Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[CH3:13][NH2:14]>CCO>[CH3:13][N:14]=[CH:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][S:2][CH3:1])[CH:6]=1
Reactant: CN
Reactant: CSCOc1cccc(C=O)c1
Solvent: CCO
Product: CN=Cc1cccc(OCSC)c1
Temperature: 40 °C

Procedure:
3-Methylsulfanylmethoxy-benzaldehyde from step 1 (3.309 g, 18.16 mmol) was dissolved in EtOH (9 mL). MeNH2 (2.55 mL, 40% in H2O) was added and the mixture was heated to 40° C. for 30 min. Upon cooling, the mixture was concentrated in vacuo. The aqueous residue was diluted with isopropanol and then concentrated in vacuo. This was repeated twice more giving 3.55 g (quant) of a pale yellow oil.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:31][C:30]3[CH:29]=[N:28][N:27]([CH3:32])[C:26]=3[NH:25][C:24]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]2=3)=[O:21])=[CH:16][C:15]=1[F:38].O>C(Cl)(Cl)Cl>[CH3:32][N:27]1[C:26]2[NH:25][C:24]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]=3[N:22]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH2:13][NH:12][CH:1]=[O:3])=[C:15]([F:38])[CH:16]=3)=[O:21])[CH2:31][C:30]=2[CH:29]=[N:28]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Reactant: O=CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Formic acid (0.85 ml, 22.5 mmol) and acetic anhydride (1.4 ml, 13.5 mmol) were combined and stirred for 1 h at room temperature. (4-Aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (113 mg, 0.3 mmol) was added and the mixture was stirred for 1 h. Water (20 ml) was added and the mixture was stirred for 1 h. It was diluted with chloroform, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield a white solid identified as the title compound (48 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1cnccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cnccn2)CC1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with pyrazine-2-carbonyl chloride (0.022 g, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (28 mg, 68%). LCMS calculated for C20H19ClN5O2 (M+H)+: m/z=396.1; Found: 396.1.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Mg]Cl)CCC.O1CCCC1.[Cl:21][CH2:22][C:23]([OH:25])=O.C(OC)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[CH2:22]([Cl:21])[C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]
Reactant: O=C(O)CCl
Reactant: COC(=O)c1ccccc1
Agent: CCCC[Mg]Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
To 5 mL of tetrahydrofuran was added hexamethyldisilazane (6.6 mmol) under the atomosphere of nitrogen gas and after the solution was cooled to 0° C., 6.67 mL of 0.9 M n-butylmagnesium chloride/tetrahydrofuran (6 mmol) was added. The mixture was stirred at 0° C. for 10 minutes. Then, after cooling to -30° C., a solution of 284 mg (3.0 mmol) of monochloroacetic acid and 136 mg (1 mmol) of methyl benzoate in 5 mL of tetrahydrofuran was added dropwise for 5 minutes. This mixture was stirred at -30° C. for 30 minutes and, while the temperature was allowed to rise to room temperature, was further stirred for 1 hour. This reaction mixture was poured in 1N-HCl (50 mL) and extracted with ethyl acetate (50 mL×2). The extract was washed with saturated aqueous NaHCO3 solution (50 mL×1) and water (30 mL×1) in that order and dries over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to provide a light-yellow oil. Comparative HPLC analysis of this oil with an authentic sample revealed that the oil was predominantly composed of the objective phenacyl chloride (reaction yield 84.3%). Methylbenzoate (reaction yield 17.5%) was obtained as a byproduct.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=C[CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)CCC>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCCCN
Product: CCCCn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 75.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), n-butylamine (0.097 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 92 mg (0.32 mmol, 75.2% yield) of the title compound.
Reaction SMILES: [CH:1]([NH2:3])=O.[NH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=O)=[CH:12][CH:11]=2)[C:6]=1[C:19]#[N:20].[OH2:21]>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[C:6]3[C:5](=[N:4][CH:1]=[N:3][C:19]=3[NH2:20])[NH:9][N:8]=2)=[CH:15][CH:14]=1)([O-:18])=[O:21]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)n[nH]c1N
Reactant: O
Reactant: NC=O
Product: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Yield: 72 %

