Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:23][C:24]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1)=[CH2:24]
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Yield: 85 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-one (802 mg, 2 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (462 mg, 3 mmol) in a 20 mL microwave vial was added PhCH3/EtOH (8 mL/4 mL), followed by 1 M Na2CO3 (3 mL, 3 mmol) and Ph(PPh3)4 (46 mg, 0.04 mmol, 2 mol %) was added and the resulting mixture was purged with argon, then microwaved 3 h at 120° C. After aqueous workup, the solution was extracted with EtOAc and was purified by flash chromatography (Hex/EtOAc 1:1) to give the crude title compound as a light yellow foam (512 mg) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.10-6.88 (m, 5H), 6.54 (t, J=7.4 Hz, 1H), 6.06 (d, J=18.0 Hz, 1H), 5.92 (d, J=7.6 Hz, 1H), 5.49 (d, J=7.6 Hz, 1H), 3.46 (d, J=8.2 Hz, 1H), 2.30-2.18 (m, 2H); MS ESI 302.0 [M+H]+, calcd for [C19H15N3O+H]+ 302.1.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([I:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ncc1I
Temperature: 80 °C
Reaction time: 6 h
Yield: 38.2 %

Procedure:
N-iodosuccinimide (15.75 g, 70 mmol) was added to a solution of 2-chloropyridin-4-amine (9.00 g, 70 mmol) in N,N′-dimethylformamide (140 mL) and the mixture was stirred at 80° C. for 6 hours. Further N-iodosuccinimide (7.80 g, 35 mmol) was added and the mixture was stirred at 60° C. overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium thiosulphate, water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (6:1 to 2:1 hexanes/ethyl acetate) to yield the title compound (6.80 g, 38%) as a beige solid.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C>[CH2:24]([N:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1)[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 71 °C
Yield: 65.6 %

Procedure:
To a dry 100 ml one necked round bottom flask equipped with a stirring bar was added 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (5 g, 20.5 mmol) under N2 (FIG. 1). Anhydrous acetonitrile (60 mL) was added followed by the additions of BnBr (2.7 mL, 22.5 mmol) and triethylamine (8.5 ml, 61.5 mmol). A condenser was then put on to the flask and the reaction mixture was heated at 71° C. for 45 minutes. The reaction mixture was allowed to come to room temperature and concentrated under reduced pressure. It was then diluted with dichloromethane and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified with flash column (PE: EA=8:1) to yield 4.5 g (66%) of 111a. MS: [M+H]+: 335
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:12]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccccc1C(F)(F)F

Procedure:
A mixture of log 2-trifluoromethyl phenol, 17 g potassium carbonate, 150 ml acetone and 7.7 ml iodomethane was heated under reflux for 2 hr. After cooling, the insoluble matters were removed by filtration, and the filtrate was evaporated. The resulting residue was dissolved in ethyl acetate, and washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered, and evaporated to give 12.15 g of 2-trifluoromethyl anisole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([N:40]=[C:41]=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1>ClCCl>[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([NH:40][C:41]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:16][CH2:17]2)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc(N2CCNCC2)c(COc2ccncc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2COc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
The impure 1-[2-(Pyridin-4-yloxymethyl)phenyl]piperazine (˜50 mg) was dissolved in 5 mL of dichloromethane along with triethylamine (50 μL, 0.36 mmol). 3,5-Bis(trifluoromethyl)phenyl isocyanate (50 μL, 0.29 mmol) was added and the reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in 2 mL methanol. The reaction mixture was purified by reverse phase HPLC to give 10 mg of product as a white solid. 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.28 (d, 2H), 8.17 (s, 2H), 7.73 (s, 1H), 7.49 (d, 1H), 7.38 (t, 1H), 7.18-7.25 (m, 4H), 5.39 (s, 2H), 3.80-3.85 (m, 4H) 3.00-3.04 (m, 4H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:24][CH3:25])=[C:11]([CH:23]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:24][CH3:25])=[C:11]([CH:23]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:21][CH:22]=1)=[O:13]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.5 ml chlorosulfonic acid were added in one portion to 6.5 g 5-Chloro-2-methoxy-N-phenethyl-benzamide. The reaction mixture was stirred at room temperature for one hour, then 100 ml dichloromethane were added and the reaction mixture was poured on ice water. The organic layer was separated washed twice with 50 ml brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 5.53 g 4-[2-(5-Chloro-2-methoxy-benzoylamino)-ethyl]-benzenesulfonyl chloride.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25]I.O>O1CCCC1>[CH3:25][N:17]([CH:14]1[CH2:15][CH2:16][N:12]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:10])=[O:11])[CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (49 mg) in tetrahydrofuran (10 ml) was added the product from part (a) (400 mg) as a solution in tetrahydrofuran (5 ml). After 30 minutes methyl iodide (90 ul) was added and the reaction stirred overnight. The mixture was poured into water and the organics extracted into ether. The ether extractions were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product. Purification by column chromatography (eluent 20% EtOAc/Hexane) gave the subtitle compound as an oil (235 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[O:12][CH2:16][C:15]#[CH:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#CCBr
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCOc1c(F)cc(C(=O)OC)cc1F
Yield: 101.7 %

