Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=[O:24])[CH3:23].B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=[O:24])[CH3:23]
Reactant: COc1ccc2cc(-c3ccc(NC(C)=O)c(OC)c3)ccc2c1
Agent: BrB(Br)Br
Product: CC(=O)Nc1ccc(-c2ccc3cc(O)ccc3c2)cc1O
Yield: 45 %

Procedure:
The compound is prepared by reaction of N-[2-methoxy-4-(6-methoxy-2-naphthyl)phenyl]acetamide (54 mg, 0.17 mol, 1 eq) with boron tribromide solution (2.52 ml, 2.52 mmol, 15 eq) according to method G. Purification by preparative thin-layer chromatography with dichloromethane/methanol 95/5 yielded the desired product in a yield of 45%, 22 mg.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH:20]=[CH:21][C:22]2[CH:40]=[CH:39][C:25]([N:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:23]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:41]N1C(=O)CCC1=O.Cl>CN(C=O)C>[Br:41][C:18]1[S:17][C:16]([CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][C:25]([N:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:39][CH:40]=2)=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCc1ccc(-c2ccsc2C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2cc(Br)sc2C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 64.6 %

Procedure:
In a three necked flask under argon, 1.00 g (1.85 mmol, 1 eq.) of YKP70 in 20 mL of DMF are cooled to −10° C. 328 mg (1.85 mmol, 1 eq.) of N-bromosuccinimide are solubilised in 10 mL of mixture [DMF/MeOH:1/1]. This solution of NBS (protected from light) is then added drop by drop (30 min) into the reaction medium. The temperature of the medium is then left to rise to ambient temperature over 2 h. The medium is hydrolysed with a 1 mol·L−1 HCl solution and extracted with ethyl ether. The combined organic phases are washed with a saturated NaCl solution then dried on anhydrous Na2SO4. After drying on Na2SO4, filtration and evaporation of the solvent, the purification is carried out on neutral alumina column with the eluent [hexane/CHCl3: 100/1]. 742 mg of final compound YKP69 are obtained in the form of a translucent oil (yield of 64.6%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[N:8](OCCC(C)C)=[O:9].C(OC(C)C)(C)C>C(O)C.Cl>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N:8]=[O:9]
Reactant: Cn1nccc1N
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: Cn1ncc(N=O)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-1-methylpyrazole (5 g) in ethanol (50 ml) was added isoamyl nitrite (6.92 ml), and then 20% hydrochloric acid (5 drops) was added at 4° C. The reaction mixture was refluxed for 2 hours and cooled to room temperature. To the reaction mixture was added diisopropyl ether (50 ml), and the mixture was stirred for 0.5 hour. The resulting precipitate was collected by filtration and dried in vacuo to give 5-amino-1-methyl-4-nitrosopyrazole (3.53 g).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:11]12[CH2:12][CH2:13][CH:14]([CH:9]=[CH:10]1)[CH:5]1[CH:6]2[C:1](=[O:8])[CH:2]=[CH:3][C:4]1=[O:7]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C1=CCCC=C1
Solvent: c1ccccc1
Product: O=C1C=CC(=O)C2C3C=CC(CC3)C12

Procedure:
A solution of 40 g of 1,4-benzoquinone and 35 mL of 1,3-cyclohexadiene in 90 mL of benzene was stirred in a closed vessel for 3 days at rt. The reaction mixture was concentrated and the residue was crystallized in EtOH to obtain 57 g of the desired compound as mixture of stereoisomers as greenish solid.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:5].[CH3:27][Mg]Br>C1COCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH3:27])[CH:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: -40 °C

