Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[N:17][C:12]2[O:13][CH2:14][CH2:15][NH:16][C:11]=2[CH:10]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C.O>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:19])[F:20])=[CH:10][C:11]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: FC(F)(F)c1ccccc1-c1cnc2c(c1)NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccccc4C(F)(F)F)cc32)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
In a 10 ml flask, 7-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (67 mg, 0.24 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (118 mg, 0.36 mmol) were dissolved in dichloromethane. Triethylamine (0.17 ml, 1.20 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(2-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (46 mg, 34%).
Reaction SMILES: C([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH3:29][N:30]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)C1CCNCC1>C(OCC)C>[CH3:28][S:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([N:30]([CH3:29])[C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)[CH2:13][CH2:12]2)=[CH:23][CH:22]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)Nc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1
Reactant: Cc1ccc(N(C)C2CCNCC2)cc1
Solvent: CCOCC
Product: Cc1ccc(N(C)C2CCN(CC(=O)Nc3ccc(NS(C)(=O)=O)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-methanesulfonylamino-phenyl)-acetamide (Example 180) and 4-(methyl-p-tolyl-amino)-piperidine [Arzneimittel Forschung/Drug Research 44(II), 989. (19994)]) according to the method described in Example 142b. Melting Point: 128-130° C. (diethylether)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=1.FC1C=C(Br)C=CC=1C(Cl)=O.C(N(C(C)C)CC)(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)Cl.O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:14])=[C:10]([F:17])[CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(Br)cc1F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)cc1F)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.8 ml (44 mmol) oxalyl chloride in 30 ml CH2Cl2 is added dropwise to a iced-cooled solution of 4.88 g (21.9 mmol) 4-bromo-2-fluorobenzoic acid in 180 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 15 h at RT. The solvent is evaporated to dryness, the resultant colorless residue is dried under vacuum and then diluted with 80 ml CH2Cl2. This solution of 2-Fluoro-4-bromobenzoyl chloride (CAS 151982-51-3) is then added dropwise to a mixture of 9.55 ml (54.7 mmol) of diisopropylethylamine, 2.01 ml (23 mmol) of morpholine in 100 ml CH2Cl2. After 1 h 30, the reaction mixture is diluted with water and the two phases are separated. The aqueous phase is re-extracted with CH2Cl2 and the combined organic extracts are washed with water, saturated brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[F:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=1[N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1>O>[F:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=1[N:39]1[CH2:44][CH2:43][C:42](=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(F)c(N2CCC(=O)CC2)cc1F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC=C1CCN(c2cc(F)c(OC)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
A reaction vessel was charged with methoxymethyltriphenyl-phosphonium chloride (1.114 g), the atomosphere indide the vessel was substituted with nitrogen, and anhydrous tetrahydrofuran (2 mL) was added, followed by further dropwise addition of 1.57 M n-butyl lithium-in-hexane solution (2 mL) at room temperature and thereafter 10 minutes' stirring at room temperature. To the reaction mixture a mixture of 1-(2,5-difluoro-4-methoxyphenyl)piperidin-4-one (676 mg) and anhydrous tetrahydrofuran (0.5 mL) was added dropwise, followed by 30 minutes' stirring at room temperature. To the reaction mixture water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Distilling the solvent off, the crude product as obtained was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=10:1) to provide 1-(2,5-difluoro-4-methoxyphenyl)-4-methoxymethylenepiperidine (257 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@H:6]([NH:13][C:14](=[O:35])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH:23]C(OCC2C=CC=CC=2)=O)[C:17]1=[O:34])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@H:6]([NH:13][C:14](=[O:35])[CH2:15][N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]1=[O:34])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(NC(=O)OCc2ccccc2)c1=O)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H](NC(=O)Cn1c(C)ccc(N)c1=O)c1cccnc1
Reaction time: 3 h

Procedure:
##STR54## To a degassed solution of the pyridone 16-5 (243 mg; 0.49 mmol) in EtOH (20 mL) was added 10% Pd on carbon (25 mg) and this was then stirred under an atmosphere of hydrogen gas (balloon) for 3 hours. The mixture was filtered through a pad of celite and the solvent removed to give the title compound (16-6) as a viscous oil which was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cccc(CBr)c1
Yield: 80.5 %

