Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([OH:20])=[O:19].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:19][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:18][C:9]1[CH:10]=[CH:11][CH:12]=[CH:17][CH:8]=1)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2ccccc2c1OCc1ccccc1
Yield: 38.5 %

Procedure:
K2CO3 (9.26 g, 67 mmol), dry DMF (20 mL), commercially available 1-hydroxy-2-naphthoic acid (1.88 g, 10 mmol), and benzyl chloride (5.6 mL). Yield: 1.41 g of yellow-orange viscous product (38.5% yield). Rf=0.38 (SiO2, 50% Hexanes/50% CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 5.13 (s, 2H), δ 5.39 (s, 2H), δ 7.32-7.41 (m, 7H), δ 7.43-7.52 (m, 5H) δ 7.57 (d, J=7.8 Hz, 1H), δ 7.63 (d, J=8.7 Hz, 1H), δ 7.84 (d, J=8.2 Hz, 1H), δ 7.92 (d, J=8.7 Hz, 1H), δ 8.24 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:34](=[O:35])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:32][CH:31]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: CCCCOC(=O)c1ccc(N=C=O)cc1
Product: CCCCOC(=O)c1ccc(NC(=O)N2C=C(C(=O)OCC)c3[nH]c4ccccc4c3CC2)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 72 by using ethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-(carbobutoxy)phenyl isocyanate (˜2.0 mg); MS (ES): 476 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@@H:10]1[NH:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.Cl[C:27]1[CH:32]=[CH:31][N:30]2[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]2[N:28]=1>C(O)(C)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@@H:10]1[N:14]([C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11]1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: CC1(C)CC[C@H](c2cc(F)ccc2F)N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2ccc(N3[C@@H](c4cc(F)ccc4F)CCC3(C)C)nc12
Temperature: 160 °C
Yield: 28.1 %

Procedure:
A sealed pressure tube was charged with (R)-5-(2,5-difluoro phenyl)-2,2-dimethylpyrrolidine HCl salt (300 mg, 1.21 mmol), diisopropylethylamine (423 μA, 2.42 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (273 mg, 1.21 mmol) and isopropanol (2.0 mL). The tube was sealed and the mixture was heated at 160° C. for 3 days. Additional ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (273 mg, 1.21 mmol) was added and the reaction was heated at 160° C. 2 days. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (eluting with 0-60% acetonitrile/H2O) to provide the title compound (136 mg, 28%) as a beige solid. MS (apci) m/z=401.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Br[CH2:14][C:15]([CH3:17])=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:16][C:15](=[CH2:14])[CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1cccc(C(=O)O)c1

Procedure:
The reaction of Ethyl 3-hydroxyl-benzoate and 3-Bromo-2-methyl-propene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-(2-Methyl-allyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.50 (m, 1 arom. H); 7.44 (m, 2 arom. H); 7.19 (m, 1 arom. H); 5.04, 4.96 (2 s, —C(CH3)═CH2); 4.50 (s, CH2—C(CH3)═CH2); 1.75 (s, C(CH3)═CH2). 13C-NMR (100 MHz, d6-DMSO): 166.93 (—C═O); 158.23; 140.62; 132.14; 129.67; 121.67; 119.53; 114.88; 112.33; 70.95; 19.13.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:18][CH2:19][C@@H:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=O)=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCn1cc(Br)cn1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a mixture of 4-bromopyrazole (1.26 g, 8.57 mmol) and cesium carbonate (4.66 g, 14.3 mmol) in DMF (20 mL) was added (3S)-3-((tert-butoxycarbonyl)amino)-4-(4-chlorophenyl)butyl methanesulfonate (2.70 g, 7.15 mmol). The mixture was stirred for 16 hours at room temperature. The mixture was diluted with DCM and washed with H2O (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (EtOAc/Hexanes, 0-25%) to give the product as an off-white solid (2.86 g, 93%). LCMS (API-ES) m/z: 428, 430 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]([S:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:25][C:24]=2[F:38])=[N:19][C:18]=1[C:39]#[N:40]
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(C#N)n2)c(F)c1