Procedure:
Under an inert atmosphere a 50 mL four necked flask (flame dried) with a magnetic stirrer was charged with 990 mg (2.65 mmol) (3SR,4RS)-1-benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide in 15 ml THF. The light yellow solution was cooled to −40° C. and 2.2 mL methylmagnesium bromide (3M in diethyl ether) was added drop wise over 5 min. The reaction was slowly warmed up to 0° C. over 2 h. The reaction mixture was quenched slowly with 20 mL aqueous NH4Cl-solution, diluted with 10 mL water and 10 mL ethyl acetate. The aqueous layer was separated and extracted once with 30 mL ethyl acetate. The combined organic layers were washed with 50 mL brine, dried over Na2SO4, filtered off and concentrated under vacuum and used without further purification in the consecutive step. MS (m/e): 327.2 [(M+H)+].
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH:8]([N:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (29.1 mL, 209 mmol) and a solution of sulphur trioxide pyridine complex (21.3 g, 134 mmol) in DMSO (100 mL) were added at 10° C. to a solution of 1-benzhydrylazetidin-3-ol (5.0 g, 20.9 mmol) in DMSO (60 mL). The resulting mixture was stirred at 10° C. for 45 minutes, then at room temperature for 4 hours, subsequently quenched by pouring onto crushed ice (˜200 g) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (400 mL) and brine (400 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (80:20 to 70:30) as eluent. The title product was obtained as a yellowish solid (4.35 g, 88%).
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:42]C(=O)C)([CH3:41])[CH2:7][CH2:8][C:9]1[N:10]([CH3:40])[C:11]([C:14]([O:26]C(=O)CCCC2C=CC(C)=C(C)C=2)=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=2)=[CH:12][CH:13]=1)(=O)C.O.[OH-].[Li+].C(Cl)Cl>O1CCCC1.CO.O>[NH2:42][C@:6]([CH3:41])([CH2:7][CH2:8][C:9]1[N:10]([CH3:40])[C:11]([C:14](=[O:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C(=CCCc2ccc(C)c(C)c2)OC(=O)CCCc2ccc(C)c(C)c2)n1C)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CCCC(=O)c2ccc(CC[C@@](C)(N)CO)n2C)cc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
(2R)-1-Acetoxy-2-acetylamino-2-methyl-4-{1-methyl-5-[4-(3,4-dimethylphenyl)-1-(4-(3,4-dimethylphenyl)butanoyloxy)but-1-enyl]pyrrol-2-yl}butane (29.6 g, 48.1 mmol) obtained in Example 2 (2a) was dissolved in a mixture of tetrahydrofuran (100 mL) and methanol (100 mL), and water (100 mL) and lithium hydroxide monohydrate (20.2 g, 481 mmol) were added thereto, followed by stirring of the mixture at 60° C. for 5 hours. After cooling, water and methylene chloride were added to the reaction mixture to separate it. An organic phase was separated and after it was washed with a saturated aqueous NaCl solution, it was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by basic silica gel (NH type) chromatography (methylene chloride:methanol, 100:1) to obtain (2R)-2-amino-2-methyl-4-{1-methyl-5-[4-(3,4-dimethylphenyl)butanoyl]pyrrol-2-yl}butan-1-ol (13.2 g, yield: 77%). A solution of fumaric acid (244 g, 2.10 mmol) in methanol (5 mL) was added to a solution of the obtained (2R)-2-amino-2-methyl-4-{1-methyl-5-[4-(3,4-dimethylphenyl)butanoyl]pyrrol-2-yl}butan-1-ol (1.50 g, 4.21 mmol) in methanol (16 mL) under ice-cooling. After methanol was evaporated under reduced pressure, the residue was dissolved in a small amount of methanol, ethyl acetate was added thereto and recrystallization was carried out to obtain a crude crystal (1.51 g) of the title compound. The obtained crude crystal (1.51 g), was subjected again to recrystallization using methanol and ethyl acetate to obtain the title compound (1.23 g, yield: 71%) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1.[C:21]([C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([S:30]([N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]
Reactant: COc1ccc(CNc2ccc(C#N)cn2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Product: COc1ccc(CN(c2ccc(C#N)cn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 18 using 6-((2,4-dimethoxybenzyl)amino)nicotinonitrile (Preparation 37) and 3-cyano-4-fluorobenzene-1-sulfonyl chloride. The residue was purified by reverse phase chromatography eluting with 0-100% MeCN in water/0.1% formic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[N:4]=[C:3]1[C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1>CCO.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]=[C:3]1[C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1
Reactant: Cn1cc(-c2nc(C(=O)OCc3ccccc3)cn2C)cn1
Agent: [Pd]
Solvent: CCO
Product: Cn1cc(-c2nc(C(=O)O)cn2C)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a flask containing a solution of benzyl 1-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylate (1 g, 3.4 mmol) in EtOH (25 ml), 10% Pd/C (100 mg) was added at RT. The resulting mixture was stirred at RT under H2 atmosphere for 3 h. The reaction mixture was filtered through a celite bed and the filtrate was concentrated. The residue was triturated twice from diethyl ether. Yield 500 mg. LC-MS: [M+1]=207.04.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=O)[CH3:18])=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[C:17]([CH3:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: NNc1ccccn1
Reactant: CC(=O)Cc1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(F)cc1)=NNc1ccccn1

