Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[CH2:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2O[C:19](=O)[S:18][N:17]=2)=[CH:12][CH:11]=1>ClC1C=CC=CC=1Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:19][S:18][N:17]=2)=[CH:14][CH:15]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:18][N:17]=2)=[CH:12][CH:11]=1
Reactant: C=C(Cl)C(=O)OCC
Reactant: O=c1oc(-c2ccc(Cl)cc2)ns1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)ns1
Product: CCOC(=O)c1csnc1-c1ccc(Cl)cc1
Yield: 17 %
Yield: 16 %

Procedure:
A solution of 40.4 g (0.30 mol) of ethyl 2-chloroacrylate and 2.14 g (0.010 mol) of 5-(p-chlorophenyl)-1,3,4-oxathiazole-2-one in 75 g of o-dichlorobenzene was held at reflux (165°-175°) for 55 minutes, at which time gas chromatography analysis indicated about 70% reaction. The reaction mixture was allowed to cool, and the supernatant was decanted from polymeric ester. Concentration of the supernatant under vacuum, chromatography of the residue on silicic acid, and crystallizations of the various materials thus obtained gave 0.30 g (16%) of ethyl 3-(p-chlorophenyl)-4-isothiazolecarboxylate, m.p. 69°-70°, and 0.31 g (17%) of ethyl 3-(p-chlorophenyl)-5-isothiazolecarboxylate, m.p. 87°-89°.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[CH:25][C:23]=3[N:24]=2)=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: Cc1cn(-c2ccc3nc(-c4ccc(C)c(I)c4)[nH]c3c2)cn1
Reactant: C#Cc1cnc2cccnn12
Product: Cc1cn(-c2ccc3[nH]c(-c4ccc(C)c(C#Cc5cnc6cccnn56)c4)nc3c2)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 2-(3-iodo-4-methylphenyl)-6-(4-methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazole (as prepared above) in a manner similar to that described for in Example 1. The title compound was obtained a pale yellow solid. Mp: 182-184° C.; 1H NMR (400 MHz, CD3OD) δ: 8.57 (2H, brs), 8.26 (1H, s), 7.98-8.05 (3H, m), 7.74 (1H, s), 7.68-7.70 (1H, d, J=8.4 Hz), 7.46-7.48 (2H, m), 7.42-7.44 (1H, d, J=8.4 Hz), 7.29-7.33 (1H, dd, J=4.4 and 9.2 Hz), 2.61 (3H, s), 2.31 (3H, s). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C26H20N7: 430.1775. found: 430.1778.
Reaction SMILES: [N+](=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[N-].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][OH:14]>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][O:14][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:18]
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: CCOC(=O)CO
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COC(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
To a solution of dimethyl diazopropanedioate (4 g, 25 mmol), prepared according to Peace, Carman, Wulfman, Synthesis, 658-661, (1971), in DCM (10 mL) was added ethyl glycolate (1.2 mL, 12.8 mmol) followed by rhodium (II) acetate dimer (2 g, 20% mol). The reaction mixture was stirred at room temperature for 24 h. The resulting suspension was filtered through a pad of Celite® and the solvent was removed in vacuo. The crude residue was purified by column chromatography (silica gel) using a 0-60% EtOAc/hexanes gradient to provide the desired product as an oil (3 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 5-fluoro-3-methyl-2-nitrobenzoic acid (8.0 g, 40 mmol) from Step A above in DMF (100 mL) was added cesium carbonate (20.0 g, 60 mmol) followed by iodomethane (3.0 ml, 48 mmol). The reaction solution was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford methyl 5-fluoro-3-methyl-2-nitrobenzoate (8.4 g, 98%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.71-7.67 (m, 2H), 3.85 (s, 3H), 2.32 (s, 3H); MS (ESI+) m/z 214 (M+H).
