Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][C:19]1(C)[O:26]C(=O)CC(=O)[O:20]1.[OH-].[Na+]>CN(C=O)C.C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:18][C:19]([OH:26])=[O:20])=[C:4]([OH:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(Cl)cc1O

Procedure:
The subtitle compound was prepared by using the product from step i). (3.48 g) was added to a solution of triethylamine (10 ml) and formic acid (7 ml) in DMF (30 ml) after 20 minutes. Meldrum's acid (3.22 g) was added and the mixture heated to 100 C for 4 hours. The solution was basified with 2M NaOH, extracted with ether (discarded). The aqueous layer was acidified with 2M HCl, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. The residue was purified by chromatography on silica eluting with diethyl ether/isohexane 1:5, yield 0.40 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:17][O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15]
Reactant: CN1CCc2c(O)ccc([N+](=O)[O-])c2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c2c1CCN(C)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirring solution of 5-Hydroxy-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (444 mg, 2.0 mmol) and in DMF (5 mL) is added potassium carbonate (553 mg, 4.0 mmol.) and the solution cooled to 0° C. Iodomethane (0.25 mL, 4.0 mmol.) is added and the reaction mixture allow to warm to room temperature and then stirred for 1 hour. The mixture is quenched with a cold water and then the precipitate is filtered, washed with water and dried under vacuum to give a white solid corresponding to 5-methoxy-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (336 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])#[N:24]
Reactant: CCCCCCOc1ccc(N)cc1C#N
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(NC(=O)c2cn(-c3ccc(F)cc3)nc2C)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.0 g), 5-amino-2-n-hexyloxybenzonitrile (1.0 g), triethylamine (1.4 g) and diethyl cyanophosphate (1.2 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from ethyl acetate to give the title compound (0.5 g), melting point: 160–161° C.
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19]>C(Cl)(Cl)Cl>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])[O:17][C:18]([CH3:19])=[CH2:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: C=C(C)OP(=O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Yield: 79.5 %

Procedure:
Methyl diphenylphosphinite (4.92 g, 22.7 mmol) was dissolved in chloroform (2 ml) in a 15 ml round bottom flask under inert atmosphere (constant flow of dry argon). The solution was then cooled to −78° C. by immersion of the reaction vessel into a dry ice/acetone bath. The methyl diphenylphosphinite was observed to freeze out of solution. To the reaction vessel at reduced temperature, a solution of chloroacetone (1.8 ml, 22.5 mmol) in chloroform (1 ml) was added. The reaction vessel was allowed to warm to room temperature over three hours with constant stirring and argon flow. As the methyl diphenylphosphinite melted into the solution, the reaction proceeded. After the completion of the three hour reaction time, the crude product was obtained by removal of the chloroform. Recrystallization from hot hexane followed by drying for 12 hours in a vacuum oven (60° C. 6 mm Hg) yielded 1-methylvinyl diphenylphosphinate (4.62 g, 79.6% overall). The melting point of the recrystallized product was determined to be from about 84.1 to 85.3° C. The proton NMR of the product in CDCl3 showed the expected resonances (relative to TMS at 0.0 ppm) at 1.01 ppm correlating to the three methyl protons, at 4.29 ppm and 4.64 ppm for the two vinyl protons, and at 7.3-7.8 ppm for the ten aromatic protons. The phosphorus NMR of the product in CDCl3 showed a simple resonance relative to 85% H3PO4 at 20.00 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](O)=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103 %