Procedure:
To 80 ml of acetonitrile were added 4.5 g of methyl 3,5-difluoro-4-hydroxybenzoate, 3.5 g of propargyl bromide and 9.4 g of cesium carbonate, and the mixture obtained was heated under reflux for 2 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.5 g of methyl 3,5-difluoro-4-(2-propynyloxy)benzoate represented by the formula:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(C(F)(F)F)c3)ccc2n1-c1ccc(OC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 24 from 2-ethoxycarbonylmethyl-1-(4-methoxyphenyl)-5-hydroxyindole-3-carboxylic acid ethyl ester (153 mg, 0.40 mmol, see (b) Example 4) and 3-trifluoromethylphenylboronic acid (114 mg, 0.60 mmol). Yield 166 mg (77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]1.S(=O)(=O)(O)O.[N+:26]([O-])([O-:28])=[O:27].[K+]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[C@:9]1([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: C[C@@]1(c2cccc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: C[C@@]1(c2cc([N+](=O)[O-])cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.25 h

Procedure:
To a solution of (4S,6S)-4-(2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.06 g, 3.41 mmol) in sulfuric acid (13.64 ml, 256 mmol) cooled in an ice bath was added potassium nitrate (0.448 g, 4.44 mmol) in one portion. After stirred for 15 min, ice bath was removed, and the mixture was stirred at room temperature for 40 min. The reaction mixture was poured into ice water containing sodium carbonate (40 g). The resulted suspension was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated and dried in vacuum to afford the crude (4S,6S)-4-(2-chloro-3-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine as a light yellow solid, which was used in next step without purification. MS m/z=356 [M+H]+. Calculated for C12H10ClF4N3O3: 355.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[CH2:16]([N+](CCCC)(CCCC)CCCC)CCC.S(OC)(OC)(=O)=O>ClCCl>[CH3:16][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[NH2:14]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1C(=O)O
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: ClCCl
Product: COC(=O)c1c(N)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
3.25 g (15 mmol) of 4-chloro-6-nitro-anthranilic acid and 9.73 ml of a 40% aqueous solution of tetrabutylammonium hydroxide are placed in 65 ml of dichloromethane. Then 1.43 ml (15 mmol) of dimethyl sulfate are added dropwise thereto and the mixture is stirred for 1 hour at room temperature and washed in succession with a small amount of water and saturated sodium chloride solution. The aqueous phases are extracted by shaking with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is stirred with a small amount of ethyl acetate. The product is precipitated with hexane and dried. 1.67 g (48.3% of theory) of 4-chloro-6-nitro-anthranilic acid methyl ester having a melting point of 114°-116° are obtained.
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:39]=[CH:40][C:41]2[O:45][C:44](=[O:46])[N:43]([CH3:47])[C:42]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:38]2[CH:39]=[CH:40][C:41]3[O:45][C:44](=[O:46])[N:43]([CH3:47])[C:42]=3[CH:48]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)cc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate (113 mg), 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (51.4 mg), [1,1′-bis[bis(1,1-dimethylethyl)phosphino-κP]ferrocene]dichloro palladium (7.34 mg) and potassium carbonate (93 mg) in acetonitrile (0.7 mL) and water (0.35 mL) was stirred at 75° C. for 2 h. The solvent was removed in vacuo and the residue was purified by flash silica chromatography eluting with 1:1 isohexane/acetone to give the subtitle compound (112 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[O:11].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
2-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with hot methanol (15 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(2-methoxy-phenyl)-urea (0.7 g, 80%) as a white solid: mp 214-216° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H, OCH3), 4.73 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.3 and 12.5 Hz, 1H, CH), 6.79-6.98 (m, 3H, Ar), 7.49 (t, H=5.7 Hz, 1H, NH), 7.77-7.89 (m, 3H, Ar), 8.04-8.08 (dd, J=1.4 and 7.3 Hz, 1H, Ar), 8.19 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 48.86, 55.64, 110.59, 118.07, 120.42, 121.22, 121.88, 127.16, 129.20, 131.61, 133.65, 134.77, 140.112, 147.40, 155.24, 167.00, 167.50, 169.83, 172.76; Anal. calcd. for C22H20N4O6+0.66H2O: C, 58.94; H, 4.79; N, 12.50. Found: C, 59.24; H, 4.86; N, 12.74.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1>[OH-].[Na+].CN(C)C=O>[OH:3][N:2]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][O:14][C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:4]=2)=[CH:19][CH:20]=1)[C:25]([OH:27])=[O:26]
Reactant: NO
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)C(=NO)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydroxylamine hydrochloride (0.089 g) in 1N sodium hydroxide solution (1.3 mL) was added to a solution of 4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid (0.291 g) in dimethylformamide and the mixture was heated on a steam bath till all the solids dissolved. The reactants were maintained in solution by intermittent heating over 2 hours, then the mixture was stirred at room temperature overnight. The formed precipitate was filtered off, then the filtrate was diluted with water and adjusted to pH 2 by the addition of dilute hydrochloric acid solution. The resulting solid was recovered by filtration and dried in vacuo to furnish 0.164 g of (Z)-alpha-(hydroxyimino-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid, mp 178°-179° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([SH:12])[C:6]=1[C:13]#[N:14])[CH3:2].Br[CH2:17][C:18]([NH2:20])=[O:19].[O-]CC.[Na+]>CO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[C:13]([NH2:14])=[C:17]([C:18](=[O:19])[NH2:20])[S:12][C:7]=2[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:15])[CH3:2]
Reactant: NC(=O)CBr
Reactant: CCOC(=O)c1cc(C)nc(S)c1C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Yield: 21 %

