Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=O)[S:29][C:30]=1[Cl:31]>ClCCCl>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:29][C:30]=1[Cl:31]
Reactant: O=Cc1cc(Br)c(Cl)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Clc1sc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Morpholine (15.2 mL), acetic acid (9.1 mL), and then sodium triacetoxyborohydride (50.3 g) is added to a solution of 4-bromo-5-chloro-2-thiophenecarbaldehyde (Preparation 61, 35.7 g) in 1,2-dichloroethane (600 mL) at 0° C. The mixture is allowed to warm to room temperature, and after 18 h, it is quenched with a 2N NaOH solution (200 mL) with ice bath cooling. The organic layer is separated and washed with 1 N NaOH solution (2×200 mL). The aqueous layers are extracted with CH2Cl2 (2×100 mL). The combined organic layers are extracted with 0.25 M HCl solution (2 L) and the resulting aqueous layer is made basic with 2N NaOH solution. The mixture is then extracted with CH2Cl2 (2 L) and the organic layer is dried (Na2SO4) and concentrated to afford 39.24 g (84%) of the title compound as a light yellow oil. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ7.03, 3.63, 3.57, 2.42; 13C NMR (100 MHz, CDCl3) δ140.9, 127.3, 125.9, 109.2, 66.9, 57.6, 53.3; MS (ESI+) m/z 296 (72, (M+H)+), 298 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1nc2cc(-n3cccc3)ccc2s1
Yield: 37.5 %

Procedure:
5-Amino-2-methylbenzothiazole (30.0 g, 0.203 mol) and 2,5-dimethoxytetrahydrofuran (27.0 g, 0.204 mol) were combined with 90 mL of acetic acid and the solution was heated at reflux for 1 hr. The mixture was evaporated to a dark slurry and purified by column chromatography. This afforded 16.3 g (39% yield) of product, m.p. 91-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(O)C1
Product: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 71(b), from benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-hydroxy-piperidine-1-carboxylate by alkylation with 2-bromomethyl-naphthalene there was obtained benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 518 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1CCN2C(=NCCC2)CC1>COCCOC>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide in 80 ml of DME, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene was added. The mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:5]1[S:1][N:2]=[CH:3][CH:4]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccns1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-isothiazole carboxylic acid (5 g, 38.7 mmol) in dichloromethane (200 mL), 4-(dimethylamino)pyridine (473 mg, 3.87 mmol), N,O-dimethylhydroxylamine hydrochloride (4.53 g, 46.4 mmol) (N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (8.17 g, 42.6 mmol) and triethylamine (13.63 μL, 97.0 mmol) were added and the reaction was stirred overnight at room temperature. The reaction mixture was then successively washed with 1N HCl, 1N NaOH and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 8.59 (s, 1H), 7.97 (s, 1H), 3.94 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][NH:10][C:9](=[O:19])[CH2:8][C:7]=2[CH:20]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:10]1[C:9](=[O:19])[CH:8]([CH2:12][C:6]2[CH:7]=[CH:20][CH:3]=[CH:4][CH:5]=2)[C:7]2[CH:20]=[C:3]([O:2][CH3:1])[C:4]([O:21][CH3:22])=[CH:5][C:6]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)C(=O)N(Cc1ccccc1)N=C2c1ccccc1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa (200 mg, 0.67 mmol) in DMF (10 ml), under an inert atmosphee, add NaH in oil (50 mg, 1.25 mmol). Then add dropwise benzyl bromide (150 μl, 1.26 mmol). After 2 hours at room temperature, evaporate the DMF. Take up the residue in CH2Cl2, wash twice with water. Dry the organic phases on Na2SO4. Purify by silica gel column chromatography (AcOEt/hexane, 4:1). Yield: 79%. 1H-NMR (200 MHz, CDCl3): d 3.35–3.56 (m, 2H, CH2Ph), 3.70 (s, 3H, OCH3), 3.80 (m, 1H, CH), 3.97 (s, 3H, OCH3), 4.87 (d, J=10.2, 1H, NCHPh), 5.30 (d, J=10.2, 1H, NCHPh), 6.61 (s, 1H, Ar), 6.93 (s, 1H, Ar), 7.06–7.42 (m, 13H, Ar), 7.59 (d, J=4.8, 2H, Ar). SM: 477 (M+H), 500 (M+H+Na).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:22])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([CH:20]=[CH2:21])[O:14]1>>[F:10][C:8]1[CH:9]=[C:2](/[CH:21]=[CH:20]/[B:15]2[O:16][C:17]([CH3:19])([CH3:18])[C:13]([CH3:22])([CH3:12])[O:14]2)[CH:3]=[C:4]([F:11])[C:5]=1[CH:6]=[O:7]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1c(F)cc(Br)cc1F
Product: CC1(C)OB(/C=C/c2cc(F)c(C=O)c(F)c2)OC1(C)C
Yield: 75.1 %

