Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][N:5]=2.[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c2ncccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c(C)nc2ncccc2c1Cl
Temperature: 100 °C
Yield: 95 %

Procedure:
Ethyl 2-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (5.18 mg, 2.23 mmol) was dissolved in POCl3. The mixture was heated to 100° C. for 1.0 h. The mixture was allowed to cool and then it was carefully poured into ice-water (250 ml). The mixture was neutralized with solid NaOH. The product was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (CH2Cl2/MeOH 97:3→96:4) giving 531 mg (95%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:10][CH2:11][C:12]([NH:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O>O1CCCC1.C(OCC)(=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH3:16])=[CH:22][CH:21]=1
Reactant: CC(NC(=O)CCCl)c1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1CCC(=O)NC(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methylimidazole (2.64 g) in dry tetrahydrofuran (THF) (40 ml ) was added over 1 minute to a stirred suspension of sodium hydride (1.54 g; 60% dispersion in oil) in THF (65 ml) under dry nitrogen. The mixture was stirred at ambient temperature for 1 hour, then heated to boiling under reflux and allowed to cool. A solution of 3-chloro-N-[1-(4-chlorophenyl)ethyl]-propionamide (5.7 g) in THF (25 ml) was added and the mixture stirred under reflux for 16 hours. The mixture was cooled and water (100 ml) was added portion-wise with stirring followed by ethyl acetate (200 ml). The acidic layer was separated and extracted with ethyl acetate and the combined ethyl acetate extracts extracted with hydrochloric acid (5M). The combined acidic extracts were basified with concentrated sodium hydroxide solution and extracted with ethyl acetate to give an oil. The oil was triturated with ether and filtered to give N-[1-(4-chlorophenyl)ethyl]-3-(2-methylimidazol-1-yl)propionamide, m.p. 135°-137° C.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10](=[O:20])[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=1)=O.O=C1[N:34](C2C=CC=CC=2)C=C(C(N)=O)C(OC2C=CC=CC=2)=C1.COC(OC)N(C)C>>[O:13]([C:12]1[C:7]([C:5]2[N:4]=[CH:3][NH:2][N:34]=2)=[CH:8][N:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10](=[O:20])[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=NC(=O)c1cn(-c2ccccc2)c(=O)cc1Oc1ccccc1
Reactant: NC(=O)c1cn(-c2ccccc2)c(=O)cc1Oc1ccccc1
Agent: COC(OC)N(C)C
Product: O=c1cc(Oc2ccccc2)c(-c2nc[nH]n2)cn1-c1ccccc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Preparation of N,N-dimethyl-N′-[(6-oxo-4-phenoxy-1-phenyl-1,6-dihydropyridin-3-yl)carbonyl]formamidine: A mixture of 6-oxo-4-phenoxy-1-phenyl-1,6-dihydropyridine-3-carboxamide (195 mg, 0.64 mmol) and N,N-dimethylformamide dimethyl acetal (270 mg, 2.3 mmol) was stirred at 120° C. for 90 min. Then the mixture was cooled down to room temperature and evaporated in vacuo. The residue was crystallized on treatment with Et2O (15 mL). The solid product was filtered and washed with Et2O (2×10 mL) to yield the title compound as beige crystals (190 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]([OH:20])=[O:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Yield: 50 %

Procedure:
A mixture of 40 parts of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid, 100 parts of a hydrochloric acid solution 6 N and 100 parts of acetic acid is started and refluxed overnight. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is washed three times with water, dried, filtered and evaporated, yielding 17 parts (50%) of 1-(4-fluorophenyl)-4-oxocyclohexanecarboxylic acid as a residue.
Reaction SMILES: [C:1]1([CH2:19][OH:20])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.Cl.Cl[CH2:23][CH2:24][CH2:25][NH2:26]>>[C:1]1([CH2:19][O:20][CH2:23][CH2:24][CH2:25][NH2:26])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: OCc1scc2c1-c1ccccc1Oc1ccccc1-2
Reactant: NCCCCl
Agent: Cl
Product: NCCCOCc1scc2c1-c1ccccc1Oc1ccccc1-2