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[CH2:13](N(CC)CC)C.[F:20][C:21]1[CH:27]=[C:26]([I:28])[CH:25]=CC=1N.C1(N)CC1>CN(C)C=O.O.C1(C)C=CC=CC=1>[CH:9]1([NH:8][C:6]([NH:3][C:2]2[CH:1]=[CH:25][C:26]([I:28])=[CH:27][C:21]=2[F:20])=[O:7])[CH2:10][CH2:13]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(I)cc1F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(I)cc1F)NC1CC1
Yield: 93.4 %

Procedure:
Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (39.9 g) were added N,N-dimethylformamide (200 ml) and triethylamine (34.3 ml) and a solution of 2-fluoro-4-iodoaniline 47 (48.5 g) in N,N-dimethylformamide (50 ml) was added dropwise with stirring under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 18 hrs. The reaction mixture was ice-cooled, and cyclopropylamine (21.3 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hr and added dropwise to water-toluene [2:1 (volume ratio), 750 ml] with stirring. The precipitated crystals were collected by filtration and dried to give 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 48 (61.3 g, yield 93.4%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.S(Cl)([Cl:16])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:16]
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
reacting the 2-(2,4,6-trichlorophenoxy)-ethanol with thionyl chloride in the presence of benzyltrimethyl ammonium chloride in a ration of 1:60 by weight at a temperature of from 50° C. to 80° C., in the presence of carbon tetrachloride as solvent to form 2-(2,4,6-trichlorophenoxy)-ethyl chloride; and
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2)[NH2:2].CO[CH:15](OC)[CH2:16][CH:17](OC)OC>CCO.C(Cl)Cl>[N:1]1([C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][N:7]=[CH:8]3)[CH:17]=[CH:16][CH:15]=[N:2]1
Reactant: COC(CC(OC)OC)OC
Reactant: NNc1cccc2cnccc12
Solvent: ClCCl
Solvent: CCO
Product: c1cc(-n2cccn2)c2ccncc2c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A suspension of 5-hydrazinylisoquinoline (22.0 g, 112 mmol) in EtOH (300 mL) was treated with 1,1,3,3-tetramethoxypropane (27.7 g, 169 mmol) and the mixture was heated to 100° C. for 10 h. The reaction mixture was then concentrated in vacuo and the residue obtained taken up in DCM (500 mL) and washed with a saturated aqueous solution of NaHCO3—gas formation. The aqueous layer was extracted twice with DCM and the combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 95:5 to DCM/MeOH 9:1) to give the title compound (16.1 g). UPLC-MS: MS 196.1 (M+H+); UPLC rt 0.62 min.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(NC(=NC(C)C)O[C:25]([CH3:28])([CH3:27])[CH3:26])(C)C.NC(=N)O>C(Cl)Cl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Agent: N=C(N)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of 3-cyclohexenyl-1H-indole-6-carboxylic acid (1 eq., prepared as described in Example 1, Step 1) in dry DCM (0.19 M) was treated with tert-butyl N,N′-diisopropylimidocarbamate (2 eq.). The resulting clear solution was heated at reflux for 36 h. Addition of a further equivalent of isourea was required after 16 h to drive the reaction to completion. After cooling down the solvent was evaporated giving a residue that was purified by silica gel chromatography (Flashmaster Personal, PE:EtOAc, 30:1) affording tert-butyl 3-cyclohexyl-1H-indole-6-carboxylate (75%) 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.22-1.53 (m, 5H), 1.54 (s, 9H), 1.70-1.86 (m, 3H), 1.95-1.98 (m, 2H), 2.69-2.86 (m, 1H), 7.29 (s, 1H), 7.49-7.57 (m, 2H), 7.93 (s, 1H), 11.09 (s, 1H); MS (ES+) m/z 300 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:31]1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reactant: ICC1CCC(OC2CCCCO2)C1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of diisopropylamine (810 μL, 5.78 mmol) in dry tetrahydrofuran (4.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.5 mL) cooled to −78° C. was treated with a 2.5M solution of n-butyllithium in hexanes (2.3 mL, 5.78 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (prepared as in Example 8, 1.10 g, 4.82 mmol) in dry tetrahydrofuran (4.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.5 mL). The resulting reaction mixture was allowed to stir at −78° C. for 1 h and then the reaction mixture was treated with a solution of 2-(3-iodomethyl-cyclopentyloxy)-tetrahydropyran (prepared as in Example 35, 1.94 g, 6.26 mmol) in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warn to 25° C., where it was stirred for 3 d. The reaction mixture was quenched with water (50 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was further diluted with water (100 mL) and then extracted with ethyl acetate 3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 7/3 hexanes/ethyl acetate) afforded the 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (1.07 g, 54%) as a yellow oil: FAB-HRMS m/e calcd for C21H30O6S (M+H)+ 411.1841. found 411.1851.