Procedure:
According to procedure for the synthesis of example A51A, by using 4-bromo-2,6-difluorobenzaldehyde (1.10 g, 4.98 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.97 mL, 5.72 mmol) to give the title compound as a colorless oil (1.10 g, 76%). 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.05 (d, J=9.6 Hz, 2H), 7.22 (d, J=8.8 Hz, 1H), 6.28 (d, J=18.8 Hz, 1H), 1.33 (s, 12H); MS ESI 295.1 [M+H]+, calcd for [C15H7BF2O3+H]+ 295.13.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[Na+].C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:18]#[N:19])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CBr)ccc1NC(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(CC#N)ccc1NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
The compound (155.1 mg) obtained in Example 519 was dissolved in dimethyl sulfoxide (5 ml). To the solution, sodium cyanide (127 mg) was added and the mixture was heated at 50° C. under stirring for 10 min. To the resulting reaction mixture, ethyl acetate was added and the organic layer was washed with water twice, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 77.7 mg of the titled compound (yield, 61%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CN(C)C=O>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 25 °C
Yield: 52.2 %

Procedure:
Ethyl 2-(1H-indazol-3-yl)acetate (408 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), 60% sodium hydride (96 mg, 2.4 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (475 mg, 2.2 mmol) was added, and reacted for 1 hour. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 354 mg, at a yield of 52.1%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[N:35]=[CH:36][O:37][C:38]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:38]6[O:37][CH:36]=[N:35][C:34]=6[CH3:33])[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1ncoc1C1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ocnc5C)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[C:12]([O:16][C:17](=[O:21])[CH2:18][Zn]Cl)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[O:9]=[C:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])=[CH:3][C:4]=2[CH2:8][O:7]1
Reactant: CC(C)(C)OC(=O)C[Zn]Cl
Reactant: O=C1OCc2cc(Br)ccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc2c(c1)COC2=O
Temperature: 105 °C