Procedure:
Starting from the alcohol 12 (0.25 mmole) and 3-chloropropylamine-hydrochloride (2.5 mmoles), an oily product was obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7].[OH-].[Na+].C>O>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)/C=C\C=C\C(=O)O
Temperature: 90 °C
Yield: 26.8 %

Procedure:
cis,cis-Muconic acid (265 g) is suspended in water (2 L) and the pH of the solution is adjusted to 5.1 with 10 M NaOH (250 mL). The mixture is heated at 90° C. for 2 hours. The progress of the isomerization is monitored by HPLC. After 2 hours of heating at 90° C., the mixture is treated with charcoal (20 g) for 30 minutes and the hot solution is filtered through a thin bed of Celite. The solution is adjusted to a pH of 2 with concentrated sulfuric acid (50 mL) and allowed to cool to 0° C. in an ice-bath. The precipitate is recovered by filtration and dried under reduced pressure overnight to yield 71 g cis,trans-muconic acid as light yellow solid. The filtrate is concentrated to 600 mL and allowed to incubate at 0° C. overnight. More precipitate is observed and is filtered and dried to yield an additional 152 g of cis,trans-muconic acid, an overall yield of 84 percent is achieved.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(C2=CC=NCC2)cc1

Procedure:
A solution of 4-(4-bromophenyl)piperidin-4-ol (500 mg, 1.95 mmol) in TFA (4 mL) was heated to 90° C. for 2 h. The crude reaction mixture was concentrated under reduced pressure to dryness, to give a yellow solid (460 mg, used without further purification). MS ESI 237.9 [M+H]+, calcd for [C11H12BrN+H]+ 238.02.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][N:4]=1.[CH2:10]([OH:13])[CH2:11][CH3:12]>>[I:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:13][CH2:10][CH2:11][CH3:12])[CH:8]=1
Reactant: Clc1cc(I)ccn1
Reactant: CCCO
Agent: [Na]
Product: CCCOc1cc(I)ccn1

Procedure:
0.58 g (25.06 mmol) sodium are carefully added to 40 mL n-propanol by several portions. The mixture is stirred until the metal is dissolved completely (ca. 45 min). Then 6.00 g (25.1 mmol) 2-chloro-4-iodo-pyridine are slowly added to the mixture. The mixture is stirred at reflux for 3 h. The reaction is quenched by the addition of some water. The solvent is removed in vacuo and to the residue are added 20 mL DMF/MeOH. The mixture is filtrated and the filtrate is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[N:25]([CH3:27])[CH3:26])=O)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][C@H:13]1[N:25]([CH3:27])[CH3:26]
Reactant: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Yield: 100.3 %

Procedure:
20% Palladium hydroxide (15 mg) was added to a solution of tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-(dimethylamino)piperidine-1-carboxylate obtained in Example (200b) (144 mg, 0.381 mmol) in methanol (4 mL) at room temperature, and the mixture was stirred in a hydrogen atmosphere at 50° C. for six hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 93 mg of the title compound (100%) as a colorless oily substance.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23](=[O:28])N(OC)C)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:28])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: c1ccc2sccc2c1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2s1

