Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]#[N:10])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[OH:11]O.[OH-].[Na+:14]>CO>[Na+:14].[N+:1]([C:4]1[C:8]([C:9]([NH-:10])=[O:11])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1c[nH]nc1[N+](=O)[O-]
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [NH-]C(=O)c1c[nH]nc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A solution was made of 8 gm. of 1-sodium salt of 3-nitro-4-pyrazolecarbonitrile in methanol, and 75 ml. of 15% H2O2 was added, followed by 5 ml. of 6 N NaOH. The reaction mixture was heated to 45° C., at which point external cooling was needed to maintain the mixture at 45°-50° C. After the exothermic reaction had subsided, the mixture was held at 45°-50° C. and stirred for 4 hours. Then the mixture was cooled and the methanol was evaporated under vacuum. The liquid remaining was cooled in an ice bath and the product was separated by filtration and dried under vacuum. The dry product was determined to be 8 gm. of 3-nitro-4-pyrazolecarboxamide sodium salt, m.p.>300° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CC(C)c1cccc(N)c1
Product: CC(C)c1cccc(NC(=O)c2ccnc(Br)c2)c1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and 3-isopropylaniline were converted to the title compound
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)=[CH2:13])C>C1COCC1.O.CCOC(C)=O>[Br:1][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ccc(F)cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-Bromosuccinimide (200 mg, 1 mmol) was added to a mixture of 2-(1-ethoxyvinyl)-5-fluoropyridine (200 mg, 1 mmol) in THF (6 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 15 min., diluted with EtOAc and washed with brine. The combined organic layer was dried with MgSO4, filtered and concentrated to give 2-bromo-1-(5-fluoropyridin-2-yl)ethanone as a clear oil, which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:25]3[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CCN1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 87 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 4-ethylpiperazine (0.43 g, 3.7 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.10 g of the title product was obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)=[CH:39][CH:40]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1cccc(C(F)(F)F)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(C(F)(F)F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-trifluoromethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 557 (M+H).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20]([OH:23])(=O)=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C=O)C>[C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20]([Cl:26])(=[O:23])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(S(=O)(=O)O)c2ccccc12)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1
Yield: 88.2 %

Procedure:
To a solution of the pyridinium salt of 4-benzoylamino-napthalene-1-sulfonic acid (2.4 g, 5.9 mmol) in DMF (10 mL), was added thionyl chloride (0.6 mL, 8.8 mmol). The resultant solution was stirred at 25° C. for 3 hours. The reaction mixture was quenched by pouring into ice water and filtered to give the title compound (1.8 g) a pale white solid. This material was used without further purification. 1H NMR (300 MHz, DMSO) δ 8.88 (d, 1H), 8.09 (d, 2H), 7.97 (d, 2H), 7.55 (m, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[CH3:15][C:16]1[NH:17][C:18]2[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([CH3:26])[C:19]=2[N:20]=1>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:23]2[CH:22]=[C:21]([CH3:26])[C:19]3[N:20]=[C:16]([CH3:15])[NH:17][C:18]=3[CH:24]=2)[CH:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1nc2c(C)cc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1.66 g (12.0 mmol) potassium carbonate were added to 0.676 g (4.40 mmol) 4,6-dichloropyrimidine and 0.649 g (4.00 mmol) 2,7-dimethyl-3H-benzimidazol-5-ol in 5.00 mL DMF and stirred for 8 h at 50° C. Then the mixture was added to ice water and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, evaporated down and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 1N aqueous sodium hydroxide solution and extracted with EtOAc. The organic phase was dried on sodium sulphate, filtered, evaporated down and dried under HV.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH:19]1[CH2:21][CH2:20]1)(C)C)(C)(C)C.C1(B(O)O)CC1>>[CH:19]1([C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]=2[OH:8])[CH2:20][CH2:21]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(F)(F)F)ccc1C1CC1
Agent: OB(O)C1CC1
Product: Oc1cc(C(F)(F)F)ccc1C1CC1
Yield: 53.4 %

