Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[O:3]1
Reactant: CC1Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1Oc2ccc([N+](=O)[O-])cc2O1
Yield: 79.6 %

Procedure:
27.2 g of 2-methyl-1,3-benzodioxole, dissolved in 150 ml of glacial acetic acid, were nitrated at 15°-25° C. with 18 ml of nitric acid (d=1.4) in 50 ml of glacial acetic acid. The precipitated crystals were removed by filtration under suction and recrystallized from methanol. There were obtained 28.8 g (79.6% of theory) of 2-methyl-5-nitro-1,3-benzodioxole of melting point 84°-95° C. after sublimation at 0.1 mm/70° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21].C1COCC1.[OH-].[Na+].Cl>CO>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-n3cc4c(n3)CCCC4)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)butyl)amino)benzoate (243.9 mg), THF (1.0 ml) and methanol (1.0 mL) was added 1M aqueous sodium hydroxide solution (1.035 mL), and the mixture was stirred at 50° C. overnight. To the reaction mixture was added 1M hydrochloric acid (1.1 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: [O:1]1[C:5](=[O:6])[NH:4][C:3](=[O:7])[NH:2]1.[CH:8]([N:11]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:12](Cl)=[O:13])([CH3:10])[CH3:9]>CN(C)C1C=CN=CC=1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:11]([CH:8]([CH3:10])[CH3:9])[C:12]([N:2]2[C:3](=[O:7])[NH:4][C:5](=[O:6])[O:1]2)=[O:13])=[CH:20][CH:19]=1
Reactant: CC(C)N(C(=O)Cl)c1ccc(F)cc1
Reactant: O=c1[nH]oc(=O)[nH]1
Agent: CN(C)c1ccncc1
Product: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A 1 L three neck round bottom flask equipped with nitrogen inlet, thermometer and water condenser was charged with dioxanes (400 mL), 1,2,4-oxadiazole-3,5-dione (30 g 0.29 moles, prepared according to Srivastava, P. and Robins, R., J. Med. Chem. 1981, 24, 1172-1177), 4-dimethylaminopyridine (36 g, 0.29 mole), and N-isopropyl-4-flourophenylcarbamoyl chloride (63 g, 0.29 moles) at room temperature. The yellow mixture was heated at reflux for 4 hours. When no starting material was detected by thin layer chromatography, heat was tuned off and mixture was cooled to room temperature. The solvent was removed under reduced pressure and the resulting solids were suspended in ethyl acetate. The mixture was washed with 1N HCl, and the aqueous layer was extracted twice with ethyl acetate. The combined organic solutions were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was crystallized from chlorobutane and hexanes, and filtered to give 47 g (57%) of the title compound as a white solid melting at 94-95° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[NH:8][C:9](=[S:12])[NH:10][N:11]=1.Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[NH:11][N:10]=[C:9]([S:12][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)c(C)o1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1cc(-c2nc(SCc3ccccn3)n[nH]2)c(C)o1
Yield: 70 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2,5-dimethylfuran-3-yl)-2H-1,2,4-triazole-3(4H)-thione (example 7a) and 2-(bromomethyl)pyridine hydrobromide. Yield 70%. 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 3H), 2.59 (s, 3H), 4.32 (s,2H), 6.35 (s, 1H), 7.28-7.29 (d, 1H), 7.35-7.36 (d, 1H), 7.75 (t, 1H) 8.62 (s, 1H). MS(M+H, 287).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
(S)-2-t-butoxycarbonylamino-succinic acid 4-benzyl ester (545 mg, 1.69 mmol) was dissolved in tetrahydrofuran (THF) to which N-methylmorpholine (NMM, 0.19 mL, 1.77 mmol) and isobutyl chloroformate (0.23 mL, 1.77 mmol) were added at 0° C., followed by stirring at that temperature for 30 min. After 30 min, the resulting white solid salt was removed by celite filtration, and a solution of sodium borohydride (96 mg, 2.53 mmol) in distilled water (2 mL) was added to the resulting clear filtrate without further concentration at room temperature. After stirring for 1 hour at room temperature, THF was distilled under reduced pressure. The reaction was diluted with ethyl acetate and was terminated by the addition of 1N HCl. The organic layer was extracted with ethyl acetate and was purified by column chromatography (ethyl acetate:hexane=1:1) to afford 468 mg (yield: 90%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]#[N:9])[CH3:2].C(N(CC)CC)C.[SH2:17].O>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[S:17])[NH2:9])[CH3:2]