Procedure:
The title compound (1.60 g) was prepared from benzo[b]thiophene (0.80 g) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (1.62 g) according to a procedure similar to that for Description 2.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[NH2:7][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:1]=1[NH2:8]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Concentrated sulfuric acid (200 mL) was added to benzene-1,2-diamine (20 g, 184.95 mmol, 1.00 equiv) at −40° C., and the solution was stirred for 30 minutes at room temperature, then overnight at 140° C. in an oil bath. Upon cooling to room temperature, the reaction was quenched by 500 g of ice. The solids were collected by filtration, and the crude product was purified by re-crystallization from water affording 9.8 g (28%) of 3,4-diaminobenzenesulfonic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:17][C:16]([NH2:18])=[N:15][N:14]=1)[CH3:9]
Reactant: NNC(N)=S
Reactant: Cc1ccccc1OC(C)C(=O)O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1OC(C)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 100 milliliter flask adapted with a paddle stirrer, thermometer, an addition funnel, condenser and drying tube was charged with 7.2 grams (0.040 mole) of 2-(2-methylphenoxy)propanoic acid, 3.6 grams, (0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (6.7 grams; 0.044 mole) was slowly added (for 20 minutes) while maintaining the temperature within 90°-95° C., a gooey white precipitate formed. When the addition was completed the mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), and then 50 milliliters of water was added and mixture was made basic by the addition of 50 percent solution of NaOH until the pH of the solution was 10. The white precipate was filtered off, washed with water and dissolved in the minimum amount of 95 percent ethanol, to which a small amount of a 10 percent sodium hydroxide solution was added to make the ethanol solution basic. Water was added until a precipitate formed and the solution was cooled in the refrigerator, then suctioned filtered. The precipitate was washed with water, and dried in a vacuum oven at 70° C. to white crystals of 5-[1-(2-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (6.8 grams--melting point 176°-179° C.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].Br[CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:15][N:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.[Br-].C(C(CCCCCCCCCC)(C)C(CCCCCCCCCC)(CCCCCCCCCC)C(CCCCCCCCCC)(CCCCCCCCCC)[PH+](CCCC)CCCC)CCCCCCCCC>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]3[S:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[O:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: CCCCCCCCCCC(C)(CCCCCCCCCC)C(CCCCCCCCCC)(CCCCCCCCCC)C(CCCCCCCCCC)(CCCCCCCCCC)[PH+](CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCOC(=O)c1cccn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid ethyl ester (70 mg) in MeCN was added 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (139 mg), Cs2CO3 (180 mg), Bu4Nl (2 mg) and hexa-n-decyltri-n-butyl phosphonium bromide (10 mg). The mixture was stirred for 4 h at 60° C., whereupon it was cooled to RT and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO4 and concentrated in vacuo to provide 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (169 mg) which was directly used in the next step. MS (ESI+): m/e 337 [M+H]+, chloro pattern.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:11])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cc(Br)c1
Temperature: 80 °C
Yield: 86.3 %

Procedure:
To a solution of 1,3-dibromo-5-nitro-benzene (85.0 g, 0.30 mol) in 1 L of ethanol was added SnCl2.2H2O (341.0 g, 1.50 mol) portion wise at room temperature. The reaction mixture was heated under reflux at 80° C. for 1.5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and the crude white solid thus obtained was basified with 4N NaOH solution to pH 12. The mixture was extracted with ethyl acetate (×3) and the combined organic layer was washed with brine solution and dried over Na2SO4. The solvent was removed under reduced pressure, to give the desired compound as a brown solid (65.0 g, 86%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)=[O:6].[ClH:20].[C:21](O)(=[O:23])[CH3:22]>CCOC(C)=O>[ClH:20].[C:21]([O:1][CH2:2][CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][NH:8]1)=[O:6])(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)NCCO
Reactant: CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCCNC(=O)[C@@H]1COCCN1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of (S)-tert-butyl 3-((2-hydroxyethyl)carbamoyl)morpholine-4-carboxylate (0.33 g, 1.2 mmol) in glacial acetic acid (0.5 mL) was added a solution of HCl in EtOAc (6 mol/L, 15 mL), then the mixture was stirred closedly at 25° C. for 12 hours. The mixture was concentrated in vacuo to give the title compound as glutinous semisolid (0.21 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].O.[Cl:8][C:9]1[CH:13]=[C:12]([CH:14]=[O:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17].[OH:20]S([O-])=O.[Na+]>CC(C)=O.Cl>[Cl:8][C:9]1[CH:13]=[C:12]([C:14]([OH:20])=[O:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=S([O-])O
Reactant: COC(=O)c1[nH]c(C=O)cc1Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1[nH]c(C(=O)O)cc1Cl
Reaction time: 4 h
Yield: 82 %