Procedure:
tert-Butyl-(2-cyclopropyl-5-trifluoromethyl-phenoxy)-dimethyl-silane (268 mg, 0.862 mmol) was reacted with cyclopropyl boronic acid (96 mg, 1.12 mmol) as described above to give 2-cyclopropyl-5-trifluoromethyl-phenol (93 mg, 53%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[F:13][CH:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1>>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH:14]([F:13])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:16]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC(C)=CC1C(C(=O)O)C1(C)C
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Product: CC(C)=CC1C(C(=O)OC(F)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
This compound was prepared from 3-(2-methylprop-1-enyl)-2,2-dimethylcyclopropanecarboxylic acid and α-fluoro-3-phenoxybenzylbromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δ ppm (solvent CDCl3): 1.24(6H, m, C(CH3)2); 1.70(6H, s, (CH3)2C=); about 1.9(2H, m, cyclopropyl protons); 4.93 and 5.43(1H, 2xd, J=7Hz, vinyl proton); 7.13(1H, d, J=56Hz, CHF); about 7.1(9H, m, aromatic protons).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14](C(=O)C(F)(F)F)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:7])[CH3:2].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][CH2:15]2)=[CH:10][CH:9]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-butanoic acid ethyl ester {0.5 g, Reference Example 5(a)} in ethanol (30 mL), under argon, was treated with sodium ethoxide (0.25 g). After stirring at room temperature for 1 hour the reaction mixture was evaporated. The residue was treated with ethyl acetate (30 mL) and the resulting solution was washed twice with saturated ammonium chloride solution (15 mL), then dried over magnesium sulfate and then evaporated to give the title compound as a yellow gum. MS (ES)=248 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21]C)[CH:5]=1)([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:11][C:12]3[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]([OH:21])=[CH:7][C:8]=3[CH:9]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(C)C)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reaction time: 1 h
Yield: 338.8 %

Procedure:
7-Isopropyl-5-methoxy-2-(4-methoxy-phenyl)-benzofuran 117 (0.26 g, 0.88 mmol) and Pyridine HCl (5 g) were heated to 200° C. After 1 hr, the reaction was cooled, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated and the product was purified by column chromatography on silica gel (25% EtOAc/hexane) to give 118 as a solid (0.80 g, 34%): Mp=192–194° C.; 1H NMR (DMSO-d6) δ 9.81 (br s, 1 H), 9.03 (br s, 1 H), 7.68 (d, 2 H, J=8.2 Hz), 6.98 (s, 1 H), 6.86 (d, 2 H, J=8.1 Hz), 6.69 (d, 1 H, J=1.4 Hz), 6.54 (d, 1 H, J=1.9 Hz), 3.31 (m, 1 H), 1.32 (d, 6 H, J=6.9 Hz); MS 269 (M+H)+
Reaction SMILES: O1CCCC1.[Si]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([F:41])[C:28]([CH:31]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[F:40])[OH:32])=[N:29][CH:30]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>C(OCC)(=O)C>[F:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[CH:31]([C:28]1[C:27]([F:41])=[CH:26][C:25]([CH2:24][OH:23])=[CH:30][N:29]=1)[OH:32]
Reactant: CC(C)(C)[Si](OCc1cnc(C(O)c2cc(F)ccc2F)c(F)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCc1cnc(C(O)c2cc(F)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
To a tetrahydrofuran (7 ml) solution of [5-(t-butyldiphenylsilyloxymethyl)-3-fluoropyridin-2-yl](2,5-difluorophenyl)methanol (853 mg, 1.68 mmol) was added a tetrahydrofuran solution (1.04 ml, 1.04 mmol) of tetrabutylammonium fluoride. The mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue thus obtained was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and then, filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give the title compound (413 mg, 1.53 mmol, 91%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.[OH-].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([N:4]1[C:5]2[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Cc1n[nH]c2cccc([N+](=O)[O-])c12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1nn(Cc2ccccc2)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-indazole (0.100 g, 0.564 mmol) in acetone (0.4M, 1.4 mL) cooled to 0° C. was added potassium hydroxide (0.0475 g, 0.847 mmol). After 15 minutes at 0° C., (bromomethyl)benzene (0.0737 ml, 0.621 mmol) was added. The mixture was allowed to stir at ambient temperature overnight and then concentrated. The residue was purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-3-methyl-4-nitro-1H-indazole (0.052 g, 34% yield) as a yellow gum.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#N)=[C:4]([O:11][CH3:12])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:23]1CCCC1>>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:23])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: C1CCOC1
Reactant: COc1cc(Br)cc(C)c1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1cc(Br)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of 4-bromo-2-methoxy-6-methyl-benzonitrile (2.8 g, 12.38 mmol) in tetrahydrofuran (24.8 ml) is added diisobutylaluminium hydride (1.2 M in toluene) (24.8 ml, 29.7 mmol) at −78° C. The reaction mixture is slowly warmed to RT and stirred at RT for 18 h. The reaction is quenched with 1 M hydrochloric acid at 0° C. The resulting mixture is stirred at RT for 1 h and extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with water (40 ml), dried over sodium sulfate and evaporated. The crude product is purified by column chromatography (silica gel, 1.5% ethyl acetate/hexane) yielding 4-bromo-2-methoxy-6-methyl-benzaldehyde (1.25 g, 5.45 mmol, 44%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7]>CN(C=O)C>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cccnc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
Phosphorus oxychloride (31.7 mL, 340 mmol) was added dropwise to a stirred suspension of 3-nitro[1,5]naphthyridine-4-ol (50.0 g, 262 mmol) in 350 mL of DMF that was cooled with a water bath surrounding the reaction vessel. The resulting green suspension was stirred at ambient temperature for 5 hours and poured into 1.5 L of ice water and stirred for an additional hour. The suspension was filtered, washed with water (3×150 mL), and the resulting orange filter cake was dissolved in dichloromethane (800 mL) and washed with saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 50.49 g of 4-chloro-3-nitro[1,5]naphthyridine as an orange solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 65 °C
Yield: 98.6 %