Procedure:
In a vessel fitted with a condenser under nitrogen, 21.8 g (0.2M) of 2-hydrazinopyridine and 30.4 g (0.2M) of (4-fluorophenyl)acetone are heated at 80°-90° for about 30 to 60 mins. Toluene is then added and the mixture refluxed until all water is azeotropically distilled off. The mixture is then evaporated to dryness yielding crude product of this step as a yellow gum. The gum is distilled under reduced pressure (150°-160° at about 50 microns) to obtain the product of this step (as a yellow gum).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[C:4]1([C:2]2[N:11]=[C:12]([NH2:14])[S:13][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: Nc1nc(-c2ccccc2)cs1
Yield: 82.4 %

Procedure:
A mixture of 2 g of phenacylbromide and 0.76 g of thiourea in 50 mL ethanol was refluxed overnight. After solvent evaporation, the residue was redissolved in 50 mL DCM and treated by 50 mL of a 2% sodium carbonate solution in water. The organic layer was dried and evaporated to yield 1.45 g (82%) of 4-phenyl-2-thiazolamine (intermediate p. Mass spectral data: m/z=177 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([OH:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:16].[CH3:17][N:18]=[C:19]=[O:20]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:14][O:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]([O:16][C:19](=[O:20])[NH:18][CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[O:15][C:19](=[O:20])[NH:18][CH3:17]
Reactant: CN=C=O
Reactant: COc1c(OC)c(O)c2ccccc2c1O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CNC(=O)Oc1c(OC)c(OC)c(OC(=O)NC)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.00 g of 2,3-dimethoxy-1,4-dihydroxynaphthalene, prepared as shown in Preparation 5, in 50 ml of tetrahydrofuran was added 0.670 g of methyl isocyanate followed by 0.12 g of 4-dimethylaminopyridine. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluting with methylene chloride, giving 2,3-dimethoxy-1,4-di(methylcarbamoyloxy)naphthalene, m.p. 228°-229° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[CH:8][CH:7]=1
Reactant: O=CC(=O)O
Reactant: Oc1ccccc1
Solvent: O
Product: O=C(O)C(O)c1ccc(O)cc1

Procedure:
condensing glyoxylic acid with phenol at a temperature of 15°-80° C. in the absence of a strong mineral base and in the presence of a tertiary amine, said tertiary amine being insoluble or slightly soluble in water and being liquid at ambient temperature, and said glyoxylic acid being in aqueous solution at a concentration greater than 50% by weight, to produce parahydroxymandelic acid, and
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:13][CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9](=[O:12])OC)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([Mg]Br)[CH:24]=[CH2:25]>C1COCC1>[CH2:25]([C:15]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][C:9](=[O:12])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH:24]=[CH2:23]
Reactant: C=CC[Mg]Br
Reactant: COC(=O)N(CCC(=O)c1ccccc1)c1cccc(Br)c1
Solvent: C1CCOC1
Product: C=CCC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of methyl 3-bromophenyl(3-oxo-3-phenylpropyl)carbamate (250 mg, 0.69 mmol) in dry THF (2 mL) was added dropwise 1 M allylmagnesium bromide (10 mL) −78° C. The reaction mixture was stirred at rt for 3 h. The resulting mixture was quenched with sattd aq NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (120 mg, 47%). 1H NMR (400 MHz, CDCl3): δ=2.48 (m, 2H), 2.55-2.7 (m, 2H), 3.23 (m, 1H), 3.51 (m, 1H), 5.04 (m, 2H), 5.72 (m, 1H), 7.01 (m, 1H), 7.11 (m, 1H), 7.23 (m, 1H), 7.3 (m, 1H), 7.35 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:14](OCC)=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:14][OH:15])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1sc(Cl)nc1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 7 %

Procedure:
To a suspension of 18.2 g (0.06 mol) of ethyl 2-chloro-4-(p-chlorophenyl)-5-thiazolecarboxylate in 100 ml of ethanol was added 2.27 g (0.06 mol) of sodium borohydride. The reaction mixture was stirred for 1 hour and filtered. The ethanol filtrate was concentrated under reduced pressure and the residue was treated with water and extracted with CHCl3. The CHCl3 extracts were dried over MgSO4 and concentrated under reduced pressure. The residual solid (1.5 g) was recrystallized from ethanol-water to give 1.1 g (6%) of 2-chloro-4-(p-chlorophenyl)-5-thiazolemethanol, mp 113°-114° C.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28]C1C=CC(C=O)=CC=1>>[F:28][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][I:1])[N:4]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(F)cc2)nc1CI