Procedure:
A solution of formamide (30 mL) and 5-amino-3-(4-nitrophenyl)-1H-pyrazole-4-carbonitrile (7.25 g, 32 mmol) was heated to 160° C. overnight under an argon atmosphere. The reaction was cooled, and 25 mL of H2O was added. The resulting solid was recovered by filtration and rinsed with cold H2O to afford 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.9 g, 72% yield). ESI-MS m/z [M+H]+ found 257.5, calculated 257.2.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:8]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=1.[F:35][C:36]1[N:41]=[C:40]([F:42])[C:39]([F:43])=[C:38](F)[C:37]=1[F:45]>CCCCC.O1CCCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:9]2[NH:10][CH:11]=[C:7]([C:38]3[C:37]([F:45])=[C:36]([F:35])[N:41]=[C:40]([F:42])[C:39]=3[F:43])[C:8]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[CH:27][CH:26]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2[nH]cc(-c3c(F)c(F)nc(F)c3F)c2-c2ccncc2)cc1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
1.8 ml (2.75 mmol) of 1.54 N solution of t-butyllithium in pentane were added to a solution of 650 mg (1.37 mmol) of 4-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in step 7(iii) above] in 15 ml of tetrahydrofuran at −78° C. and the mixture was stirred for 10 minutes. At the end of this time, 165 μl (1.51 mmol) of pentafluoropyridine were added to the reaction mixture. The cooling bath was then removed and the mixture was stirred for 30 minutes. At the end of this time, 70 ml of water and 50 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, and then this was extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 4:1 by volume mixture of hexane and ethyl acetate as the eluant to give 346 mg (yield 65%) of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[Cl:9][S:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:23])=[CH:16][N:17]=[CH:18]2)(=[O:12])=[O:11]>>[ClH:9].[ClH:9].[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([S:10]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[C:15]([CH3:23])=[CH:16][N:17]=[CH:18]3)(=[O:11])=[O:12])[CH2:5]1
Reactant: CC1CNCC(C)N1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Product: Cc1cncc2cccc(S(=O)(=O)N3CC(C)NC(C)C3)c12
Product: Cl
Yield: 120.6 %

Procedure:
Using 0.23 g of 2,6-dimethylpiperazine and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.47 g of the objective compound (white crystals).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=O.CC1(C)C(C)(C)OB([C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=2)O1.[NH3:31]>>[OH:3][CH2:1][C:4]1[CH:9]=[C:8]2[C:7]([CH2:28][C:24]3[C:25]([C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=4)=[N:27][NH:31][C:23]=32)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: N
Product: NC(=O)c1ccc(-c2n[nH]c3c2Cc2ccc(CO)cc2-3)cc1

Procedure:
The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 44C and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide in Example 1D. MS (DCI/NH3) m/z: 306.0 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 3.88 (s, 2H), 4.59 (s, 2H), 5.22 (s, 1H), 7.25 (d, J=7.80 Hz, 1H), 7.32-7.45 (m, 1H), 7.52 (d, J=7.80 Hz, 1H), 7.65 (s, 1H), 7.88 (s, 2H), 7.99 (d, J=7.80 Hz, 2H), 13.29 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[CH2:29]([NH2:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>COCCO.C(O)(C)C>[S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=1)([OH:45])(=[O:44])=[O:43].[C:23]1(/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:6][CH:7]=2)=[C:12](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:13]([F:16])([F:15])[F:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCCN
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: COCCO
Product: CCCCCCNCCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
2.23 g (5 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, are dissolved in a mixture of 5.0 g (50 mmoles) of n-hexylamine and 10 ml of 2-methoxyethanol. The mixture is boiled for 30 minutes, then evaporated, and the residue is passed through a chromatographic column filled with 50 g of silica gel. The column is eluted with benzene. The fractions which are chromatographically uniform are combined and evaporated, the residue is dissolved in 5 ml of isopropanol, and a solution of 1.20 g (6 mmoles) of p-toluenesulfonic acid in 6 ml of isopropanol is added. The separated crystals are filtered off and washed with ether. 2.14 g (91.8%) of the aimed compound are obtained; m.p.: 151°-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][CH:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(Cl)Cl>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH2:12][CH:9]2[N:8]3[C:33](=[O:34])[NH:1][C:2]4=[CH:3][CH:4]=[CH:5][C:6](=[C:7]34)[O:11][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cccc(N)c3N2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc4[nH]c(=O)n2c34)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Toluene-4-sulfonic acid 5-amino-3,4-dihydro-2H-benzo[1,4]oxazin-3-ylmethyl ester (6.7 g , ˜10 mmole) was dissolved in methylene chloride (100 mL), N, N-diisopropylethylamine (5.22 mL, 30.0 mmole) was added, followed by carbonyldiimidazole (4.05 g, 25.0 mmole), and the mixture was stirred at room temperature under nitrogen overnight. The mixture was diluted with methylene chloride (100 mL), washed with water (2×200 mL), saturated sodium bicarbonate (200 mL) saturated sodium chloride (200 mL) and dried (Na2SO4). Filtration, evaporation in vacuum and column chromatography on silica gel with 1% methanol/methylene chloride as eluent gave 2.0 g of the title compound as an off white solid, m.p. 140-142° C. 1H NMR (DMSO-d6): δ 10.7 (s, 1H); 7.63 (d, 2H); 7.47 (d, 2H); 6.82 (t, 1H); 6.57 (d, 1H); 6.52 (d, 1H); 4.53 (m, 1H); 4.43 (dd, 1H); 4.34 (dd, 1H); 4.16 (dd, 1H); 4.10 (dd, 1H); 2.38 (s, 3H). MS (ESI) m/z359 ([M−H]−).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]1[C:18]([C:19](OCC)=[O:20])=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[CH:16]=[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:14]=1.C(OCC)(=O)C>O1CCCC1>[OH:20][CH2:19][C:18]1[C:13]([CH3:12])=[N:14][C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:16][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CO
Temperature: 0 °C
Yield: 30.5 %