Procedure:
The title compound was prepared in manner similar to that described in Example 88 using (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.78 (d, J=1.6, 1H), 8.18 (dd, J=7.9, 1.4, 1H), 8.01 (m, 1H), 7.63 (m, 1H), 7.56 (m, 1H), 7.40-7.32 (m, 3H), 5.43 (s, 2H), 4.46-4.36 (m, 1H), 3.55-3.46 (m, 1H), 3.43-3.28 (m, 2H), 1.76 (t, J=5.7, 1H), 0.99 (d, J=6.6, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=[O:30])=[O:29]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(CCCCCCl)NCCCCO
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCCCO
Yield: 91.7 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(4-hydroxybutyl)-5-chloropentanesulfonamide (515.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]pentanesulfonamide (934.3 mg) as a pale yellow oil (91.7%).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:46])([C:42]([F:45])([F:44])[F:43])[C:24]([F:41])([F:40])[C:25]([F:39])([F:38])[O:26][C:27]([F:37])([F:36])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]([O:26][C:25]([F:38])([F:39])[C:24]([F:40])([F:41])[C:23]([F:22])([F:46])[C:42]([F:43])([F:44])[F:45])([F:37])[F:36])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (6.0 g, 21 mmol) and 5-(2-(nonafluorobutoxy)-2,2-difluoroethoxy)-1-bromopentane (12 g, 23 mmol; prepared by combining 1,5-dibromopentane with 2-(nonafluorobutoxy)-2,2-difluoroethanol). After refluxing overnight, the resulting crude product was isolated by filtration and further purified by recrystallization from ethanol, followed by Kugelrohr distillation (b.p. 190°-200° C. at 0.1 torr; yield of 6.4 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br-:20]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:20][CH:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: [Br-]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)C(Br)Cc1ccc([N+](=O)[O-])cc1
Yield: 90.4 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 3-(4-nitro-phenyl)-1-phenyl-propan-1-one prepared in the step and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. The obtained product was a white solid in a yield of 90.4%, mp: 97-98 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.48 (1H, dd, J=14.28, 7.28 Hz), 3.75 (1H, dd, J=14.28, 7.28 Hz), 5.31 (1H, t, J=7.28 Hz, CHBr), 7.46˜7.51 (4H, m, ArH), 7.61 (1H, t, J=8.00 Hz, ArH), 7.98 (2H, d, J=8.68 Hz, ArH), 8.17 (2H, d, J=8.68 Hz, ArH); FAB-MS: 336.1 (M+2, 90), 334.1 (M, 90), 254.2 (58), 238.2 (36), 105.1 (100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CO)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
(3-Nitro-5-(trifluoromethyl)phenyl)methanol (2.6 g, 11.6 mmol) in methanol (30 mL) was flushed with nitrogen, and treated with palladium (10% on charcoal, 260 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography on silica gel (50% ethyl acetate/hexanes) afforded 1.9 g (85%). 1H-NMR (CDCl3, 500 MHz) δ 6.95 (s, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 4.61 (s, 2H). Mass spec.: 192.15 (MH)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:13])[C:5]1=[O:14])=[N+:2]=[N-:3].[BH4-].[Na+]>CO>[N:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:13])[CH:5]1[OH:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1Cc2c(F)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NC1Cc2c(F)cccc2C1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
To a solution of 2-azido-4-fluoro-2,3-dihydro-1H-inden-1-one (0.81 g, 4.5 mmol) in MeOH (15.0 mL), was added NaBH4 (0.19 g, 4.5 mmol) in one portion. After stirring for 10 min at r.t., the solution was concentrated in vacuo. The residue was taken up in EtOAc (100 mL), and this solution was washed with saturated NaHCO3 (aq) (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 0.64 g (73% yield) of 2-azido-4-fluoro-2,3-dihydro-1H-inden-1-ol as a white solid, which was used without further purification: 1H NMR (400 MHz, CDCl3): 7.23 (m, 2H), 6.97 (t, 1H), 5.15 (dd, 1H), 4.37 (q, 1H), 3.17 (d, 1H), 2.40 (d, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Yield: 69.6 %

Procedure:
A solution of 2-bromo-4-(3-methylphenyl)-1,3-thiazole (2.03 g, 7.99 mmol), tert-butyl piperazine-1-carboxylate (2.98 g, 16.0 mmol) and potassium carbonate (1.10 g, 7.99 mmol) in dimethylformamide (25 ml) was stirred at 120° C. for 12 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.00 g (69.7%) of the desired product as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[S:6][CH:7]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H-].[Na+]>CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]2=[O:17])[S:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CSc1csc(-n2c(=O)[nH]c3ccccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 1-[4-(methylthio)-1,3-thiazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-one from Step B (710 mg, 2.67 mmol) and tert-butyl bromoacetate (578 mg, 2.97 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (194 mg of a 60% dispersion in mineral oil, 4.85 mmol). The mixture was stirred at 0° C. for 15 min, then quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×35 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 70:30, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:16]([O:18][CH2:19][C:20]([O:22][C@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=1[Cl:33])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:33][C:26]1[CH:27]=[N+:28]([O-:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[CH2:24][C@@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:22][C:20](=[O:21])[CH2:19][O:18][C:16](=[O:17])[C:15]1[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:14]=1
Reactant: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.296 g, 0.367 mmol) in DCM (20 ml), HCl 4M in dioxane (0.919 ml, 3.67 mmol) was added, and the mixture was stirred at RT for 3 days. Additional HCl 4M in dioxane (1.838 ml, 7.34 mmol) was added over 2 days with stirring at the same temperature. The volatiles was removed under vacuum, and the crude was triturated with MeOH. The precipitate was collected by filtration and washed with Et2O to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonamido)benzoyloxy)-acetoxy)ethyl)pyridine 1-oxide as a white solid (0.215 g, 0.305 mmol, 83% yield, MS/ESI+ 705.25 [MH]+, [αD]=−28.15, c=0.53, DCM).
Reaction SMILES: COC(=O)[C@H](CC1C=C(I)C(OC2C=C(I)C(O)=C(I)C=2)=C(I)C=1)N[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]2=[O:19])[CH:8]=1.C1(=O)N(C2C=C(C=CC=2)C(O)=O)C(=O)C=C1.S(Cl)([Cl:59])=O>>[C:17]1(=[O:18])[N:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([Cl:59])=[O:20])[C:14](=[O:19])[CH:15]=[CH:16]1
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)c1cccc(N2C(=O)C=CC2=O)c1
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1cccc(N2C(=O)C=CC2=O)c1
Product: O=C(Cl)c1cccc(N2C(=O)C=CC2=O)c1