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH-].[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:5]([O-:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([O-:15])=[O:14])([C:9]([O-:11])=[O:10])[OH:8].[CH2:23]([N+:18]1[CH:2]=[CH:1][CH:21]=[CH:20][CH:19]=1)[CH3:22].[CH2:23]([N+:18]1[CH:2]=[CH:1][CH:21]=[CH:20][CH:19]=1)[CH3:22].[CH2:23]([N+:18]1[CH:2]=[CH:1][CH:21]=[CH:20][CH:19]=1)[CH3:22]
Reactant: c1ccncc1
Reactant: CCI
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [OH-]
Product: CC[n+]1ccccc1
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Pyridine is reacted with ethyl iodide; the halide intermediate is converted to the hydroxide with Rexyn 201 (Fisher Scientific Co.), and then reacted with citric acid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Br[C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12]>CO>[CH3:1][O:2][C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12]
Reactant: Cc1nc(N)sc1Br
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1sc(N)nc1C
Temperature: 0 °C

Procedure:
Sodium methoxide was freshly prepared by dissolving 0.408 g (17.7 mmol) of sodium metal in 25 mL of abs. MeOH. After cooling to 0° C., 5-bromo-4-methyl-thiazol-2-ylamine (1.00 g, 5.18 mmol) was added and the cooling bath removed. After 15 Min., TLC indicated the absence of starting material. The reaction mixture was poured onto crashed ice/NH4Cl, twofold extracted with ethyl acetate, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=1/1), yielded 0.441 g of the title compound as brown oil; it should be stored at −28° C.
Reaction SMILES: [N+]([O-])(O)=O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][CH2:17][C:18]([CH2:20][C:21](=O)[CH3:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:11]([C:12]1[N:14]=[C:18]([CH2:17][O:16][CH3:15])[CH:20]=[C:21]([CH3:22])[N:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: COCC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: COCc1cc(C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A mixture of 4.5 g of phenylguanidine nitrate, 3.3 g of methoxyacetylacetone and 12 g of anhydrous sodium carbonate was heated with stirring and allowed to react at 150° C. for 2 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with 150 ml of toluene. The toluene layer was washed with water, dried over Glauber's salt and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.5 g (yield: 68%) of 2-anilino-4-methoxymethyl-6-methylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][NH:10][C:4]=2[CH:3]=1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>N1C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:11])[NH:9][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: O=c1[nH][nH]c2cc(Cl)ncc12
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1[nH]c(=O)c2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (2.64 g, 15.57 mmol) in pyridine (10 mL) and water (14 mL) was added ethyl chloroformate (3.38 g, 31.1 mmol) drop-wise at 0° C. The reaction was removed from the ice bath and was stirred at room temperature overnight. The reaction mixture was filtered and the solid rinsed with water to afford ethyl 6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate, which was carried onto the next step without further purification. MS ESI calc'd. for C9H8ClN3O3 [M+1]+242. found 242.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14].I[CH3:16]>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[I:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]([CH3:16])[C:7]2=[O:14]
Reactant: CI
Reactant: O=c1[nH]cnc2ccc(I)cc12
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cn1cnc2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Suspend sodium hydride (1.13 g, 47 mmol) in a solution of 6-iodo-3H-quinazolin-4-one (2.5 g, 9.2 mmol) in DMF. Stir at room temperature for 20 min, add iodomethane (6.6 g, 46 mmol) into the mixture and stir for 2 h. Dilute the mixture with 3:1 chloroform/isopropyl alcohol and wash with saturated sodium chloride solution. Dry the organic phase (sodium sulfate) and concentrate in vacuo. Purify the residue with flash chromatography (dichloromethane to dichloromethane/methanol) to give 2.5 g (95%) of the titled compound as a white solid. MS ES+ m/e 287 