Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.OO.C([O-])([O-])=[O:15].[Na+].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][N+:3]=1[O-:15]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1ccc(C(F)(F)F)cc1Cl
Temperature: 50 °C

Procedure:
To a solution of 2-chloro-4-trifluoromethylpyridine (1.81 g, 10 mmol) in trifluoroacetic acid (12 mL) was added 30% hydrogen peroxide (8 mL), and the mixture was stirred at 50° C. over a weekend. The reaction mixture was poured into ice-cold H2O, neutralized with solid Na2CO3 with stirring, and extracted with EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and dried to give analytically pure 2-chloro-4-trifluoromethylpyridine N-oxide (1.67 g) as a brown oil: 1H NMR (CDCl3) δ 8.45 (d, J=6.9 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.47 (dd, J=6.9, 2.4 Hz, 1H); GC-MS m/z 197 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)[CH2:5][C:6]1[C:7]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][C:9]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccccc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A mixture of 2-(3,5-bis-trifluoromethyl-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester (0.35 g, 0.78 mmol) (from Example 8b supra) and aniline (2.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then triturated with ethyl acetate-hexanes. The resulting solid was collected by filtration and washed with diethyl ether to give crude 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-propionic acid methyl ester as an off-white solid which was used in the next step without further purification. (Yield 0.47 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[CH3:7][C:8]1[O:9][CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[OH2:4].[OH2:9].[CH2:5]([O:4][CH2:3][CH2:2][N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:15]2[N:14]([CH2:13][C:12]3[CH:11]=[CH:10][O:9][C:8]=3[CH3:7])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:29][CH2:28]1)[CH3:6]
Reactant: CCOCCCl
Reactant: Cc1occc1Cn1c(NC2CCNCC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCN1CCC(Nc2nc3cccnc3n2Cc2ccoc2C)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
A mixture of 1.2 parts of 1-chloro-2-ethoxyethane, 3.1 parts of 3-[(2-methyl-3-furanyl)methyl]-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 1.6 parts of sodium carbonate and 45 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into 50 parts of water. Petroleum ether was added and after stirring, the crystallized product was filtered off, washed with water and petroleum ether and stirred in 1,1'-oxybisethane. The product was filtered off and dried at room temperature, yielding 1.6 parts (38.1%) of N-[1-(2-ethoxyethyl)-4-piperidinyl]-3-[(2-methyl-3-furanyl)methyl]-3H-imidazo-[4,5-b]pyridin-2-amine dihydrate; mp. 84.5° C. (compound 32).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C.Cl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)cc1NC1CCCCC1

Procedure:
A mixture of 4-bromo-2-fluorobenzoic acid (1.0 g) and cyclohexylamine (10 ml) was stirred under reflux for 5 hours. The mixture was poured into ethyl acetate (50 ml) and water (50 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-bromo-2-(cyclohexylamino)benzoic acid (1.32 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1.Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)cc1C
Yield: 42.5 %

Procedure:
In methyl ethyl ketone (10 mL), 3-[2-(2-hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (150 mg, 0.38 mmol), ethyl 2-bromo-2-methylpropionate (146 mg, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) were suspended. The suspension was refluxed for 20 hours, and allowed to room temperature. After insoluble was filtered off, the mixture was washed with methyl ethyl ketone to removed the solvent. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (8/1) to give the desired compound (83 mg) as colorless oil (yield 43%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CS(=O)(=O)c1ccc(Cl)nn1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCN(c3ccc(S(C)(=O)=O)nn3)CC2)c1
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixture of 3.2 parts of 3-chloro-6-(methylsulfonyl)pyridazine, 3 parts of 1-(3-methylphenyl)piperazine, 2 parts of N,N-diethylethanamine and 180 parts of benzene was stirred for 24 hours at reflux. The reaction mixture was evaporated. Water was added to the residue. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from methanol. The product was filtered off and dried, yielding 5 parts (89%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-(methylsulfonyl)pyridazine; mp. 201° C. (compound 209).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:16]2[S:15][C:14](=[S:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.CI.[CH3:20]COC(C)=O>CN(C=O)C>[Br:7][C:8]1[C:16]2[S:15][C:14]([S:17][CH3:20])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: S=c1[nH]c2cccc(Br)c2s1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2cccc(Br)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (67 mg, 0.49 mmol) was added to a solution of 7-bromo-1,3-benzothiazole-2(3H)-thione (100 mg, 0.41 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 30 min. Methyl iodide (25 μL, 0.41 mmol) was added and the resulting mixture was stirred at room temperature for 30 min. EtOAc was added the separated organic fraction was washed with water and brine, dried over sodium sulfate, and concentrated. The title compound thus obtained was used without further purification. MS (ESI): 260.34, 262.32 [M+H]+; HPLC tR=1.54 min (HPLC: Anayltical—2 min).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH2:24][CH3:25])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:27]1([CH2:26][NH:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH2:24][CH3:25])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCS(=O)(=O)Nc1ccc(CCCOCCCCCCBr)cc1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)Nc1ccc(CCCOCCCCCCNCc2ccccc2)cc1
Reaction time: 2 h
Yield: 55.5 %