Procedure:
Analogously to the-building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and 4-fluorobenzaldehyde gave 2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole.
Reaction SMILES: O(CC1C(=O)NC2C(N=1)=CC=CC=2)C1C=CC=CC=1.[CH3:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([CH2:31]OC2C=CC=CC=2C(NC2C=CC=CC=2)=O)[C:22]1=[O:48].CNC1C=CC=CC=1N.C(O)(=O)C(C)=O>C(O)C>[CH3:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([CH3:31])[C:22]1=[O:48]
Reactant: Cn1c(=O)c(COc2ccccc2C(=O)Nc2ccccc2)nc2ccccc21
Agent: CC(=O)C(=O)O
Agent: CNc1ccccc1N
Agent: O=c1[nH]c2ccccc2nc1COc1ccccc1
Solvent: CCO
Product: Cc1nc2ccccc2n(C)c1=O
Temperature: 50 °C

Procedure:
A particularly preferred embodiment of the phenoxymethylquinoxalinone compounds of the present invention, 2-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-N-phenylbenzamide, was synthesized as follows. The compound 1,3-Dimethyl-1H-quinoxalin-2-one (Compound A) was prepared by dissolving N-methyl-1,2-phenylenediamine (6.68 g, 54.7 mmol) and pyruvic acid (3.8 mL, 54.7 mmol) in ethanol (230 mL) and warming the mixture to 50° C. The color changed dramatically from a dark, cloudy brown to clear orange. Ethanol was evaporated and the crude product was filtered through a silica bed with CH2Cl2/EtOAc (1:1) to give 7.36 g of product as a yellow solid (mp. 75-77° C., 42.3 mmol, 77.2%). FT-IR (KBr): 3075-2975 cm (aromatic CR), 2950-2850 (aliphatic CR), 1650 (C═O), 1600 (C═N). 1H-NMR (CDCl3): δ 7.80 (d, 1H, J=7.9 Hz), 7.52 (t, 1H, J=7.8 Hz), 7.33 (m, 2H), 3.70 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](O)([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([F:7])([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ncccc2Cl)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution of DAST (0.837 mL, 6.3 mmol) in DCM (20 mL) at −78° C. a solution of 3-chloro-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (1.8 g, 5.8 mmol) in DCM (50 mL) was slowly added and allowed to warm to room temperature. Further DAST (0.6 mL) was added at 0° C. and stirred at room temperature for 30 minutes. Sodium hydrogen carbonate (sat.aq.) and DCM were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a white solid (0.13 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[Br:41][C:42]1[S:46][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:44][CH:43]=1>O1CCCC1.O>[Br:41][C:42]1[S:46][C:45]([S:47]([N:14]2[C:10]([C:9]3[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[C:11]([F:25])[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13]2)(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccc(Br)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (143 mg) and 5-bromothiophene-2-sulfonyl chloride (196 mg) were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a colorless oil (yield 248 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5].[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.[H-].[Na+]>O1CCOCC1.ClCCl>[CH2:7]([N:6]([CH2:9][CH3:10])[C:4](=[O:5])[C:3]1[CH:11]=[CH:12][CH:13]=[N:14][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH3:8]
Reactant: Cc1ccccc1N
Reactant: CCN(CC)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccnc1Nc1ccccc1C
Temperature: 100 °C
Yield: 44.9 %

Procedure:
To a solution of 2-chloro-N,N-diethylnicotinamide (10.0 g, 47.2 mmol) and o-toluidine (5.0 g, 47.2 mmol) in 1,4-Dioxane (50 mL) was added sodium hydride (60%, 4.72 g, 118 mmol). After addition, the reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (100 mL), washed with water (3×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% hexane in ethyl acetate) to afford the desired product, N,N-diethyl-2-(o-tolylamino)nicotinamide (6.0 g) as a yellow oil. LCMS: 284 [M+H].
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>CO.C(Cl)(Cl)Cl>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl) thiophene-2sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(4-ethylphenyl) thiophene (47.1 mg, 11.16 mmol) with 5-amino-4-bromo-3-methyl isoxazole (29 mg, 0.16 mmol) yielded, after flash chromatography using 10% MeOH/CHCl3, a pale brown solid (46 mg, 66% yield), m.p. 172°-175° C.
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)[CH:26]=CC=C[CH:22]=1>>[ClH:1].[CH:21]([C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3[CH2:5][CH2:4][NH:3][CH2:2][C:14]=3[C:13]=2[CH:12]=1)([CH3:26])[CH3:22]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cc(C(C)C)ccc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 4-isopropylhydrazine for phenylhydrazine in Step 1a).