Procedure:
4-(2-Carboxyphenyl)piperidine-1-carboxylic acid t-butyl ester (5.0 g, 16 mmol, 1.0 eq.) and THF (130 mL, 1.7 mol) were combined at room temperature under nitrogen. Boranc dimethyl sulfide complex (2.9 mL, 33 mmol, 2.0 eq.) was added dropwise and the mixture was stirred for 5 minutes, then heated at reflux for 1 hour. The mixture was cooled to room temperature, and the reaction was quenched dropwise with MeOH (40 mL), then concentrated by rotary evaporation. The material was azeotroped with MeOH (2×40 mL). The mixture was then diluted with EtOAc (100 mL), and washed with 1 M HCl (2×50 mL), then NaHCO3 (2×50 mL), then saturated aqueous NaCl (1×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield 4-(2-hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (4.8 g) as a clear, light yellow oil that solidified upon sitting.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:18])[C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)=[CH:19][CH:20]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: O=C(NCc1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNC(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Yield: 73 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of N-(4-hydroxybenzyl)-4-nitrobenzamide INT-1 (647 mg, 2.38 mmol) in DCM (10 mL) at 0° C. was added TEA (1.03 mL, 7.13 mmol) followed by 4-(heptyloxy)benzoyl chloride (12.4 mL, 2.85 mmol). The suspension was sonicated until clear then diluted with DCM (50 mL) and washed with NaHCO3 (20 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to provide 857 mg (73%) of 4-((4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-2. LCMS-ESI (m/z) calculated for C28H30N2O6: 490; found 491 [M+H]+, tR=3.41 min (Method 5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:24]2[C:25]([F:37])=[C:26]([NH:30]C(=O)OCC=C)[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:26]1[C:25]([F:37])=[C:24]([C:9]2[N:10]=[C:11]([C:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 2-propen-1-yl (3-{5-(2-chloro-4-pyrimidinyl)-2-[1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-1,3-thiazol-4-yl}-2-fluorophenyl)carbamate (1.28 g, 2.336 mmol), tri-n-butyltin hydride (0.624 mL, 2.336 mmol) in dichloromethane (DCM) (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.135 g, 0.117 mmol) followed by water (0.2 mL). After 30 min, the reaction was concentrated. The residue was purified via chromatography on silica gel to obtain the title compound (0.81 g 74% yield). MS (ESI): 464.1 [M+H]+
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: COC(=O)CC(N)c1ccc(OC)c(OC2CCCC2)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-cyclopentyloxy-4-methoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.78-6.88 (m, 3H), 4.76 (s, 1H), 4.34 (t, 1H, J=5 Hz), 3.80 (s, 3H), 3.66 (s, 3H), 2.62 (d, 2H, J=5 Hz), 1.82-1.92 (m, 8H), 1.58 (s, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[O:11][C:12](=[O:34])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C(C)(C)C)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:12]([O:11][CH:10]([CH2:9][OH:8])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:34])/[CH:13]=[CH:14]\[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OC(COCCCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)OC(CO)COCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.7 %

Procedure:
To a mixture of 4a (348.4 mg, 0.4704 mmol) and glacial acetic acid (120 μL) was added 1.0 M TBAF in 2 mL THF over a period of 15 min at 5-10° C. (ice-water bath) with constant stirring. The reaction mixture was stirred at RT for 48 hours. It was then poured into water (100 mL), extracted with diethyl ether (100 mL, 2×), washed successively with saturated aqueous NaHCO3 (100 mL) and water (100 mL), and dried over anhydrous Na2SO4. After removal of solvent, the crude product was chromatographed on silica gel using dichloromethane-methanol to obtain 5a (140.8 mg, 48% yield). TLC: RF=0.65 (CH2Cl2:MeOH, 95:5 v/v); NMR (in CDCl3): δ in ppm 0.85 (3H, t, J=7.5 Hz), 0.95 (3H, t, J=7.0 Hz) 1.23 (26H, m), 1.54 (2H, m), 2.05 (2H, m), 2.38 (4H, m), 2.80 (10H, m), 3.44-3.50 (5H, m), 3.62-3.68 (2H, m), 3.85 (1H, br s, D2O exchangeable), 5.29-5.35 (12H, m); 13C NMR (in CDCl3): δ in ppm 14.3, 18.3, 22.7, 22.9, 25.7, 25.8 (2), 26.3, 29.6, 29.7 (2), 29.8 (2), 29.9 (2), 32.1, 64.4, 70.7, 72.1, 72.7, 127.2, 127.8, 128.1, 128.2, 128.3 (2), 128.4, 128.5, 128.8, 129.7 (2), 132.2, 177.9; FT-IR (cm−1) 3370 (br), 3013, 2954, 2918, 2850, 1712, 1470, 1397, 1382, 1326, 1239, 1123, 1060, 719; HRAPCI-MS m/z: measured 627.5349 ([M+H]+, calcd. 627.5352 for C41H71O4).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[CH3:10][OH:11]>>[CH3:10][O:11][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CC(Br)C(=O)Cl
Reactant: CO
Product: COC(=O)C(Br)CC(C)C

Procedure:
2-Bromo-4-methylpentanoyl chloride (IV, Example 2) is added dropwise to methyl alcohol (200 ml.) at 0°. After two hours the methanol is removed under reduce pressure and the residual oil is partitioned between chloroform and water. The chloroform is separated from the water and removed under reduced pressure to give a residual oil which is distilled under reduced pressure to give the title compound, b.p. 78°-90°/30 mm.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].CCCCOCCO.N>>[CH3:11][C:9]1[CH:8]=[C:7]([CH3:12])[C:3]2[C:4](=[O:6])[NH:20][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][C:2]=2[N:10]=1
Reactant: Nc1ccccc1N
Reactant: Cc1cc(C)c(C(=O)O)c(Cl)n1
Agent: N
Solvent: CCCCOCCO
Product: Cc1cc(C)c2c(n1)Nc1ccccc1NC2=O
Temperature: 170 °C

