Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]2)=[CH:52][N:51]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCCC(O)CCC>CCCCCC.C(OCC)(=O)C.O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:51]=[CH:52][C:53]([O:56][CH2:57][CH:58]5[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]5)=[CH:54][N:55]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)OCC(COc2cnc(Cl)nc2)CO1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCNCC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(OCC6COC(C)(C)OC6)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To 6.02 g (8.92 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 2.16 g (8.35 mmol) of 2-chloro-5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine, which was prepared by a method similar to that of Reference Example 20, and 6.06 g (18.6 mmol) of cesium carbonate, 30 ml of 4-heptanol was added, and the reaction mixture was stirred at 150° C. for 8 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate three times. The obtained organic phases were combined, washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Reaction and aftertreatment similar to those described above were further performed using 2.00 g (2.96 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, 0.72 g (2.78 mmol) of 2-chloro-5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine and 2.02 g (5.73 mmol) of cesium carbonate. The obtained residues were combined and subjected to silica gel column chromatography [n-hexane/ethyl acetate=85/15-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, then n-heptane was added thereto, and the precipitate was obtained by filtration to provide 7.35 g of the title compound as a white solid (yield: 74%).
Reaction SMILES: [OH-].[NH4+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([S@:13]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)=[O:14])[NH:10][C:9]=2[CH:26]=1>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([S:13]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)=[O:14])[NH:10][C:9]=2[CH:26]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 0.17 h

Procedure:
To a 50 mL beaker was added about 1 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl-1H-benzimidazole to 30 mL of dimethylformanide (DMF) containing 1 mL of ammonium hydroxide. Additional (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole was added to the resulting solution until a suspension of the material was formed. The solution was stirred for approximately 10 minutes, and then filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) or Nylon filter. The resulting saturated solution was placed in a shallow petri dish, covered and stored under ambient conditions (approximately 25° C.) and a humidity range of 0 to 50 percent until crystals formed (between 14 days). The identity of the title compound is confirmed by single crystal x-ray diffraction and/or Raman spectroscopy. The resulting material was shown to contain between about 96 and 98 percent (w/w) of the 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 2 and 4 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.
Reaction SMILES: CC1C=CC(S(NC2C=C(C3C=CC4N(C=C(NC(=O)C)N=4)N=3)C=CC=2)(=O)=O)=CC=1.Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=2)[N:37]=1.[CH3:45][S:46]([C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[N:53][CH:54]=1)(=[O:48])=[O:47]>>[CH3:45][S:46]([C:49]1[CH:50]=[C:51]([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=3)[N:37]=2)[CH:52]=[N:53][CH:54]=1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Agent: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3cncc(S(C)(=O)=O)c3)ccc2n1

Procedure:
Following the procedure described for compound N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.084 g, 0.40 mmol) was reacted with 5-(methylsulfonyl)pyridin-3-ylboronic acid (0.14 g, 0.72 mmol, Combi-Blocks, San Diego, Calif.) to afford the title compound as a yellow solid. MS (ESI positive ion) m/z: 332 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.97 (s, 1H), 9.56 (d, J=2.2 Hz, 1H), 9.19 (d, J=2.2 Hz, 1H), 8.89 (t, J=2.2 Hz, 1H), 8.39 (s, 1H), 8.19 (d, J=9.4 Hz, 1H), 8.00 (d, J=9.4 Hz, 1H), 3.31 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)([CH3:17])[CH3:16])=[CH:11][CH:10]=1.[OH-:25].[Na+].[C:27](Cl)(Cl)=[O:28]>C(Cl)Cl.O>[CH3:17][C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH3:16].[C:27]([OH:28])([OH:8])=[O:25]
Reactant: O=C(Cl)Cl
Reactant: [OH-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)O

Procedure:
A 1000 ml four neck flask was fitted with a mechanical stirrer, a pH probe, aqueous caustic inlet tube and a Claisen adapter to which was attached a dry ice condenser and a gas inlet tube. To the flask was added 280 ml water, 340 ml methylene chloride, 1.4 ml triethyl amine (0.01 mole) and 57 g (0.25 mole) bisphenol-A. With stirring the pH was raised to 10 by addition of 25% aqueous sodium hydroxide, then 0.00925 mole (3.7 mole%) based upon mole of BPA of the acid or acid chloride end-capping agent was added. Phosgene was introduced into the flask at 1 g/min for 30 minutes (0.3 mole) with pH maintained at 9.5 to 11.5. The pH was adjusted to 11 at the end of the reaction. The resin layer was separated from the brine layer, then washed with 3 wt. % aqueous HCl until washing remained acidic, then twice with distilled water. The resin was then precipitated into 1500 ml of methanol in a Waring blender and washed with 500 ml more methanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[NH3:14]>>[OH:1][CH2:2][CH2:3][C:4]1[N:14]=[CH:8][C:7]2[C:6]([CH:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=Cc1ccccc1C#CCCO
Reactant: N
Product: OCCc1cc2ccccc2cn1
Temperature: 80 °C
Yield: 73.3 %

Procedure:
A solution of 2-(4-hydroxybut-1-ynyl)benzaldehyde (Description 110; 8.50 g, 48.8 mmol) in 2M methanolic ammonia (122 ml, 244 mmol) contained in a Parr flask was heated at 80° C. for 2 hours (approx 35 psi achieved). The cooled mixture was evaporated and the residue purified by column chromatography on silica elution with a gradient rising from 1% MeOH in DCM+0.5% NH4OH to 5% MeOH in DCM+0.5% NH4OH to give the title compound (6.2 g, 73%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccnc(C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C)ncc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
To a stirred solution of 4-methoxy-2-methylpyridine (25 g, 0.148 mol) in conc. H2SO4 (17 mL, S. D. Fine, India), a mixture of H2SO4 (17 mL, S.D. Fine, India) and 65% HNO3 (22 mL, Rankem, India) was added in a drop-wise fashion at 0° C. over 30 min. The resulting solution was heated at 65° C. for 12 h. After completion, the reaction mixture was poured in to ice water and neutralized (PH-8) with 40% NaOH solution to give a yellow precipitate. The precipitate was further stirred and filtered, dried to give a mixture of 3-nitro (major product) and the desired 5-nitro isomers. The product was isolated by column chromatography, silica gel (230-400), eluting with 15% EtOAc in petroleum ether to give the title compound as yellow needles. 1H NMR (400 MHz, DMSO-d6) δ: 8.86 (s, 1H), 7.33 (s, 1H), 3.99 (s, 3H), 2.52 (s, 3H). MS (ESI, positive ion) m/z: 169.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26][NH2:27]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1cc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc(OC)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (145 mg, 0.41 mmol) and 3,5-dimethoxy benzylamine (65 mg, 0.39 mmol). The title compound was obtained as a solid (55 mg, 34% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.35 (1H, m), 8.98 (2H, m), 8.48 (1H, s), 6.43 (2H, m), 6.38 (1H, m), 4.32 (2H, m), 3.70 (6H, m). MS m/z: 498.16, 500.08 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N+:13]([O-])=[C:12]([CH3:18])[C:11]=2[CH3:19])[CH2:4][O:3]1.C([O-])(=[O:23])C.[Na+].C(OC(=O)C)(=O)C.C(OC(C)C)(C)C>O>[OH2:3].[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:18][OH:23])[C:11]=2[CH3:19])[CH2:4][O:3]1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
To a mixture of 4-(2,2-dimethyl-1,3-dioxan-5-yl)methoxy-2,3,5-trimethylpyridine N-oxide (1.20 kg) and sodium acetate (0.18 kg) heated at 50° C. to 60° C., acetic anhydride (1.10 kg) was added dropwise over 1.5 hours. After 0.5 hours, the mixture was heated at 80° C. for 4.5 hours and cooled to an inner temperature below 30° C. or less, allowed to stand, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.0 L) and the solution was added to a mixture of a 48% aqueous sodium hydroxide solution (0.71 kg) and cold water (2.85 L) for one hour. After stirred at room temperature for 5 hours and 45 minutes, the mixture was concentrated under reduced pressure. To the residue thus concentrated, water (3.0 L) was added and the mixture was extracted with toluene (2.3 L×4). The toluene layers were combined and washed with water (1.2 L). The obtained organic layer was filtrated through celite and concentrated. To the residue obtained, diisopropyl ether (1.15 L) was added at a room temperature and further warm water (45° C., 74 mL) was added. After crystal precipitation was confirmed, the mixture was stirred at 25° C. for one hour. After heptane (3.6 L) was poured, the mixture was stirred overnight. The mixture was further stirred under ice-cool for 5 hours and then filtrated to obtain yellow crystal. To the yellow crystal obtained, diisopropylether (3.5 L) was added and the mixture was dissolved at 50° C. After insoluble substance was removed by filtration, the mixture was gradually cooled and allowed to stand at 5° C. overnight. The obtained crystal was filtrated and washed with heptane (0.5 L) and dried by air to obtain a desired product (0.69 kg).