Procedure:
To a mixture of 4-bromo-3,5-dimethyl-phenol (40.2 g, 0.200 mol) and potassium carbonate (55.2 g, 0.400 mol) in acetone (200 mL) was added methyl iodide ( 24.9 mL, 0.600 mol) at room temperature under N2. The reaction mixture was then refluxed at 65° C. for 8 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The resulting clear liquid was distilled under reduced pressure (70° C./0.1 Torr) to give 42.4 g (99%) of title compound as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 6.663 (s, 2H), 3.778 (s, 3H), 2.402 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 158.165, 139.203, 118.357, 113.953, 55.520, 24.319. MS (EI): m/z 214 [M+, 79Br 100], 216 [M+, 79Br, 96].
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8](C(O)=O)=[C:7]([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:15])[C:3]=1[CH3:16].Cl>N1C2C(=CC=CC=2)C=CC=1>[OH:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:15])[C:3]=1[CH3:16]
Reactant: Cc1cc2c(C)c(C(=O)O)oc2c(O)c1C
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Cc1cc2c(C)coc2c(O)c1C

Procedure:
The carboxylic acid from Step 1 (80 g, 0.37 mole) was dissolved in quinoline (750 mL) and Cu powder (16 g) was added to the solution. The reaction was heated to reflux for 90 min, cooled and 6N HCl (2L) was added. Extraction with EtOAc followed by chromatography on silica gel produced the title compound.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][NH:19]2)=[C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:14]=1>CN(C)C=O>[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:15]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:14]=1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 103.4 %