Procedure:
Preparation of m-maleimidobenzoyl thyroxine methyl ester (as described by Monji, N., Malkus, H, and Castro, A., Biochem. Biophys. Res. Commun., 1978, 85, 671-677). m-Maleimidobenzoic acid (225 mg, 1.06 mmol) was dissolved in 4 mL of thionyl chloride and refluxed for 30 minutes. Removal of excess thionyl chloride under reduced pressure afforded m-maleimidobenzoyl chloride as a pale yellow solid. The acid chloride (220 mg dissolved in 10 mL of tetrahydrofuran) was added dropwise to a stirred suspension of 400 mg (0.51 mmol) of thyroxine methyl ester and 400 mg of sodium carbonate. After the addition was complete, the mixture was refluxed for 30 minutes. Removal of the solvent under reduced pressure yielded a crude yellow product. The material was purified by silica gel chromatography with chloroform as the eluent. 1NMR (CDCl3) δ 3.85 (3 H,s), 3.92 (1 H,m), 5.77 (1 H,s), 6.90 (2 H,s), 7.12 (2 H,s), 7.57 (2 H,m), 7.70 (2 H,s), 7.80 (2 H,m). Anal. calcd. for C27H18I4N2O7 : C, 32.8; H, 1.82; N, 2.80. Found: C, 32.7; H, 2.09; N, 2.42.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([Si](C)(C)[O:19][CH2:20][CH2:21][N:22]([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[S:35]([N:38]2[CH2:59][CH2:58][C:41]3([N:45]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:55])[F:54])[CH:47]=4)[NH:43][C:42]3=[O:57])[CH2:40][CH2:39]2)(=[O:37])=[O:36])=[C:29]([CH3:60])[CH:28]=1)[S:23]([CH3:26])(=[O:25])=[O:24])(C)(C)C>C(#N)C.C(OCC)(=O)C>[OH:19][CH2:20][CH2:21][N:22]([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[S:35]([N:38]2[CH2:39][CH2:40][C:41]3([N:45]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:54])([F:55])[F:56])[CH:47]=4)[NH:43][C:42]3=[O:57])[CH2:58][CH2:59]2)(=[O:37])=[O:36])=[C:29]([CH3:60])[CH:28]=1)[S:23]([CH3:26])(=[O:24])=[O:25]
Reactant: Cc1cc(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(N(CCO)S(C)(=O)=O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
A 10% aqueous citric acid solution (0.14 ml, 0.067 mmol) was added to a solution of N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-N-(3-methyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-methanesulfonamide (14.3 mg, 0.0192 mmol) in acetonitrile (0.2 ml), and the mixture was stirred at 60° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give N-(2-hydroxy-ethyl)-N-(3-methyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-methanesulfonamide (12.5 mg, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].O1CCCC1.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25]>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To a 20 mL volume two-necked flask, 0.50 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 10 ml of tetrahydrofuran (anhydrous), 0.27 g of acetophenone and 130 mg of acetic acid were added under a nitrogen atmosphere, and the mixture was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (60 ml) was added to the residue and the resultant was extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure and subjected to silica gel column, chromatography (ethyl acetate:chloroform=3:1) to give 0.32 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-phenyl-1-ethylidene)hydrazine ((40-b)-(15)-6).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([NH2:23])[CH:10]=1)=[O:8].[C:24](OC(=O)C)(=[O:26])[CH3:25].[OH-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([NH:23][C:24](=[O:26])[CH3:25])[CH:10]=1)=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1

Procedure:
A mixture of 10.0 g (32.8 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone and 40 ml of acetic anhydride is heated on a steam bath for 1 hour. The reaction is concentrated in vacuo to give a residue which is suspended in water and made basic with 10% NaOH. The aqueous phase is extracted with ether and the dried extracts are evaporated to give 3-acetamido-4-benzyloxyphenyl 2-pyridyl ketone.