Procedure:
To a suspension of lithium aluminum hydride (0.32 g) in a mixture of dry tetrahydrofuran (4 ml) and diethyl ether (8 ml) was dropwise added a solution of ethyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (1 g) in dry tetrahydrofuran (4 ml) at -20° C. to -10° C. The excess lithium aluminum hydride was decomposed by a careful addition to ice water. Ethyl acetate (25 ml) was added thereto and the separated organic layer-was washed with 10% sulfuric acid (15 ml), saturated aqueous sodium bicarbonate and aqueous sodium chloride successively and concentrated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with chloroform. The fractions containing the desired compound were combined and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (0.27 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:20](=O)[CH2:19][C:17](=O)[NH:16][C:14]2=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:17]1[CH:19]=[C:20]2[C:6]3[C:5]([CH2:11][CH2:12][N:13]2[C:14](=[O:15])[N:16]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3
Reactant: COc1ccc(CCN2C(=O)CC(=O)NC2=O)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2

Procedure:
A mixture of 1-(3,4-dimethoxyphenylethyl)barbituric acid (20.2 g) and phosphorus oxychloride (100 ml) is refluxed for 2.5 hours at 100°-110° C. The excess of phosphorus oxychloride is distilled. The residue is poured onto crushed ice and made basic with a cold solution of 30% aqueous sodium hydroxide. A yellow gummy precipitate is separated and extracted with chloroform. The extract is washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is purified by passage over a silica gel column using chloroform as eluent to give the desired compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][NH2:38])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.[N+]([O-])(O)=O.CC1C=C(C)[N:46]([C:50](=N)[NH2:51])N=1.CCN(C(C)C)C(C)C.C([O-])=O>CC#N>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]2)=[CH:22][C:23]=1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][NH:38][C:50]([NH2:51])=[NH:46])=[CH:33][CH:34]=1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: O=C[O-]
Solvent: O=[N+]([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCNC(=N)N)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 34.2 %

Procedure:
To a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(2-aminoethoxy)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (44, 31 mg, 0.057 mmol) and 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate (23 mg, 0.11 mmol) in CH3CN was added DIPEA (30 μL, 0.17 mmol). The reaction was heated at 60° C. for 4 hours, then cooled to room temperature and concentrated under vacuum. The residue was dissolved in MeOH and treated with a few drops of NaOMe (25 wt % in MeOH) for 1 hour. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (C18 30×100 mm column, 5-40% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) to give urea 46 (9 mg, 34% yield) as the formate salt. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.11-7.20 (m, 3 H), 7.07 (d, J=8.6 Hz, 2 H), 6.81-6.89 (m, 2 H), 4.39 (d, J=9.3 Hz, 1 H), 4.12 (d, J=9.1 Hz, 1 H), 4.08 (t, J=4.9 Hz, 2 H), 3.94 (s, 2 H), 3.58 (t, J=5.1 Hz, 2 H), 3.34-3.48 (m, 3 H), 2.20 (s, 3 H), 2.14 (s, 3 H); MS (ES+) [M+H]+=462.
Reaction SMILES: [OH-].[K+].CC1C=CC(S([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([F:23])=[CH:16][C:15]=2[Cl:24])(=O)=O)=CC=1[N+]([O-])=O>O.O1CCOCC1>[Cl:24][C:15]1[CH:16]=[C:17]([F:23])[C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[OH:13]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc([N+](=O)[O-])c(F)cc2Cl)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Yield: 81.1 %