Procedure:
KMnO4 (2.53 g, 16.0 mmol) was dissolved in acetone and water and added dropwise over a 2 hr period to a solution of methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (1.50 g, 8.00 mmol) in acetone (250 mL). After stirring for 4 hr the solution was poured into a solution of NaHSO3 in 1N HCl. This was extracted with EtOAc and the organic layer was washed with water. The organic layer was dried over MgSO4 and evaporated to afford the title compound (1.33 g, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.15 (br. s., 1H), 12.75 (br. s., 1H), 6.78 (d, 1H), 3.77 (s, 3 H). LCMS: m/z 203.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:14])[F:13])=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[CH2:25][S:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:6]=1.COC(=O)CC1C=CC(OC(F)F)=C(OC2C=CC(N)=CC=2CSCC(F)(F)F)C=1.[C:63](Cl)(=[O:68])[C:64]([CH3:67])([CH3:66])[CH3:65]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:14])[F:13])=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:63](=[O:68])[C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:18][C:17]=2[CH2:25][S:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:6]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: COC(=O)Cc1ccc(OC(F)F)c(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Product: COC(=O)Cc1ccc(OC(F)F)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CSCC(F)(F)F)c1

Procedure:
{4-Difluoromethoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester was reduced to {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-difluoromethoxy-phenyl}-acetic acid methyl ester as described in Example 21, Step 9, which was treated with pivaloyl chloride as described in Example 21, Step 10 to provide {4-difluoromethoxy-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester. Hydrolysis of the ester to the acid was carried out as described in Example 21, Step 11.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: COC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL pressure tank reactor, was placed (S)-2-(methoxymethyl)pyrrolidine (96.45 mg, 0.85 mmol, 5.00 equiv), methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (50 mg, 0.17 mmol, 1.00 equiv), potassium carbonate (46.7 mg, 0.34 mmol, 2.00 equiv), toluene/DMSO (2/0.4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 17 mg (27%) of (S)-methyl 3-(2-(methoxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:27]=O)=[C:24]([CH3:26])[CH:25]=1)=[O:20])[CH3:13]>>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:27]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:24]([CH3:26])[CH:25]=1)=[O:20])[CH3:30]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1cc(C)c(C=O)[nH]1
Product: CCN(CC)CCCNC(=O)c1cc(C)c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]1
Yield: 8.7 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.16 g, 0.75 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (0.2 g, prepared by method C) to give 30 mg (8%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19](F)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(N4CCN(C)CC4)c(F)cc3cc2c1=O
Yield: 63.9 %

Procedure:
The 3-ethoxycarbonyl-1-ethyl-7,9-difluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 3 but starting from 1.4 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 4 g of 1-methylpiperazine. 1.1 g of 3-ethoxycarbonyl-1-ethyl-7,9-difluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 206° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.C(=O)([O-])[O-:20].[Na+].[Na+]>C(O)C>[CH:14]1[CH:15]=[CH:16][C:11]([CH:9]2[O:10][CH:8]2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:20])=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccccc1)C1OC1c1ccccc1
Reaction time: 3 h
Yield: 22 %

Procedure:
1.040 g (5 mmol) of chalcone was dissolved in 15 ml of ethanol and to the solution was added 2 ml of 25% hydrogen peroxide and 2 ml of an aqueous solution of 1 M sodium carbonate. The precipitate which was formed after stirring for 3 h was isolated and recrystallized from DMSO-water to give 250 mg (22%) of chalcone epoxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:43]>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:43])=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
3-(3-Diethoxyphosphoryl-4-hydroxymethyl-phenyl)propionic acid methyl ester (330 mg, 1 mmol), PPh3 (289 mg, 1.1 mmol) and CBr4 (365 mg, 1.1 mmol) were dissolved in 5 mL dry THF. The reaction mixture was stirred at 25° C. for 1 hr. The mixture turned cloudy. Solid was filtered and the filtrate was concentrated. The residue was further purified by flash column chromatography on silica gel (EtOAC/hexane 3/1, Rf=0.40). Pure product was obtained as an oil 150 mg (yield 38%).