Procedure:
N,N-Dimethylformamide (60 ml), isobutyl bromide (2 ml, 18 mmol), and potassium carbonate (3 g) were added to 2-chloro-6-morpholin-4-yl-9H-purine (5 g, 17 mmol) and the resulting mixture was stirred at 80° C. for 5 hours. The reaction mixture was cooled and partitioned with ethyl acetate and water and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.2 g, 100%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][S:5][C:6]1[N:7]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)([CH3:13])[CH3:12])=[CH:9][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[Br:41]Br>C(Cl)Cl>[Br:41][C:9]1[N:10]=[C:6]([S:5][CH2:4][C:3]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:2]=2[Cl:1])[N:7]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:8]=1[C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1c(Br)nc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a solution of 2-(2-chloro-6-fluorobenzylthio)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (950 mg, 1.81 mmol) and sodium carbonate (634 mg, 5.98 mmol) in DCM:H2O (5 mL:5 mL) was added bromine (0.1 mL, 2.00 mmol) dropwise at 0° C. The resulting mixture was stirred for 3 h and diluted with DCM (15 mL). The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified with flash chromatography to afford the title compound (970 mg, 89%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.62 (s, 6H), 4.35 (s, 2H), 6.43 (m, 2H), 6.80 (t, 2H), 6.84 (dd, 1H), 6.95 (t, 1H), 6.99 (dd, 1H), 7.16 (m, 2H), 7.25 (t, 1H); MS (EI) m/z 602 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.[NH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[C:10]1[C:11]([OH:13])=[N:21][C:22]2[N:23]([CH:24]=[CH:25][N:26]=2)[C:16]=1[OH:18]
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Oc1nc2nccn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-(2,4,6-trifluorophenyl)malonate (U.S. Pat. No. 6,156,925) (870 mg, 3.0 mmol), 2-aminoimidazole (Hel. Acta. Chim. 76, 2066 (1993))(274 mg, 3.3 mmol), and 1.0 mL of tributylamine is stirred under nitrogen atmosphere at 160° C. for 0.5 h and cooled to room temperature. The mixture is dissolved in ethyl acetate and the organic layer is washed with 1.0 N hydrochloric acide (×3) and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is dissolved in ethyl acetate (5 mL) and to this solution is added hexanes (50 mL). The precipitates are collected by filtration, washed with hexanes to give 6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine-5,7-diol as a tan solid (180 mg). MS: m/z 279.9(M−H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:5])[CH3:4].[OH-].[Na+].I[CH2:9][CH:10]=[CH:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:35]([NH:36][C:37](=[O:67])/[C:38](=[N:64]\[O:65][CH3:66])/[C:39]3[N:40]=[C:41]([NH:44]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:42][CH:43]=3)[C:34](=[O:68])[N:16]2[C:17]=1[C:18]([O:20]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C(OCC)(=O)C.CCCCCC>[NH2:44][C:41]1[S:42][CH:43]=[C:39](/[C:38](=[N:64]/[O:65][CH3:66])/[C:37]([NH:36][CH:35]2[C:34](=[O:68])[N:16]3[C:17]([C:18]([O-:20])=[O:19])=[C:12](/[CH:11]=[CH:10]/[CH2:9][N+:3]([CH3:5])([CH3:4])[CH3:2])[CH2:13][S:14][C@H:15]23)=[O:67])[N:40]=1
Reactant: CN(C)C
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[N+](C)(C)C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylamine hydrochloride (6.31 g, 66 mmole) was added to an aqueous NaOH solution (2N, 33 ml) covered with ethyl acetate (100 ml). The organic layer was separated, dried over NaOH pellets, and added to a suspension of diphenylmethyl 3-(3-iodo-1-propen-1-yl)-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (X-1, 32 g, 33 mmole) in a mixture of ethyl acetate and n-hexane (300 ml/150 ml). The mixture was stirred for one hour at room temperature and then filtered to give the blocked title compound, which was treated with trifluoroacetic acid (50 ml) and anisole (10 ml) for one hour at room temperature. The mixture was concentrated under reduced pressure and the residue was triturated with ether to give 10.3 g of dark brown solid, which was treated with water (100 ml) at room temperature. After removal of insolubles by filtration, the filtrate was chromatographed on a column of HP-20 (200 ml) by eluting with 30% aqueous methanol. The eluate was concentrated and lyophilized to give 2.3 g of the crude title compound, which was purified by preparative HPLC (Waters Associates, System 500, PrepPAK 500/C18, 15% CH3OH) to afford 880 mg (5%) of the title compound I-1D. Estimated purity 75% (by HPLC).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[OH:17][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: O=Cc1ccccc1
Product: N#CC(c1ccccc1)C(O)c1ccccc1
Yield: 53 %

Procedure:
Reaction of phenylacetonitrile and benzaldehyde on a 15 mmol scale according to the procedure in Example 1, and recrystallization from toluene/hexane gave 1.81 g of the desired anti-aldol product (53%). NMR (1H, 13C), IR, and Mass spectra were consistent with the structure assigned previously by Wade et al. (J. Org. Chem. 52, 2973-2977 (1987)).