Procedure:
The product of stage (ii) (0.85 g) was added dropwise over 5 min to stirred benzylamine (1.17 g) at 120° under nitrogen. The solution was stirred at 120° under nitrogen for 2 h, cooled and diluted with dichloromethane (100 ml). The mixture was washed with 2N hydrochloric acid (40 ml), the aqueous phase was re-extracted with further dichloromethane (2×40 ml), and the combined organic extracts were washed with 8% sodium bicarbonate solution (80 ml), dried and evaporated in vacuo to give the title compound as a yellow oil (0.5 g). T.l.c. (System C 39:10:2) Rf 0.49.
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:8]=1[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])([O-])=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][S:2][C:7]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:8]=1[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10]
Reactant: CCCCOC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1ccc(C(F)(F)F)cc1SC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
Sodium thiomethoxide (0.91 g; 13.0 mmol; 1.3 equiv) was dissolved in water (3.4 mL). Tetrabutylammonium bromide (0.48 g; 1.50 mmol; 0.15 equiv) was added. Butyl 2-nitro-4-trifluoromethylbenzoate (5b; 2.91 g; 10.0 mmol) was dissolved in toluene (5 mL) and added to the mixture. The reaction mixture was stirred at ambient temperature for 2.5 h to completely consume 5b according to thin layer chromatography (tlc) analysis. The reaction mixture was diluted with toluene and water and the layers were thoroughly mixed and then separated. The organic layer was dried over Na2SO4 and concentrated to afford 2.85 g (98%) of 6b which contained a small amount of tetrabutylammonium bromide. The crude product was flash chromatographed and eluted with 5% ethyl acetate in heptane to afford 2.32 g (79%) of pure 6b.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:17]1CCC[C:18]1=[O:22]>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([NH2:17])=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CN1CCCC1=O
Product: NC(=O)N(Cc1ccccc1)Cc1ccccc1
Yield: 62 %

Procedure:
As described in Example 6, but using a 20strength solution of dibenzylamine in N-methylpyrrolidone instead of dodecylamine at a temperature of 70 C, N,N dibenzylurea was obtained in a yield of 62% of theory after recrystallizing from water/acetone.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:22]([C:24]1[CH:29]=[C:28]([CH2:30][O:31][Si](C)(C)C)[CH:27]=[CH:26][N:25]=1)#[N:23]>O1CCCC1>[C:22]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][N:25]=1)#[N:23]
Reactant: C[Si](C)(C)OCc1ccnc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccn1
Yield: 32 %

