Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:14][CH2:15][CH:16]=[C:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[OH-:30].[Na+].[BH4-].[Na+].[OH-]>O.O1CCCC1>[C:1]([C:4]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH2:14][CH2:15][CH2:16][C:17]([OH:30])([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1
Reactant: [OH-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, 8-acetyl-8-phenyl-12-methyl-11-heptadecenoic acid (4.8 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution in 3M solution hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 8-acetyl-8-phenyl-12-hydroxy-12-methyl-heptadecanoic acid as a yellow viscous oil which is purified by chromatrography on silica gel with 4% methanol in chloroform as eluant.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][O:15]C(=O)C2C=CC=CC=2)[O:11][C:10]([CH3:25])([CH3:24])[O:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6](=[O:26])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:25])([CH3:24])[O:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 3.64 g (10 mmol) of the 2-[(4R,6S)-2,2-dimethyl-6-benzoyloxymethyl-1,3-dioxan-4-yl]acetic tert-butyl ester produced in Example 26 in methanol (36 mL) was added 10 mL of 1N-aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours. This reaction mixture was adjusted to pH 7 by gradual addition of 1N-hydrochoric acid under ice-cooling. The methanol was then distilled off under reduced pressure and the residual aqueous solution was extracted with 2 portions of methylene chloride, 70 mL each. The organic layer was dehydrated over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a colorless oil. This residue was purified by silica gel column chromatography (Kieselgel 60, product of Merck; hexane:acetone=5:1) to give 2.34 g of 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic tert-butyl ester (white solid). Yield 90%.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:36])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:21]=[C:20]([CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[O:19][N:18]=3)[CH:15]=2)[N:10]([C:32](=[O:34])[CH3:33])[C@@H:9]([CH3:35])[CH2:8]1)[CH3:3].[ClH:37].CCOCC>O1CCOCC1>[ClH:37].[C:32]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:21]=[C:20]([CH2:22][CH2:23][NH2:24])[O:19][N:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:36])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:35])(=[O:34])[CH3:33]
Reactant: CC(=O)N1c2ccc(-c3noc(CCNC(=O)OC(C)(C)C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)N1c2ccc(-c3noc(CCN)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of 1-methylethyl((2S,4R)-1-acetyl-6-{5-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1,2,4-oxadiazol-3-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 76) (260 mg, 0.518 mmol) in 1,4-Dioxane (1 mL) was treated with HCl (4N in 1,4-dioxane, 1.00 mL, 4 mmol) and the resulting mixture was stirred at room temperature for 16 h. Et2O (10 mL) was then added and the precipitate formed was triturated then filtered off to give 1-methylethyl {(2S,4R)-1-acetyl-6-[5-(2-aminoethyl)-1,2,4-oxadiazol-3-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (195 mg, 0.446 mmol, 86%) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].CS([C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1)=O.C(O)(C)(C)C.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 80 °C

Procedure:
To a mixture of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (Combi-Blocks Inc, Cat#: SS-3744; 342 mg, 1.55 mmol) and tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52) (521 mg, 1.30 mmol) in tert-butanol (10 mL, 105 mmol) was added DIEA (0.57 mL, 3.25 mmol). The reaction mixture was heated at 80° C. in an oil bath for 21 h. The resulting brown suspension was concentrated under reduced pressure and the crude solid was suspended in Et2O (ca. 20 mL) and filtered affording the crude material of tert-butyl (3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (1a) as a green solid. m/z (ESI, +ve ion) 558.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.57 (1H, s), 8.73 (1H, s), 8.14 (1H, s), 7.89 (1H, d, J=9.4 Hz), 7.57 (1H, d, J=8.4 Hz), 7.42 (3H, t, J=8.0 Hz), 7.28 (1H, d, J=8.8 Hz), 6.87 (1H, d, J=8.6 Hz), 6.53 (1H, d, J=2.3 Hz), 6.43 (1H, d, J=9.4 Hz), 6.05 (1H, br. s.), 3.73-3.82 (3H, m), 3.06 (4H, br. s.), 2.36-2.47 (4H, 2.15-2.26 (3H, s), 1.45 (9H, s).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH2:35].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].CN(C=O)C>[CH2:37]([O:36][C:34]([C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)[C:7]=1[CH3:8])=[CH2:35])[CH2:38][CH2:39][CH3:40]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: C=COCCCC
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(OCCCC)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 100 °C
Yield: 28.5 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 101.5 mg, 0.17 mmol), bis[1,2-bis(diphenylphosphino)ethane]-palladium (0) (16.5 mg, 18.3 μmmol), n-butyl vinyl ether (60 μl, 0.46 mmol), triethylamine (0.5 ml, 3.6 mmol) and DMF (6 ml) were placed in a Schlenk vessel equipped with a magnetic stirring bar. The vessel was purged with argon, sealed, and heated at 100° C. overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (27.3 mg, 28%).