Procedure:
10 g (73.4 millimoles) of m-methyl-benzoic acid are dissolved in 75 ml of anhydrous carbon tetrachloride, whereupon 0.2 g of 2,2'-azo-bis-(2-methyl-propiontirile) and 13.72 g (77.07 millimoles) of N-bromo-succinimide are added. The reaction mixture is refluxed for 20 minutes, the formed succinimide is removed by filtering the warm mixture. The organic filtrate is washed with 15 ml of water, dried over sodium sulfate, filtered and the filtrate is evaporated in vacuo. The crude product thus obtained is recrystallized from a fivefold amount of carbon tetrachloride. Thus 12.71 g of the title compound are obtained, yield 80.5%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:46])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:42])[NH:32][C:33]5[S:34][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:36][N:37]=5)=[CH:27][C:26]=4[N+:43]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O.C(OCC)(=O)C.[Fe]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:46])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:42])[NH:32][C:33]5[S:34][C:35]([C:38]([CH3:41])([CH3:39])[CH3:40])=[CH:36][N:37]=5)=[CH:27][C:26]=4[NH2:43])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c(N)c2)s1
Temperature: 90 °C
Yield: 90.5 %

Procedure:
The product of Example 161C (336 mg, 0.516 mmol), ammonium chloride (181 mg, 3.382 mmol), and iron powder (177 mg, 3.175 mmol) in a mixture of water (3 mL), ethanol (6 mL) and tetrahydrofuran (6 mL) was heated at 90° C. under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to give the product as a light yellow solid (290 mg, 90%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[O:14])[N:10]=2)[CH2:3]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][S:27]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[O:14])[N:10]=2)[CH2:5]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 3-hydroxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (457 mg, 1.25 mmol) (obtained as described in Reference Example 62(3)) in methylene chloride (25 ml) were added methanesulfonyl chloride (0.29 ml, 3.75 mmol) and triethylamine (0.53 ml, 3.80 mmol) in an ice bath. After stirring the mixture for 10 minutes in the ice bath, the resulting mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl)azetidine (499.4 mg, yield 90%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of (+/−)-methyl 6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinate (30 mg, 0.069 mmol) in tetrahydrofuran (3 mL) was added lithium hydroxide (0.103 mL, 2N in water, 0.207 mmol). The mixture was stirred at 50° C. overnight. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinic acid (25 mg, 87%) as a white solid. MS (M+1): 419.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[NH:25]1[CH:34]2[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([N:25]3[CH:34]4[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:28][CH2:27][CH2:26]3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: C1CCC2NCCCC2C1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(N2CCCC3CCCCC32)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 90.9 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with decahydroquinoline (26 mg, 0.26 mmol) to give the title compound (57 mg, 90%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Br[C:12]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=1[CH:14]=O>>[Br:20][C:17]1[CH:16]=[C:13]2[C:12](=[CH:19][CH:18]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:10]=[CH:14]2
Reactant: O=Cc1cc(Br)ccc1Br
Reactant: COc1ccc(NN)cc1
Product: COc1ccc(-n2ncc3cc(Br)ccc32)cc1

Procedure:
In analogy to Example 187, step 1, 4-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a light brown solid. MS (m/e)=303.0 [M+H+].
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:7]2[S:11][C:10]([CH:12]3[O:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: Brc1ccc(C2OCCO2)s1
Reactant: Fc1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Cc2ccc(C3OCCO3)s2)cc1
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
n-Butyl lithium (2.6N hexane solution, 3.3 mL, 8.47 mmol) was added dropwise to a solution of 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (1.8 g, 7.7 mmol) in tetrahydrofuran (20 mL) that had been cooled to from −75° to −70° C., and the solution was stirred for 30 minutes. 4-Fluorobenzyl bromide (1.1 mL, 8.47 mmol) was added dropwise to this reaction solution while keeping it at −70° C. or less. After completion of dropwise addition, the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned, silica gel was added to the organic layer, which was then evaporated in vacuo for adsorption, purification by silica gel column chromatography (hexane, then hexane:ethyl acetate=20:1, then 10:1) was carried out, and the title compound (560 mg, 2.04 mmol, 26.4%) was obtained as a brown oil.
Reaction SMILES: [CH:1]1([N:6]([CH3:28])[C:7]2[C:8]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([N:6]([CH3:28])[C:7]2[C:8]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
To a solution of methyl 3-(cyclopentyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120.0 mg, crude) in methanol (20 mL) was added sodium hydroxide (50.0 mg, 1.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 6 with hydrochloric acid (1N). The product was precipitated and filtered to afford 3-(cyclopentyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (20 mg).
Reaction SMILES: [CH:1]1([CH:7]([C:11](=O)[CH3:12])[C:8](=O)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1)[NH2:16]>>[CH:1]1([C:7]2[C:11]([CH3:12])=[N:16][N:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][OH:25])=[CH:21][CH:22]=3)[C:8]=2[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNc1ccc(CCO)cc1
Reactant: CC(=O)C(C(C)=O)C1CCCCC1
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-cyclohexylpentane-2,4-dione (Tetrahedron, 1991, 47, 6511) and 2-(4-hydrazinophenyl)ethanol hydrochloride: 1H-NMR (CDCl3) δ 7.36-7.30 (4H, m), 391 (2H, t, J=6.6 Hz), 2.91 (2H, t, J=6.6 Hz), 2.31 (3H, s), 2.24 (3H, s), 1.82-1.26 (11H, m).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[C:12]1([C:18]#[C:19][C:20]2[O:24][C:23]([C:25](ON3C(=O)CCC3=O)=[O:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C=O)C.C(N(CC)CC)C>C(OCC)C>[C:12]1([C:18]#[C:19][C:20]2[O:24][C:23]([C:25]([NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[O:26])=[CH:22][CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C#Cc2ccccc2)o1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(C#Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
(R)-aminocarnitine (16 mg, 0.1 mmol) and 2,5-dioxopyrrolidin-1-yl 5-(phenylethynyl)furan-2-carboxylate (60 mg, 0.19 mmol) were dissolved into DMF (1 mL). Triethylamine (50 μL, 0.36 mmol) was added and the solution was stirred at room temperature for 18 h. Diethyl ether (20 mL) was added and a white precipitate was collected. The powder was purified by silica gel chromatography (elution 10% MeOH/CH2Cl2 to 100% MeOH) to give the title compound as a white powder (10 mg, 24%). 1H NMR (400 MHz, D2O) δ 7.35-7.33 (m, 2H), 7.25-7.16 (m, 3H), 7.02 (d, 1H, J=3.7 Hz), 6.58 (d, 1H, J=3.6 Hz), 4.90-4.80 (m, 1H), 3.63-3.55 (m, 1H), 3.47-3.42 (m, 1H), 3.04 (s, 9H), 2.51-2.41 (m, 2H); MS ESI 355.1 [M+H]+, calcd for [C20H22N2O4+H]+ 355.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[CH:5][C:6]([N+:16]([O-])=O)=[C:7]([O:9][CH2:10][C:11](OCC)=[O:12])[CH:8]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.CC#N.O.FC(F)(F)C(O)=O>C(O)C>[CH3:1][O:2][C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[CH:5][C:6]2[NH:16][C:11](=[O:12])[CH2:10][O:9][C:7]=2[CH:8]=1
Reactant: CCOC(=O)COc1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.7 %