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1.Cl.[O:13]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[CH:25]=[C:26]4[NH:32][C:31]([NH:33][C:34](=[O:37])[O:35][CH3:36])=[N:30][C:27]4=[N:28][CH:29]=3)=[CH:23][C:18]=2[CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:16]2[CH2:17][C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]5[NH:32][C:31]([NH:33][C:34](=[O:37])[O:35][CH3:36])=[N:30][C:27]5=[N:28][CH:29]=4)[CH:21]=[CH:20][C:19]=3[O:13][CH2:14][CH2:15]2)=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(Cl)N1CCC(CF)CC1
Reactant: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A mixture of 4-(fluoromethyl)piperidine-1-carbonyl chloride (reagent preparation 37) (24 mg, 0.13 mmol), methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride (34 mg, 0.091 mmol), and diisoproylethylamine (59 mg, 0.45 mmol) in dichloromethane (0.5 mL) and N,N-dimethylformamide (0.5 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated then dissolved in methanol (2 mL) and purified directly by preparative reverse phase HPLC to give methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate, (21 mg, 48% yield), (400 MHz, DMSO-d6): 8.41 (br, 1H), 7.87 (s, 1H), 7.54 to 7.44 (m, 2H), 7.05 (d, 1H), 4.45 (s, 2H), 4.31 (dd, 2H), 4.19 (m, 2H), 3.67 to 3.55 (m, 4H), 2.74 (t, 2H), 1.84 (br, 1H), 1.67 to 1.58 (m, 2H), 1.29 to 1.18 (m, 2H); MS (EI) for C24H27FN6O4: 483 (MH+).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][O:48][C:49]1[CH:50]=[CH:51][C:52]2[NH:58][C:57](=[O:59])[N:56]([CH:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)[CH2:55][CH2:54][C:53]=2[CH:66]=1.Br[C:68]1[CH:69]=[N+:70]([O-:86])[CH:71]=[C:72]([C:74]([N:76]2[C:84]3[C:79](=[CH:80][C:81]([F:85])=[CH:82][CH:83]=3)[CH2:78][CH2:77]2)=[O:75])[CH:73]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:85][C:81]1[CH:80]=[C:79]2[C:84](=[CH:83][CH:82]=1)[N:76]([C:74]([C:72]1[CH:71]=[N+:70]([O-:86])[CH:69]=[C:68]([N:63]3[CH2:64][CH2:65][CH:60]([N:56]4[CH2:55][CH2:54][C:53]5[CH:66]=[C:49]([O:48][CH3:47])[CH:50]=[CH:51][C:52]=5[NH:58][C:57]4=[O:59])[CH2:61][CH2:62]3)[CH:73]=1)=[O:75])[CH2:77][CH2:78]2
Reactant: O=C(c1cc(Br)c[n+]([O-])c1)N1CCc2cc(F)ccc21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)c[n+]([O-])c3)CC1)C(=O)N2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 5.0 mg (0.02 mmol) palladium(II)acetate and 14 mg (20 μmol) BINAP were added to 69 mg (0.25 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 84 mg (0.25 mmol) 3-bromo-5-(5-fluoroindoline-1-carbonyl)-pyridine-1-oxide and 0.12 g (0.38 mmol) caesium carbonate in 4.0 mL dioxane and the mixture was stirred overnight at 120° C. The reaction mixture was then evaporated down and the residue was dissolved in DMF/MeOH and purified by preparative HPLC-MS. The product-containing fractions were combined, the organic solvent was evaporated down and the residue was made alkaline with a 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:56]1[C:64]2[C:59](=[C:60]([CH2:65][NH2:66])[CH:61]=[CH:62][CH:63]=2)[CH:58]=[N:57]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:66][CH2:65][C:60]2[CH:61]=[CH:62][CH:63]=[C:64]3[C:59]=2[CH:58]=[N:57][NH:56]3)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCc1cc(C(=O)O)sc1C(=O)OC
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
To a solution of 3-Ethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (130 mg, 0.61 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.26 mL, 1.83 mmol), HBTU (0.35 g, 0.92 mmol), HOBT (0.099 g, 0.73 mmol), and C-(1H-Indazol-4-yl)-methylamine (100 mg, 0.67 mmol). The mixture was stirred at room temperature 2 d, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-80% EtOAc in hexane to afford the desired product (0.095 g, 46% yield).