Reaction SMILES: [OH:1][C@@H:2]1[C@@:9]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:8]2[C:17](=[O:18])[C@@:4]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])([C:5]([O:20]C)=[CH:6][C:7]2=[O:19])[CH2:3]1.[OH-].[Li+]>>[OH:20][C:5]1[C@:4]2([CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])[C:17](=[O:18])[C@@H:8]([C@:9]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:2]([OH:1])[CH2:3]2)[C:7](=[O:19])[CH:6]=1
Reactant: COC1=CC(=O)[C@H]2C(=O)[C@]1(CC=C(C)C)C[C@H](O)[C@@]2(C)CCC=C(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)=CCC[C@@]1(C)[C@H]2C(=O)C=C(O)[C@@](CC=C(C)C)(C[C@@H]1O)C2=O
Yield: 98 %

Procedure:
Prepared according to representative procedure on a scale of 0.037 mmol of 20 (13.2 mg) and 0.421 mmol of lithium hydroxide (10.1 mg). The crude material was filtered through silica gel using 10:1 dichloromethane:methanol as the eluent to give 53 as a white solid in a 98% yield (12.4 mg). 1H NMR (500 MHz, CDCl3) δ ppm 5.68 (s, 1H), 5.07 (t, J=7.0 Hz, 1H), 4.99 (t, J=6.3 Hz, 1H), 3.78 (dd, J=5.3, 11.8 Hz, 1H), 3.19 (s, 1H), 2.44 (ddd, J=7.3, 14.7, 39.0 Hz, 2H), 2.29-2.16 (m, 1H), 2.05-1.92 (m, 2H), 1.81 (t, J=12.5 Hz, 1H), 1.67 (s, 3H), 1.64 (s, 3H), 1.63 (s, 3H), 1.62 (s, 3H), 1.40-1.29 (m, 2H), 0.95 (s, 3H). HRMS-ESI (m/z): [M+Na]+ calculated for C21H30O4, 369.2036. found 369.2034.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[B:10].C(=O)([O-])[O-].[Na+:15].[Na+]>C(OCC)C.O>[Na+:15].[F:9][C:4]1[CH:3]=[C:2]([B-:10]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: [B]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Fc1cc(F)cc([B-](c2cc(F)cc(F)c2)(c2cc(F)cc(F)c2)c2cc(F)cc(F)c2)c1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A dried flask made of Pyrex glass (capacity of 500 ml) provided with a reflux condenser was charged with an inert gas to purge the air from theflask. Then, metallic magnesium (4.65 g) and anhydrous diethyl ether (100 ml) were fed to the flask, and the resulting solution was stirred and cooled by ice bath. A solution prepared separately by adding anhydrous diethylether (50 ml) to 1-bromo-3,5-difluorobenzene (43.52 g) was added dropwise thereto over one hour, and the resulting solution was left still for three hours. At the end of the reaction, a liquid containing boron trifluorideethercomplex (4.542 g) in anhydrous diethyl ether was added dropwise over 40 minutes, and left still for 16 hours with stirring at the room temperature. Then, an aqueous solution of sodium carbonate (30 g) in pure water (100 g) was dropped with 30 minutes. After the solution was kept stirring at the room temperature for 24 hours, the water phase and the organic phase were separated from each other. The separated organic phase was dried with sodium sulfate and filtered; the filtrate was put into an evaporator (oil bath temperature: 70° C.); and diethyl ether was evaporated, thereby obtaining a liver-brown colored solid. The liver-brown colored solid was further purified with silica gel, and a white solid of tetrakis(3,5-difluorophenyl)borate sodium salt (10.3 g) was obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].C(O)(=O)C>O1CCOCC1.O>[N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(N2CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)c1cccc(N2CCCCC2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
The compound of Example 38 (540 mg, 2.466 mmol) was dissolved in dioxan (12 ml) and water (8 ml). Lithium hydroxide hydrate (300 mg, 7.143 mmol) was added and the mixture stirred at 40° C. for 1 h. The mixture was acidified with acetic acid, evaporated, azeotroped with toluene and chromatographed on silica (eluant 60/40/2, v/v/v, EtOAc/hexanes/AcOH) to provide a colourless solid (450 mg, 90%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([OH:28])=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.CN(C=O)C>CCCCCC.CCOC(C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([O:28][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCCOc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 16 h