Reactant: CCn1cccc1C#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1cccc1C(N)=S
Yield: 65 %

Procedure:
The 1-ethylpyrrole-2-carbonitrile obtained above (3.0 g, 25 mmole) is dissolved in a solution of triethylamine (12.5 g, 125 mmole) in pyridine (13 ml), and therein hydrogen sulfide is blown at 20° C. for 6 hours. To the reaction mixture is added water (300 ml). The precipitated crystals are separated by filtration, dried, and then recrystallized from ligroin to give 1-ethylpyrrole-2-carbothioamide (2.5 g, yield: 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][C@@H:9]1[C:23]#[N:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+].Cl.C(N(CC)CC)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:10][C@@H:9]1[C:23]1[NH:27][N:26]=[N:25][N:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NOCc2ccccc2)CC[C@@H]1C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](NOCc2ccccc2)CC[C@@H]1c1nnn[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of trans-5-benzyloxyamino-2-cyano-piperidine-1-carboxylic acid-1-tert-butyl ester (6 gm, 0.018 mol) in toluene (120 ml) were added sodium azide (5.88 gm, 0.090 mol), triethylamine hydrochloride (12.42 gm, 0.090 mol) and the resulting mixture was heated to 100° C., under stirring for 2 hours. The reaction mixture was cooled to 25° C. to 35° C. and poured into saturated aqueous ammonium chloride solution (150 ml). The mixture was stirred for 15 min. and aqueous layer was extracted with ethyl acetate (1×120 ml). The combined organic layer was dried over sodium sulfate and was concentrated under vacuum to obtain the step-1 product as colorless oil, in 6.0 gm quantity (yield 89%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:11])[C:4]([CH:12]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[Cl:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[C:3]1[S:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:12][C:4]2=1
Reactant: COC(=O)CS
Reactant: Cn1c(Cl)c(C=O)c2cccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3cccc(Cl)c3n(C)c2s1
Yield: 83 %

Procedure:
Prepared from (47) (6.5 g), K2CO3 (11.17 g) and methyl 2-mercaptoacetate (4.46 ml) yielding (50) 6.62 g (83%). M.p. 166°-168° C.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2].[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[C:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: NCCc1ccccn1
Reactant: N#Cc1ncc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncc(F)cc1NCCc1ccccn1
Temperature: 115 °C
Yield: 37.8 %

Procedure:
841 mg of 2-cyano-3,5-difluoropyridine, 880 mg of 2-(2-aminoethyl)pyridine and 1.658 g of potassium carbonate in 12.5 ml of dimethyl sulphoxide are introduced into a 20 ml microwave tube reactor. The mixture is then heated in a microwave for 1 and a half hours at 115° C. The reaction medium is run into 100 ml of water and 100 ml of ethyl acetate. The aqueous phase is re-extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. After purification by flash chromatography on 70 g of silica gel, elution being carried out with a mixture of ethyl acetate and cyclohexane (40/60 by volume), and the first eluted product being recovered, 549 mg of 2-cyano-5-fluoro-3-(2-pyridin-2-ylethylamino)pyridine are thus obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([CH2:32][OH:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([CH2:32][OH:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(CO)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nc(CO)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-3-hydroxymethyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (82 mg, 0.138 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.43 ml, 5.6 mmol) was added. The reaction was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.56 ml, 8.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with dichloromethane. The resulting precipitate was filtered, washing with water and dichloromethane then dried under high vacuum to provide 46 mg (68%) of 2-(6-fluoro-3-hydroxymethyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow powder. MS: (M+H)+=463; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.30 (br. s, 1H), 9.12 (s, 1H), 8.79 (dd, J=9.6, 3.2 Hz, 1H), 8.55 (d, J=4.9 Hz, 1H), 8.44 (d, J=7.9 Hz, 1H), 8.40 (d, J=5.7 Hz, 1H), 7.07-7.17 (m, 1H), 5.61 (t, J=5.7 Hz, 1H), 4.94 (d, J=5.3 Hz, 2H), 4.50-4.81 (m, 3H), 4.20-4.32 (m, 1H), 4.14 (dt, J=10.3, 5.2 Hz, 1H), 3.81-3.93 (m, 1H), 1.40 (t, J=6.0 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]([O:17]C)=[O:16])[CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=1)[C:15]([OH:17])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
