloroformate (4 mL). This process was continued with 3N aqueous NaOH (65 mL) and ethyl chloroformate (8 mL, total of 20 mL, 209 mmol) over a period of ca. 10 minutes. After stirring for 1 hour at 0° C. the solution was acidified with 6 M H2SO4, and the precipitated carbamate was extracted into 8% isopropanol in dichloromethane (2×300 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford 37.3 g of N-ethoxycarbonyl L-phenylglycine as a white solid. The carbamate was dissolved in 170 mL of THF, cooled to 0° C., treated with borane-dimethylsulfide (33.5 mL of a 10 M solution), and stirred at room temperature for 17 hours. Excess borane was cautiously quenched with water (100 mL), and the bulk of the THF removed under reduced pressure. The white slurry was diluted with additional water (350 mL) and then extracted with dichloromethane (2×500 mL). The combined organic layers were washed with 100 mL of saturated aqueous NaHCO3, dried (Na2SO4), and concentrated to give 27.4 g of (S)-2-ethoxycarbonylamino-2-phenylethanol as a white solid. The crude alcohol was dissolved in 200 mL of THF, cooled to 0° C., and treated with n-butyllithium in hexane (6 mL of a 2 M solution). After heating at 55° C. for 6 hours, the solution was treated with acetic acid (1 ml) and concentrated. The residue was dissolved in dichloromethane (300 mL), washed with 100 mL of brine, dried (Na2SO4), and concentrated to a white solid. Recrystallization from toluene gave 17.14 g (63%) of (S)-4-phenyloxazolidin-2-one; mp 132°-133° C.; [α]D20 +49.5° (c=2.1, CHCl3); IR (CHCl3) 3460, 3020, 1760, 1500, 1480, 1460, 1400, 1230 cm-1 ; 1HNMR δ7.45-7.30 (m, 5, ArH), 6.42 (br s, 1, NH), 4.96 (br t, 1, J=7.8 Hz, OCH2CH), 4.72 (t, 1, J=8.6 Hz, one of OCH2CH), 4.17 (dd, 1, J=6.7, 8.7 Hz; one of OCH2CH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C(O)c1ccccc1
Temperature: 25 °C

Procedure:
To the solution of 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbaldehyde (112.3 mg, 0.3 mmol) in THF (1.0 mL) was added phenylmagnesiumbromide (3.0 M in diethyl ether, 1.0 mL, 3.0 mmol) at 0° C. under argon atmosphere. After addition, the reaction mixture was slowly warmed to room temperature and further stirred overnight. To the reaction mixture was then added 2.0 mL of saturated aqueous NH4Cl at 0° C., dissolved in EtOAc (50 mL) and washed with H2O (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography (eluent: EtOAc in Hexanes: 0 to 33%) to afford (2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanol as a colorless oil. MS (ES+): 452.0 (MH+).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:17])[CH2:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: C=C(C)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CC(C(=O)c1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl methacrylate (12.65 mL, 119 mmol) was added to a solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (30 g, 113 mmol, Example 1, Step A) in tetrahydrofuran (283 mL). Potassium tert-butoxide (1.27 g, 11.3 mmol) was then added and the reaction was stirred at room temperature for 2 days. The solvent was removed under a vacuum and replaced with 300 mL of ethyl acetate. The organic phase was washed with brine (50 mL), water (3×50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under a vacuum to afford methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate as an approximately 1:1 mixture of diastereomers.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[C:17]([N+:6]([O-:9])=[O:7])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Yield: 92 %

Procedure:
A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3×600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (−) m/z 220 (M-1) detected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]O)=[CH:9]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42].[H-].[Na+]>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3ccc(CCCO)c3)c(F)c2)C(=O)O1
Reactant: CS(N)(=O)=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3ccc(CCCNS(C)(=O)=O)c3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
A solution of 100 mg (0.266 mmol) of the compound of Example 25 (previously dried at 60° C. under 0.1 mmHg for 18 h prior to use) and 88 mg (120 μL, 0.88 mmol) of triethylamine in 2 mL dichloromethane at 0° C. was treated with 85 mg (58 μL, 0.73 mmol) of methanesulfonyl chloride, followed by stirring at 0° C. for 30 min. The solution was diluted with dichloromethane and extracted with water (2×) and saturated sodium bicarbonate solution. Drying (Na2SO4) and concentration in vacuo afforded a solid which was dissolved in 2 mL DMF and treated via cannula to a 0° C. solution of 38 mg (0.40 mmol) of methanesulfonamide in 2 mL DMF which had been previously treated with 10 mg (17 mg of 60% in oil, 0.43 mmol) of sodium hydride. The solution was then warmed at 60° C. for 18 h. The solution was cooled and the DMF removed in vacuo, and the residue was dissolved in ethyl acetate and extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded a solid which was subjected to radial chromatography on a 2 mm chromatotron plate, eluting with 1-4% (v/v) methanol in dichloromethane. These procedures afforded 31 mg (26%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.61, 7.56, 7.35, 7.23, 6.92, 6.81, 6.19, 6.06, 4.81, 4.29, 4.07, 3.82, 3.67, 3.22, 2.95, 2.62, 2.04, 1.90. ##STR5##