Yield: 76.2 %

Procedure:
Add methyl 4-bromobutyrate (1.9 mL, 10.4 mmol) to a mixture of 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-benzo[d]azepine (310 mg, 1.0 mmol), DBU (0.23 mL, 1.6 mmol) and DMF (10 mL) at ambient temperature under nitrogen. Stir the reaction mixture for 16 h. Dilute with hexane/EtOAc (1:1, 60 mL), wash the mixture with 10% aqueous NaCl (4×25 mL), dry the organic layer over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 2:3) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-propyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (303 mg, 73%). MS (ES+) m/z: 398 (+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22](Cl)(=[O:24])=[O:23])=[CH:17]2)(=[O:10])[CH3:9].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[C:8]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])=[O:23])=[CH:17]2)(=[O:10])[CH3:9]
Reactant: NCc1ccccc1
Reactant: CC(=O)Oc1cccc2cc(S(=O)(=O)Cl)ccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Triethylamine (50 μl, 0.36 mmol) and 5-(acetyloxy)naphthalene-2-sulfonyl chloride (84.9 mg, 0.30 mmol) were added to benzylamine (32.1 mg, 0.30 mmol) dissolved in tetrahydrofuran (3 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent; n-hexane: ethyl acetate=2:1→1:1) to give the title compound as a light yellow white crystal (72.1 mg, 67.6%).
Reaction SMILES: I[Si](C)(C)C.[Br:6][C:7]1[CH:31]=[C:30]([C:32]2[C:41]3[C:42]4[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=4[S:44][C:40]=3[C:39](Br)=[C:38]3[C:33]=2[CH:34]=[CH:35][CH:36]=[CH:37]3)[CH:29]=[C:28]([Br:50])[C:8]=1[O:9][C@H:10]([CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[C:11]([O:13]C)=[O:12]>C(Cl)Cl>[CH:48]1[C:42]2[C:41]3[C:32]([C:30]4[CH:31]=[C:7]([Br:6])[C:8]([O:9][C@H:10]([CH2:15][CH2:16][N:17]5[C:18](=[O:27])[C:19]6[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=6)[C:25]5=[O:26])[C:11]([OH:13])=[O:12])=[C:28]([Br:50])[CH:29]=4)=[C:33]4[C:38](=[CH:39][C:40]=3[S:44][C:43]=2[CH:45]=[CH:46][CH:47]=1)[CH:37]=[CH:36][CH:35]=[CH:34]4
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1Br
Reaction time: 2 h
Yield: 44.6 %

Procedure:
Iodotrimethylsilane (0.203 mL, 1.43 mmol) was added to a rt, stirred solution of (R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid, methyl ester (0.770 g, 0.953 mmol) in methylene chloride (8 mL) under a dry nitrogen atmosphere. After 2 h, iodotrimethylsilane (3×0.203 mL, 4.29 mmol) was added to the resulted dark brown solution at rt three times every 12 h. The solution was quenched with water (0.4 mL), concentrated, chased with benzene (3×50 mL). The resulted residue was dissolved in ethyl acetate (60 mL) and silica gel (acid washed, 8 mL) was added. Solvent was removed and the adsorbate was flash chromatographed (eluent 7:3 pet. ether:ethyl acetate) to provide the title compound as a yellow solid (0.304 g, 45%): mp: 222-223° C.; NMR (CDCl3); δ8.37 (s, 1 H), 7.95(d, J=8 Hz, 1 H),7.89-7.85 (m, 2 H), 7.79 (dd, J=8,1 Hz, 1 H), 7.78-7.71 (m, 2 H), 7.64 (d, J=10 Hz, 1 H), 7.62 (d, J=10 Hz, 1 H), 7.59 (dd, J=8, 1 Hz, 1 H), 7.55 (ddd, J=8, 7, 1 Hz, 1 H), 7.46 (ddd, J=8, 7, 1 Hz, 1 H), 7.40 (ddd, J=8, 7, 1 Hz, 1 H), 7.19(ddd, J=8, 7, 1 Hz, 1 H), 6.88(d, J=8 Hz, 1 H), 5.27 (t, J=7 Hz, 1 H, 1 H, CH), 4.12 (m, 2 H), 2.65 (t, J=6 Hz, 2 H); MS (FAB-): [M-H]-, 2 bromine isotope pattern, 713, 714, 716; Anal. Calc. for C34H21Br2NO5S: C, 57.08, H, 2.96, N, 1.96. Found: C, 56.43, H, 2.74, N, 1.90.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and pyridin-3-ylboronic acid. HPLC (Condition 4) tR=4.45 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=445.