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.O.O.[OH-].[Li+]>C1COCC1.CO>[C:23]([O:22][C:20]([N:18]([CH3:19])[CH:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][CH:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(=O)C1Oc2ccc(CC(C)N(C)C(=O)OC(C)(C)C)cc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)O2)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 21 mg (0.06 mmol) of 1D in 0.5 mL of THF, 0.5 mL of methanol, and 1 mL of water was added 50 mg (1.19 mmol) of lithium hydroxide monohydrate as solid. The reaction mixture was allowed to stir at room temperature for 2.5 hours and concentrated to dryness. To the residue, 10 mL of water was added, and pH of the resulting mixture was adjusted to 2 using phosphoric acid. This was extracted with 3×35 mL of ethyl acetate. Organic layers were combined, dried (anhydrous Na2SO4) and concentrated to dryness to give 10 mg (0.029 mmol, 53%) of 1M (M+Na, 360).
Reaction SMILES: C[O:2][C:3]1[C:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:7][CH:6]=[C:5]([O:20][CH3:21])[N:4]=1.[BrH:22].CCOCC>C(O)(=O)C>[BrH:22].[O:19]=[C:10]1[C:11]2[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:14])[N:9]1[C:8]1[C:3]([OH:2])=[N:4][C:5]([O:20][CH3:21])=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(O)n1
Reaction time: 18 h
Yield: 67 %

Procedure:
1,3-Dioxo-2-(2-hydroxy-6-methoxypyridin-3-yl)-isoindoline hydrobromide (6) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (155 mg, 0.546 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at room under N2 for 18 h. Dry ether was added slowly until the solution became cloudy. White crystals were precipitated, filtered and washed with ether and ethyl acetate to afford 6 (127 mg, 67%) as white powdery crystals: mp 250° C.; 1H NMR (DMSO-d6) δ 7.97-7.94 (m, 211), 7.91-7.88 (m, 211), 7.64 (d, J=8.2 Hz, 1H), 6.25 (d, J=8.2 Hz, 1H), 3.86 (s, 311); 13C NMR (DMSO-d6) δ 167.5, 162.1, 159.1, 142.8, 135.4, 132.1, 123.7, 108.2, 96.4, 54.8; MS (CI/CH4) 270 [M]+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[N:13]1([C:20]2[C:25]([CH2:26][NH:27][C:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[C:34]=4[Cl:41])[N:31]=[N:30][N:29]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[Cl:41][C:34]1[C:35]([Cl:40])=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[C:28]([NH:27][CH2:26][C:25]2[C:20]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH:2]([CH3:4])[CH3:1])[CH2:15][CH2:14]3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:29][N:30]=[N:31]1
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2N2CCCNCC2)c(Cl)c1Cl
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CCCN(c2ncccc2CNc2nnnn2-c2ccc(F)c(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (0.5 mL) was added to a mixture of the product of Example 289 (80 mg, 0.183 mmol) and sodium triacetoxyborohydride (77 mg, 0.366 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by preparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size) using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min to provide the title compound. MS (ESI+) m/z 479.3 (M+H)+; Rt=1.63 min. 1H-NMR (400 MHz, DMSO-d6) δ 0.96 (d, J=6.6 Hz, 1H), 1.80 (m, 2H), 1.90 (s, 2H), 2.65 (m, 2H), 2.70 (m, 2H), 2.86 (m, 1H), 3.38 (m, 4H), 4.44 (d, J=5.3 Hz, 1H), 5.75 (s, 1H), 6.84 (dd, J=4.8 Hz, J=7.5 Hz, 1H), 7.52 (dd, J=1.9 Hz, J=7.5 Hz, 1H), 7.58 (t, J=50.5 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 7.86 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.07 (dd, J=1.9 Hz, J=4.7 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22]C)[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1.Cl>CN(C)C=O.C(OCC)(=O)C.CO.O1CCOCC1>[NH2:24][C:15]1[N:14]=[C:13]([NH:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[NH:17][C:18](=[O:22])[N:19]2[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCCO3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (400 mg) in dry N,N-dimethylformamide (6 ml) at room temperature and under nitrogen was added potassium carbonate (630 mg) in one go. The reaction was stirred at 60° C. for 1.5 hours and then cooled to 40° C. 2-(bromomethyl)tetrahydrofuran (156 μl) was added in one go and the reaction heated to 50° C. overnight and then at 90° C. for 2 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic layer was separated and concentrated in vacuo. The product was semi-purified by MDAP to afford a mixture. To this mixture, in dry methanol (5 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (1.5 ml) in one go. The reaction was left to stir at room temperature overnight. The reaction was concentrated in vacuo and the product purified by MDAP (slower-running isomer). This afforded the title compound as a white solid (15 mg).