Procedure:
Ethyl {[5-(methyloxy)-2-nitro-4-(trifluoromethyl)phenyl]oxy}acetate (0.71 g, 2.2 mmol), was dissolved in 20 mL of ethanol. Tin chloride dihydrate (2.97 g, 12.5 mmol) was added to the solution and the mixture was stirred and maintained at room temperature for 18 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) indicated that all of the starting material (Rt=7.65 min) was consumed and a new single peak formed (Rt=5.9 min). The mixture was allowed to cool to room temperature before all volatiles were removed by rotary evaporation. The crude residue was dissolved in 100 mL of ethyl acetate and washed with 10% hydrochloric acid solution (3×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (40 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: hexanes, B: ethyl acetate, B: 0% to 85% over 40 min; detection at 214 nm) to give 7-(methyloxy)-6-(trifluoromethyl)-2H-1,4-benzoxazin-3(4H)-one (0.39 g, 1.6 mmol, 73%) as an off-white amorphous solid. MS (ES) m/e 248 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[N:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:26][CH2:25][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=4)[CH2:29][CH2:28]3)[C:10]=2[CH:11]=1
Reactant: Fc1ccc2nnn(CCCCCl)c2c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
1-(4-chlorobutyl)-6-fluoro-1H-benzotriazole (8.2 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.3 g compound (I-32) with a yield of 65.7%. ESI-MS [M+H]+: m/z 422.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[C:38]([O:42][NH2:43])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42]/[N:43]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reactant: CC(C)(C)ON
Product: CC(C)(C)O/N=C/c1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 76E and O-(tert-butyl)hydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH:7]=[CH2:8].C1(O)C=CC=CC=1>N1C=CC=CC=1>[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH:7]=[CH2:8]
Reactant: C=CCc1ccccc1O
Reactant: ClCC1CO1
Solvent: Oc1ccccc1
Solvent: c1ccncc1
Product: C=CCc1ccccc1OCC(O)CCl
Temperature: 90 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a flask are placed 92.5 g (1 mol) of epichlorohydrin, 33.5 g (0.25 mol) of o-allylphenol and 0.3 ml of pyridine is added. The mixture is taken to 80° C. in about 1 hour then the temperature is raised to 90° C. and maintained for about 6 hours until the phenol has disappeared completely. The mixture is then cooled and the excess of epichlorohydrin evaporated. The remaining oil is taken up in 100 ml chloroform and 50 ml of HCl (d415 -1.19) are slowly added. The organic phase is then washed two to three times in water then dried over Na2SO4. After evaporation of the chloroform, 56.6 g (yield: about 100%) are obtained of 1-(o-allylphenoxy)-3-chloro-2-propanol in the form of an oil, dark brown in colour.