Procedure:
Tetra-n-butylammonium fluoride trihydrate (1.1 g, 3.5 mmol) was added to a solution of 2-cyano-4-(trimethylsilyloxymethyl)pyridine (600 mg, 2.9 mmol, Reference compound No. 10-1) in tetrahydrofuran (15 mL) at room temperature, then the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 120 mg of the title reference compound as a yellow solid. (Yield 32%)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:23]=[CH:22][C:15]2[CH2:16][CH2:17][CH:18]=[CH:19][C:20](=[O:21])[C:14]=2[CH:13]=1)([O-:11])=[O:10]>C1C=CC=CC=1.C(O)C>[CH2:1]([NH:8][CH:18]1[CH2:17][CH2:16][C:15]2[CH:22]=[CH:23][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][C:14]=2[C:20](=[O:21])[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Solvent: c1ccccc1
Solvent: CCO
Product: O=C1CC(NCc2ccccc2)CCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
A solution of benzylamine (8.18 g) in benzene (100 ml) was added dropwise to a suspension of 8,9-dihydro-3-nitro-5H-benzocyclohepten-5-one (15.51 g) in ethanol (155 ml) at ambient temperature over 20 minutes. The resulting mixture was stirred at the same temperature for 3 hours 30 minutes, allowed to stand at the same temperature overnight, and filtered. The filtrate was evaporated in vacuo to afford 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (25.41 g) as a dark brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13]([O-:16])(=O)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13]([Cl:19])(=[O:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(NCCS(=O)(=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(NCCS(=O)(=O)Cl)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
A mixture of sodium 2-[(4-nitrophenyl)amino]ethanesulfonate (8) (5.36 g, 0.02 mol), phosphorus pentachloride (4.58 g, 0.022 mol) and 50 mL of anhydrous xylene was heated at about 40-50° C. for 4 hours. After remaining at room temperature overnight, the mixture was heated for 3 hours in a boiling water bath. The resulting mixture was filtered while hot and the insoluble matter was washed three times with hot xylene. The filtrate was left to cool. A yellow solid formed, and was filtered off and reslurried in water. 2.4 g of expected product were isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.[OH-].[Ba+2].[OH-].COCCOC>O>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: OB(O)c1ccccn1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2ccccn2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-bromopyrimidine (0.299 g, 1.72 mmol), 2-pyridylboronic acid (1.57 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (8 mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenylphosphine) palladium(0) (99.0 mg, 0.086 inmol) is added, and the resultant solution is stirred at 80° C. for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc. The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]1([S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:27](/[S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:26])\[C:28]#[N:29])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
M33 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and phenylsulfonly acetonitrile under similar conditions as decribed for M26.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24]Br>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Clc1cc(Cl)cc(CBr)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(Cl)cc(Cl)c2)c(=O)[nH]c1=O
Yield: 52.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (220 mg, yield: 52.7%).
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]4=[O:36])=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCCCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Under inert conditions, 5 ml of DMSO are admixed with 30 mg of NaH (60% in paraffin oil), and the mixture is heated at 75° C. for 30 min, until the evolution of gas has ceased. A solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophene-carboxamide (from Example 161) in 5 ml of methylene chloride is then added dropwise, and the mixture is stirred at room temperature overnight. The reaction is terminated and the mixture is poured into 100 ml of water and extracted with ethyl acetate. The evaporated organic phase is chromatographed on an RP-8 column and the product is eluted with acetonitrile/water. This gives 20 mg (7.5% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:39])=[C:10]([O:40][CH3:41])[CH:9]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:39])=[C:10]([O:40][CH3:41])[CH:9]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Yield: 82.4 %

Procedure:
A solution of 3-aminoisoxazole (0.664 ml, 8.98 mmol) and racemic perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (4.705 g, 8.16 mmol) in 100 mL THF, was cooled to 0° C. LHMDS 1N in THF (17.15 ml, 17.15 mmol) was added dropwise. After stirring for an hour, HCl 1N aqueous (32.7 ml, 32.7 mmol) was added, and the reaction mixture was extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was triturated with ether, and the resulting solid was collected and dried yielding 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (3.20 g, 6.72 mmol, 82% yield). A portion of this material was resolved. Chiral separation was performed by SFC: (S,S) Whelk-O, 50% isopropanol yielding (P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.150 g, 0.315 mmol, 3.86% yield) and (M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.154 g, 0.323 mmol, 3.96% yield). Analytical data for both isomers is identical. m/z (ESI) 476.1 (M+H)+. 1H NMR (ACETONITRILE-d3) δ: 8.37 (d, J=1.9 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.97 (d, J=9.6 Hz, 1H), 7.78 (dd, J=8.9, 2.2 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.3, 2.1 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.71-6.79 (m, 2H), 6.45 (d, J=1.8 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(N)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)c([N+](=O)[O-])cc1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
To stirred conc H2SO4 (70 mL) at 0° C. was added 45 (6.0 g, 41.8 mmol) in portions. To the resulting dark brown solution was added dropwise 70% HNO3 (3.5 mL, 54 mmol) at 0° C. After the addition, the reaction mixture was stirred at 50° C. under N2 for 2.5 h, cooled to room temperature and poured into crushed ice (about 700 g). The mixture was basified to pH 9 by the addition of 40% aq. NaOH dropwise with stirring and cooling (ice-water bath). The precipitate was filtered, washed with water (4×100 mL) and MeOH (3×25 mL), and dried to give 5.28 g (67%) of 46 as a yellow powder, mp 214°-5° C. (lit. 214°-6° C., Cress et al., J. Org. Chem. 93-6 (1976)). 1H NMR (DMSO-d6) δ 2.445 (s, 3H), 8.011 (bs, 2H), 8.340 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](CC2C=CC(OC)=CC=2OC)[CH2:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(O)c2ccc(OCc3ccccc3)cc2CN1Cc1ccc(OC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc2cc(OCc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
Dichloromethane (100 mL) was cooled to 0° C. and 5.7 g (12 mmol) of 7-benzyloxy-2-(2,4-dimethoxy-benzyl)-4-hydroxy-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester and 1.31 mL (18 mmol) of thionyl chloride were added. The reaction was stirred for one hour and then allowed to warm to room temperature and stirred for an additional 3 hours. 60 mL of hexanes was added to the resultant slurry and the white solid was collected by filtration through a medium glass fitted filter. The solid was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.7 g, white solid); MS (ESI+): 324.3 e/z (M+1)