Preparation H6, Step 1: To a solution of dimethyl 5-tert-butylisophthalate (2.5 g, 10 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (168 mg, 7 mmol) in 5.0 mL of water. The reaction mixture was stirred at RT for 3 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 700 mg of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid. MS found: (M+H)+=237.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[N:21]#[C:22]Br>C1COCC1.CCOC(C)=O>[CH2:13]([N:6]([CH2:5][C@H:2]1[CH2:3][O:4][C:22]([NH2:21])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: N#CBr
Reactant: CCN(C[C@H](N)CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C[C@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 74.8 %

Procedure:
To a stirred solution of (S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (128 mg) at r.t. in THF (5 ml) under an argon atmosphere were added potassium carbonate (182 mg) and a solution of cyanogen bromide (140 mg) in THF (5 ml). Stirring at r.t. was continued for 21 h. The mixture (off-white suspension) was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to provide (S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (108 mg, 75%) as an off-white solid. MS (ISP): 220.4 ([M+H]+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]2[CH2:21][C:22]3=[O:27])=[CH:15][CH:14]=1.I[CH3:29]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]2[CH:21]([CH3:29])[C:22]3=[O:27])=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CC3CCC2CC3=O)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CC3CCC2C(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
LHMDS (2.2 mL, 2.16 mmol, 1.0 equiv, 1.0 M in THF) was added to an oven-dried flask under N2 and cooled to −78° C. A solution of 2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2]octan-5-one (2-1, 500 mg, 2.16 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (8.6 mL) was added dropwise via cannula, and the resulting mixture was allowed to stir for 20 min at −78° C. Following this duration, the enolate mixture was added via cannula to a solution of iodomethane (0.68 mL, 10.8 mmol, 5.0 equiv) in anhydrous tetrahydrofuran (2.2 mL). After 1 h, the reaction contents were removed from the −78° C. bath and allowed to gradually warm to RT. After 18 h, LCMS showed complete consumption of starting material. The reaction was quenched with saturated NH4Cl (15 mL), added to ethyl acetate (20 mL) and diluted with water (5 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange solid. Purification by normal-phase HPLC (0-40% CH3CN:0.1% TFA in H2O) provided 7-1 as a pale yellow solid (inconsequential 1:1 mixture of diastereomers).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)[NH:8][CH2:7][CH2:6]2.CC(C)([O-])C.[K+].[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=1[CH3:41]>C1COCC1>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N:12]4[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]4)[CH:10]=3)[CH:6]=[CH:7]2)=[O:37])=[CH:34][C:33]=1[CH3:41]
Reactant: COc1cc2c(cc1N1CCN(C(=O)OC(C)(C)C)CC1)NCC2
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2ccn(C(=O)c3ccc(Br)c(C)c3)c2cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
To a mixture of intermediate 2 (0.25 g, 1.0 mmol) and potassium t-butoxide (0.114 g, 1 mmol) in dry THF (15 ml) was added 4-bromo-3-methyl benzoyl chloride (0.238 g, 1.0 mmol) in dry THF (10 ml). The resulting mixture was stirred at room temperature for 72 h, then poured onto water and extracted with dichloromethane (3×). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo to give the crude product Purification by Fcc eluting with 3% methanol/dichloromethane gave the title compound as a pale yellow oil (70 mg, 15%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]=[CH2:14].ClC1C=C(C=CC=1)C(OO)=[O:20]>ClCCl>[CH3:1][O:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:14][O:20]1