Procedure:
A solution of 12.84 g (0.195 mole) of potassium hydroxide in 200 mL of water was added to a vigorously stirred solution of 34.0 g (0.097 mole) of 2-chloro-4-fluoro-5-nitrophenyl 4-methyl-3-nitrophenylsulfonate in 190 mL of p-dioxane. The resultant mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was filtered and the filtrate acidified with concentrated hydrochloric acid. The acidic solution was extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure to leave a solid. The solid was washed with petroleum ether to yield 15.07 g of 2-chloro-4-fluoro-5-nitrophenol.
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])(=[O:4])=[O:3].[OH-].[Na+].Cl>CC#N>[CH2:31]([O:30][C:24]1[CH:23]=[C:22]([CH:16]([N:9]2[C:8](=[O:33])[C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]2=[O:15])[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH3:32]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NS(C)(=O)=O)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (0.8 g, 1.39 mmol) and 2N NaOH (1.59 mL, 3.18 mmol) in CH3CN (120 mL) was stirred at room temperature for 8 hours. The mixture was neutralized with 6N hydrogen chloride (0.6 mL) and then concentrated. The residue was dissolved in methylene chloride (90 mL), washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulting solid was slurried in ethanol (50 mL) to give after isolation by filtration 2-[1-3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-[(methylsulfonyl)amino]isoindoline-1,3-dione (0.6 g, 86%) as a white solid: mp 191-193° C.; 1H NMR (DMSO-d6) δ 9.31 (s, 1H), 7.85-7.74 (m, 2H), 7.61 (d, J=6.6 Hz, 1H), 7.08 (s, 1H), 7.00-6.91 (m, 2H), 5.80-5.74 (m, 1 H),.4.38-4.28 (dd, J=10.5, 14.3 Hz, 1H), 4.19-4.11 (dd, J=4.5, 14.3 Hz, 1H), 4.03 (q, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.27 (s, 3H), 3.00 (s, 3H0, 1.32 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ 167.43, 166.71, 148.92, 147.87, 136.26, 135.73, 131.91, 129.40, 125.01, 119.79, 118.39, 117.59, 112.41, 111.76, 63.83, 55.48, 53.00, 47.35, 41.06, 40.63, 14.64; Anal. Calcd. for C21H24N2O8S3+0.05 didulfonamide: C, 50.56; H, 4.86; N, 5.60; S, 13.12. Found: C, 50.25; H, 4.81; N, 5.60; S, 13.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:30][C:28](=[O:29])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(Cl)cc1)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
In a reaction vessel were placed 0.20 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.10 g of 4-chlorophenylacetic acid, 0.08 g of potassium carbonate and 5 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 30 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.22 g of 3,5-dichloro-4-(3-(4-chlorophenylacetyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy) benzene (90% yield), nD22.0 1.5698.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:29])[C:25]=1[O:26][CH2:27][CH3:28])[C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([O:21]C)[CH:9]=1)=[O:6].B(Cl)(Cl)Cl.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:29])[C:25]=1[O:26][CH2:27][CH3:28])[C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:21])[CH:9]=1)=[O:6]
Reactant: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(OC)c2)cc1Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)O)c(O)c2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
A solution of tert-butyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5) (55 mg, 0.13 mmol) in DCM (5 mL) was cooled to 0° C. and treated dropwise with a solution of 1 M boron trichloride in DCM (349 μL, 349 μmol). The reaction mixture was stirred at 0° C. for 1 h and then at RT for 2 h. The reaction mixture was cooled to 0° C. and water (0.5 mL) and sat. aq. NaHCO3 (2 mL) were added. The resulting white precipitate was collected by filtration and washed with water (2 mL). The solid was dried, then purified by capture and release on SAX, eluting with 5% AcOH in THF to afford 4-(3,5-dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid (AAA-057) (11 mg, 24%) as a white solid: m/z 370 [M+H]+ (ES+), 368 [M−H]− (ES−); 1H-NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 8.06 (2H, s), 7.76 (1H, d), 7.48 (1H, d), 7.28 (1H, dd), 4.14 (2H, q), 1.91 (1H, s), 1.40 (3H, t), 1.35 (1H, s).