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:47][OH:48]>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH:47][OH:48])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 47.6 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide was prepared by the procedure of example 8 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.2 g, 1.3 mmol) and hydroxylamine hydrocloride (0.1 g, 1.4 mmol) in THF (10 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide as white solid (0.25 g, 50% yield): mp 148-150° C.; 1HNMR (CDCl3): δ1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.19 (s, 3H, CH3CO), 3.19 (dd, J=5, 15 Hz, 1H, CH2), 3.47 (dd, J=10, 15 Hz, 1H, CH2), 4.02 (q, J=7.0 Hz, 2H, OCH2CH3), 5.75-5.82 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, CF2H), 7.02-7.07 (m, 3H, Ar), 7.36 (d, J=7.5 Hz, 1H, Ar), 7.54 (t, J=7.5 Hz, 1H, Ar), 8.64 (d, J=8.8 Hz, 1H, Ar), 9.40 (s, 1H, NHCO). 13CNMR (CDCl3): δ 14.5, 24.8, 34.6, 51.1, 64.7, 111.8, 113.5, 115.1, 115.9, 120.1, 122.6, 124.9, 131.0, 136.0, 136.7, 137.4, 140.0, 150.5, 167.1, 167.7, 169.3, 169.6 Anal Calcd for C22H21F2N3O7+0.3 H2O: C, 54.73; H, 4.51; N, 8.70. Found: C, 54.36; H, 4.25; N, 8.54, 0.1% H2O.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].O[C@@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C1C=CC=CC=1>[Br:38][C:16]1[CH:17]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:19]=[C:14]([Br:13])[C:15]=1[O:39][C@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Yield: 90.4 %

Procedure:
Diethylazodicarboxylate (0.437 mL, 2.74 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (1.00 g, 1.83 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.494 g, 2.74 mmol), triphenylphosphine (0.72 g, 2.74 mmol) and benzene (12 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 3.5 h. Upon cooling to room temperature, the reaction mixture was diluted with dichloromethane and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (96:4 petroleum ether:ethyl acetate) to provide the title compound as a white solid (1.20 g, 90%): mp 138-139.5° C.: NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd., J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J =8, 7, 1 Hz, 1 H), 7.60 (dd, J=5, 2 Hz, 2 H), 7.60-7.48 (m, 2 H), 7.46-7.28 (m, 6 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.74 (ddd, J=8, 1, 1 Hz, 1 H), 5.26 (t, J=8 Hz, 1 H), 3.76 (s, 3 H), 3.59 (dd, J=8, 5 Hz, 2 H); MS (FAB+): [M+], 3 bromine isotope pattern, 722 (30%), 724 (70%) 726 (100%) 728 (35%); Anal. Calc. for C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00. Found: C, 52.60, H, 2.68, N, 0.07.
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][CH2:12][C:13]([C:16]([OH:18])=[O:17])([F:15])[F:14])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[NH3:19].[OH-].[Na+]>>[C:1]([C:5]([C:8]([O:11][CH2:12][C:13]([C:16]([O-:18])=[O:17])([F:15])[F:14])([F:9])[F:10])([F:7])[F:6])([F:4])([F:3])[F:2].[NH4+:19]
Reactant: O=C(O)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)F
Reactant: N
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C(F)(F)COC(F)(F)C(F)(F)C(F)(F)F
Product: [NH4+]

Procedure:
An aqueous solution of CF3CF2CF2OCH2CF2COONH4 (20.2% by mass) was prepared in the same manner as in Synthesis Example 1 except that the CF3CF2CF2OCH2CF2COOH prepared in Synthesis Example 1 was neutralized to pH 7 using aqueous ammonia in lieu of the aqueous solution of sodium hydroxide.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]>O1CCCC1.C(OCC)(=O)C>[ClH:7].[ClH:7].[NH2:6][C:2]([CH3:5])([CH3:1])[CH2:3][NH:4][CH2:30][CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:8]([Cl:7])=[C:9]([CH:24]=1)[C:10]([NH:12][CH2:13][C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:11]
Reactant: CC(C)(N)CN
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(N)CNCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl
Temperature: 60 °C

Procedure:
2-Methyl-1,2-propanediamine (0.12 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) in tetrahydrofuran (4 ml) and heated at 60° C. in a sealed tube for 12 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25-95%) gave the title compound as the acetate salt. Treatment with 4M hydrochloric acid in dioxane gave the title compound as the dihydrochloride salt (0.045 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH:27][C:26]1[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:7]
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)O
Product: COc1ccc(NC(=O)c2cc(S(=O)(=O)N3CCCCC3)ccc2OC)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 2-methoxy-5-(piperidin-1-ylsulfonyl)benzoic acid and 4-methoxyaniline as the starting materials.