Reactant: C=Cc1ccc2c(c1OC)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(C2CO2)ccc2c1COC2=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-Methoxy-5-vinyl-2-benzofuran-1(3H)-one (120 mg, 0.63 mmol, 1.0 eq) was added into a 100 mL round bottom flask and dissolved in dichloromethane (5 mL). The solution was cooled to 0° C., and 3-chloroperoxybenzoic acid (327 mg, 1.89 mmol, 2.0 eq) was added portion wise. The mixture was then purged with N2 and stirred at r.t. for 18 hr. To above solution was added water (5 mL). The crude product was extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (hexane/EtOAc 0-50%). The desired product was obtained. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.56 (1H, aromatic, d, J=7.6 Hz), 7.31 (1H, aromatic, d, J=7.6 Hz), 5.50 (2H, m, CH2 lactone), 4.23 (1H, m), 4.02 (3H, s, Me), 3.22 (1H, m), 2.72 (1H, m).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Zn]>[NH2:20][C:19]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N)c(NCc2ccccc2)c1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
To a stirring solution of ethyl 3-(benzylamino)-4-nitrobenzoate (1.52 g, 5 mmol) in ethanol (50 mL) and acetic acid (7 mL) was added zinc dust (2.3 g, 35 mmol). After 1 hr at room temperature, the solids were filtered and the remaining solution was concentrated. The resulting residue was diluted with ethyl acetate (200 mL) and washed with dilute aq. NaHCO3 (1×100 mL), then the organic layer was dried (MgSO4), filtered and then concentrated to provide 1.44 g (˜100%) of crude ethyl 4-amino-3-(benzylamino)benzoate as an orange/brown oil. This material was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][CH:21]=[C:20]2[C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: COC(=O)C(=O)c1c[nH]c2c(OC)cccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c12
Temperature: 25 °C
Yield: 17 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.491 g, 2.61 mmol) and (7-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.611 g, 2.62 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (10 mL, 10 mmol) dropwise over 5 minutes. The mixture was heated at 65–70° C. for 15 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated to ˜40 mL. Upon standing, a bright orange solid precipitated which was isolated by filtration and dried under vacuum at 80–100° C. overnight affording the title compound (0.165 g, 17%). The mother liquor was concentrated onto SiO2 and flash chromatography (30–50% EtOAc/hex) afforded additional product (0.212 g, 22%). 1H NMR (400 MHz, DMSO-d6) 11.98 (br s, 1H), 11.13 (s, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.60 (dd, J=8 Hz, 1H), 7.25 (d, J=3.1 Hz, 1H), 6.97 (dd, J=7, 7 Hz, 1H), 6.88 (dd, J=7, 1 Hz, 1H), 6.54 (d, J=7 Hz, 1H), 6.48 (d, J=3.1 Hz, 1H), 6.43 (dd, J=8, 8 Hz, 1H), 5.98 (d, J=8 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370.1 (M−−1). HRMS 372.1330 (M++1, calcd for C22H18N3O3 372.1348). Anal. Calcd for C22H17N3O3: C, 71.15; 4.61; N, 11.31. Found: C, 70.80; H, 4.58; N, 11.06.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(cc1N)OCCO2
Yield: 96.1 %

Procedure:
According to the procedure described in Example 6A Step 3 a mixture of ethyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.72 g, 6.8 mmol) and Pd/C (10%, 0.2 g) in EtOAc (100 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford ethyl 7-amino-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as a solid (1.459 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 6.18 (s, 1H), 5.41 (br, 2H), 4.30 (m, 4H), 4.19 (q, 2H), 1.38 (t, 3H); LC-MS (ESI) m/z 224 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([OH:21])=[CH:13][C:14]=3[N+:18]([O-])=O)[C:9]2=[O:22])[CH2:6][CH2:5][C:4](=[O:23])[NH:3]1.[H][H]>[Pd].C1COCC1>[NH2:18][C:14]1[CH:13]=[C:12]([OH:21])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:22]
Reactant: [H][H]
Reactant: O=C1CCC(N2C(=O)c3cc(O)cc([N+](=O)[O-])c3C2=O)C(=O)N1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(O)cc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
In yet another embodiment, the process provided herein for preparing 4-amino-2-(2,6-dioxopiperidin-3-yl)-6-hydroxyisoindoline-1,3-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprises the step of reducing 2-(2,6-dioxopiperidin-3-yl)-6-hydroxy-4-nitroisoindoline-1,3-dione with hydrogen in the presence of (i) a catalyst, in one embodiment, Pd/C; in (ii) a solvent, in one embodiment, THF; to form 4-amino-2-(2,6-dioxopiperidin-3-yl)-6-hydroxyisoindoline-1,3-dione.