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 3H) 3.46-3.61 (m, 4H) 5.43 (s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.44-7.54 (m, 1H) 7.74-7.90 (m, 3H) 8.02 (d, J=1.95 Hz, 1H) 8.58 (dd, J=4.69, 1.56 Hz, 1H) 8.64 (d, J=2.35 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [OH-].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][C:21]([O:24][N:25]2[C:30]([CH3:32])([CH3:31])[CH2:29][CH:28]([O:33]C(=O)C3C=CC=CC=3)[CH2:27][C:26]2([CH3:43])[CH3:42])([CH3:23])[CH3:22])[C:14]([CH3:45])([CH3:44])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:33][CH:28]1[CH2:29][C:30]([CH3:31])([CH3:32])[N:25]([O:24][C:21]([O:20][N:15]2[C:14]([CH3:45])([CH3:44])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]2([CH3:19])[CH3:18])([CH3:23])[CH3:22])[C:26]([CH3:43])([CH3:42])[CH2:27]1
Reactant: CC(C)(ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(ON1C(C)(C)CC(O)CC1(C)C)ON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by the basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 34A.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Si:9]([N:16]1[C:19](=[O:20])[CH2:18][C@H:17]1[C:21]([OH:23])=[O:22])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1CCC1.CC(C1C=C(C(C)C)C(S([N:43]=[N+:44]=[N-:45])(=O)=O)=C(C(C)C)C=1)C>C1COCC1>[N:43]([C@H:18]1[C:19](=[O:20])[N:16]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:17]1[C:21]([OH:23])=[O:22])=[N+:44]=[N-:45]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C1CNC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@H](N=[N+]=[N-])[C@H]1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To LDA (1.8M, 4.99 mL) and THF (10 mL) at −78° C. was added dropwise (S)-1-t-butyldimethylsilyl-4-oxo-2-azetidinecarboxylic acid (4, 1.0 g) in THF (15 mL). The resulting solution was warmed to −30° C. or −10° C. for 30 min. If a slurry formed, additional THF was added to solublize the azetidine. After 30 min., the solution was cooled to −78° C. A pre-cooled solution (−10° C.) of trisyl azide (1.61 g) in THF (10 mL) was added slowly. The reaction mixture was stirred for one hour before quenching with TMSCl (0.82 mL). The cold bath was then removed and the solution allowed to stir for an additional hour. Saturated sodium bicarbonate (100 mL) was added and the aqueous layer was extracted with diethyl ether (2×100 mL). The organic extracts were discarded. The aqueous layer was then brought to pH=7 by slow addition of 1N HCl and extracted with Et2O (2×100 mL) and the organic layers were discarded. The aqueous layer was then brought to pH=3 by slow addition of 1N HCl and extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield 131 which was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.Br.Br[CH2:15][C:16]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=O.C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([NH2:12])[C:7]2[C:8]([N:9]=1)=[N:10][C:16]([C:18]1[C:23]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH:15][N:11]=2
Reactant: COCc1cc(N)c(N)c(N)n1
Reactant: O=C(CBr)c1ncccc1C(F)(F)F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCc1cc(N)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Methoxymethyl-2,3,4-triamino-pyridine (353 mg, 2.10 mmol), 2-bromo-1-(3-trifluoromethyl-pyridin-2-yl)-ethanone hydrobromide (771 mg, 2.21 mmol; synthesis described in Example 2E, below), and NaHCO3 (554 mg, 6.59 mmol) are dissolved into a solution of dioxane (20 mL) and water (20 mL). The reaction mixture is stirred 1 hour at room temperature and 3 hours at 100° C. The mixture is cooled and filtered through Celite. The Celite bed is washed with EtOAc (20 mL). The aqueous mixture is extracted with EtOAc (4×100 mL). The combined organic extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product purified by column chromatography on silica gel eluting with acetone/hexanes (1:1) to yield the title compound as a white solid.