Procedure:
To a 20 mL microwave tube charged with 5-bromo-2-benzofuran-1(3H)-one (500 mg, 2.35 mmol) and palladium tetrakis triphenylphosphine (136 mg, 0.117 mmol) in THF (5 mL) was added (2-tert-butoxy-2-oxoethyl) (chloro) zinc (6.57 mL, 0.5 M, 3.29 mmol). The mixture was purged with nitrogen 3 times, and heated to 105° C. for 30 minutes in a microwave reactor. The reaction mixture was poured into water and filtered then extracted with ethyl acetate twice. The organic layer was ashed with brine, dried, and evaporated to dryness. The residue was purified by MPLC on a 40 g ISCO Redi-Sep column to yield tert-butyl (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate. 1H-NMR (500 MHz, CDCl3) δ ppm 7.89 (d, J=7.7 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.44 (s, 1H), 5.33 (s, 2H), 3.69 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cc2cc[nH]c2cn1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nn1ccc2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
A solution of pyrrolo[2,3-c]pyridine (8.47 mmol) and potassium tert-butoxide (16.9 mmol) in DMF (38 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (84.6 mL) is added drop-wise at rt, and the reaction mixture is stirring at rt for 2 h., quenched with 5% Na2S2O3 aqueous solution (10 mL), and extracted with ether. The organic layer is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford pyrrolo [2,3-c]pyridin-1-ylamine (226 mg, 11%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.96 (br, 2N—H), 6.43 (d, H), 7.29 (m, H), 7.50 (d, H), 8.29 (d, H), 8.89 (s, H).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23][S:24][CH3:25])[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:17][CH2:16]1.C(=O)([O-])[O-:36].[Na+].[Na+]>CO.O>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23][S:24]([CH3:25])=[O:36])[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:17][CH2:16]1
Reactant: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: CS(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
Sodium periodate (11.3 mg, 0.053 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL). After 30 min excess sodium periodate (22 mg, 0.11 mmol) was added. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 431 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([C:26]1[N:27]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[S:55](=[O:58])(=[O:57])[NH2:56])=[CH:45][CH:44]=2)[C:28](=[O:41])[N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[N:30]=1)[CH2:23][CH2:24][CH3:25].N12CCCN=C1CCCCC2>C1COCC1>[C:1]([NH:56][S:55]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:27]2[C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:30][N:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[C:28]2=[O:41])=[CH:44][CH:45]=1)(=[O:58])=[O:57])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 145 mg (1.18 mmole) of benzoic acid and 192 mg (1.18 mmole) of 1,1'-carbonyldiimidazole in 1 mL of THF was stirred under N2 at 55° C. for 2 hours. Then a solution of 157 mg (0.296 mmole) of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) and 133 mL (135 mg, 0.888 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 1 mL of THF was added dropwise. After being stirred overnight at 55° C., the mixture was partitioned between ethyl acetate and 5% citric acid (aqueous). The organic layer was washed with H2O and then with saturated NaCl solution. The ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue as in Example 16, Step D, gave 159 mg (85%) of the title compound, homogeneous by TLC in 98:2 CH2Cl2 --MeOH and comparable in physical properties to the product made according to Example 16, Step D.
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: O=C1CCC(N2C(=O)c3cc(O)cc([N+](=O)[O-])c3C2=O)C(=O)N1
Reactant: [H][H]
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.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH:4]1[C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[CH:2][C:3]=1[B:20]([OH:23])[OH:21]
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)oc1ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2oc3ccccc3c2c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
In a 300 mL three-neck flask was put 3.6 g (14 mmol) of 3-bromodibenzofuran. The air in the flask was replaced with nitrogen. To this mixture was added 70 mL of THF, and this solution was cooled to −80° C. Then, 10 mL (16 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, this solution was stirred at the same temperature for 2 hours. Then, 3.4 mL (30 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 4 days while its temperature was returned to room temperature. After that, about 30 mL of diluted hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. Then, the aqueous layer of this mixture was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give a solid. The solid was washed with hexane, whereby 0.70 g of a white powder was obtained in 27% yield, which was the substance to be produced.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[CH2:13][C:12]=2[CH:28]=1.CN([CH:32]=[O:33])C>>[CH:32]([C:9]1[C:8]([O:7][CH3:6])=[CH:28][C:12]2[CH2:13][C:14]3[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=3[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:11]=2[CH:10]=1)=[O:33]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CC1Cc2cc(C=O)c(OC)cc2Cc2ccccc21
Temperature: 90 °C
Yield: 21 %

Procedure:
POCl3 (17 mL) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate (1.0 g, 3 mmol) in dry DMF (40 mL) at RT under argon, and the dark solution was heated at 90° C. for 48 hr. The reaction was concentrated on the rotavap and the residue was partitioned between H2O and EtOAc. The organic layer was separated, dried (MgSO4), and concentrated on the rotavap. The residue was reconcentrated from xylenes (to remove any remaining DMF) then was chromatographed on silica gel (7% EtOAc in hexanes) to afford the title compound (230 mg, 21%) as a colorless oil: MS (ES) m/e 339.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1>ClCCl.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]2=3)=[O:16])=[CH:12][C:11]=1[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1/C=C/C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)OC(C)(C)C
Yield: 82 %

Procedure:
4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid from Example E45.1 (1.1 g, 4.2 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (720 mg, 3.6 mmol) were dissolved in dichloromethane (50 ml) and triethylamine (0.75 ml). DMAP (4.45 g, 3.6 mmol) and WSCD (1.36 g, 7.1 mmol) were added and the mixture was heated at re-flux for 2 days. The solution was diluted with di-chloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.35 g, 82%).