Procedure:
To a stirred solution of 2-cyanothioacetamide (3.52 g, 35 mmol) and ethyl 2,4-dioxovalerate (5.0 g, 32 mmol) in anhydrous EtOH (75 mL) at room temperature was added triethylamine (0.5 mL) and the reaction was stirred overnight. Filtration and washing of the precipitates with EtOH gave 3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester as a yellow solid (4.54 g, 64.5%). A mixture of this ester (3.54 g, 16 mmol), bromoacetamide (2.15 g, 16 mmol) and sodium ethoxide (2.18 g, 32 mmol) in MeOH was heated at reflux overnight. It was then allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH provided 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester as a solid (0.94 g, 21.1%).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>CO.O>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)cc2)c2cc(CC)oc2c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCc1cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A suspension of ethyl 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylate (400 mg, 1.0 mmol) and LiOH.H2O (200 mg, 4.7 mmol) in MeOH (20 mL) and water (2 mL) was stirred for 4 hr at room temperature. TLC (petroleum ether/EtOAc 4:1) indicated the reaction was complete. The reaction mixture was concentrated to dryness and poured into water (30 mL). The aqueous layer was acidified to pH˜2 with conc. HCl and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (25 mL×2), dried over Na2SO4 and concentrated to afford the desired product (350 mg, 99%) as a yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[Li+].[Br-].P(Br)(Br)[Br:24]>CN(C=O)C>[Br:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(CBr)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 417A (1.50 g, 5.51 mmol) in DMF (18.0 mL) at 0° C. was treated with LiBr (526 mg, 6.06 mmol) and PBr3 (1.64 g, 6.06 mmol), warmed to room temperature, and stirred for 30 minutes. The solution was purified by flash column chromatography on silica gel with 3:7 ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].O>C(O)C>[CH:12]([C:11]1[C:3]([CH2:2][S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1)([CH3:14])[CH3:13]
Reactant: O=C(O)CS
Reactant: CC(C)c1cc2c(cc1CCl)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1cc2c(cc1CSCC(=O)O)OCO2
Yield: 58.8 %

Procedure:
A suspension of 3.3 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole (crude oil) in 10 ml of ethanol was added to a liquid mixture comprising 2.1 g of mercaptoacetic acid, 3 g of sodium hydroxide, 25 ml of ethanol and 25 ml of water to carry out the reaction at 80° C. for 40 minutes. The reaction mixture was concentrated, followed by the addition of water. The obtained mixture was washed with ethyl acetate. Concentrated hydrochloric acid was added to the mixture to acidify the aqueous layer, followed by the extraction with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by column chromatography to obtain 2.45 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc([N+](=O)[O-])cn2)c1=O
Yield: 34.1 %

Procedure:
To a solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 77 mg (0.556 mmol) of 2-amino-5-nitropyridine was added. The resulting mixture was irradiated in microwave oven for seven hours at 120° C. The final product was collected by filtration and washed with diethylether to yield the title compound (36 mg, 34.3% yield).