Procedure:
A mixture consisting of 9.3 gm of 2-chloro-4,6-dimethyl-nicotinic acid, 5.41 gm of o-phenylenediamine and 25 ml of butyl glycol was heated at 170° C. for 90 minutes while stirring. The mixture was subsequently cooled to 60° C. and poured over ice. After adjusting it to a pH-value of 8 with ammonia, the mixture was suction-filtered, and the filter cake was washed with water and recrystallized from aqueous 70% acetic acid, yielding 53% of theory of the compound named in the heading, which had a melting point of 297°-299° C.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:24]1([C:2]2[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=2)[C:5]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[O:6])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Br)c2F)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C3CC3)c2F)CC1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a solution of 107 mg of tert-butyl 4-(3-bromo-2-fluorobenzoyl)piperazine-1-carboxylate in 2.0 ml of toluene and 0.1 ml of water was added 72 mg of cyclopropylboronic acid, 3.2 mg of palladium acetate, 0.052 ml of tricyclohexylphosphine (15% toluene solution) and 207 mg of potassium phosphate, successively. The reaction solution was stirred at 150° C. for 10 minutes using a microwave reaction apparatus. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=1/1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[C:5]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:3]=1[OH:4]>C(OCC)C>[CH3:1][C:2]1[C:3](=[O:4])[C:5]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:6]([CH3:11])[C:7](=[O:10])[C:8]=1[CH3:9]
Reactant: Cc1c(C)c(O)c(C(=O)CCCCCO)c(C)c1O
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C(=O)CCCCCO)=C(C)C1=O

Procedure:
A solution of 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)-hydroquinone (formula III-1 wherein R=H3C, X=Y=OH, n=4, in the free form) (0.1 part) in diethyl ether (10 volume parts) was stirred with 3% aqueous ferric chloride solution at room temperature for 2 hours. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer and diethyl ether extract were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The residue was subjected to chromatography on silica gel and eluted with diethyl ether to give 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)-1,4-benzoquinone (formula IV-1 wherein R=H3C, n=4, in the free form) (0.088 part) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: COC(CCBr)OC
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(CCn1cc([N+](=O)[O-])cn1)OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (4.50 g, 39.80 mmol) in MeCN (135 mL), 3-bromo-1,1-dimethoxypropane (7.25 mL, 47.76 mmol) and Cs2CO3 (16.30 g, 50.0 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h and allowed to reach rt overnight. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitioned between brine and EtOAc, then the org. layer was separated and the aq. layer was extracted with EtOAc (2×). The comb. org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(3,3-dimethoxypropyl)-4-nitro-1H-pyrazole as a yellow oil which was used in the next step without further purification. LC-MS conditions B: tR=0.54 min, [M+H]+=no ionization.
Reaction SMILES: C([S:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([F:14])[CH:13]=1)[N:10]=[CH:9][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]2[OH:20])#N.SC[C@H]([C@@H](CS)O)O>CN(C=O)C>[F:14][C:12]1[CH:13]=[C:4]([SH:3])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]2[OH:20]
Reactant: CCOC(=O)c1cnc2c(F)cc(SC#N)cc2c1O
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(F)cc(S)cc2c1O
Temperature: 0 °C

Procedure:
A mixture of 20 g of ethyl 6-(cyanosulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate from preparation No. 16, 125 mL of DMF and 12.6 g of dithiothreitol is stirred for 5 h at 25° C. It is poured into 1 L of deoxygenated ice water and the precipitate collected by filtration, washed with two 200 mL portions of distilled water, and then dried in a stream of nitrogen. The title compound is obtained as 10.5 g of a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][NH:30]1>>[CH2:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][N:30]1[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3Cc4ccccc4C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with isoindoline via General Procedure E to give 10.7 mg of 276 following reverse phase purification. MS (Q1) 481.2 (M)+
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:35])[CH3:34]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:53]6[CH2:54][CH2:55][N:50]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51][CH2:52]6)[CH:41]=5)[CH:34]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)n1
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (1.85 g, 2.80 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (1.055 g, 5.61 mmol) were dissolved in 1,2-dichloroethane (30 mL) and acetic acid (0.177 ml, 3.08 mmol) was added. The mixture was stirred for 30 minutes and then MP-Triacetoxyborohydride (3.61 g, 8.41 mmol) was added. The mixture was stirred overnight. It was then filtered through a glass fiber filter paper and washed 2× with 20 mL of DCE. The solvent was evaporated and the residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified on a Combiflash on an 80 g silica column eluted with 0-10% MeOH/CH2Cl2. Product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl 4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-methyl-3-biphenylyl)methyl]-1-piperazinecarboxylate (1.8 g, 2.140 mmol, 76% yield) as a white solid. LC-MS m/z 830 (M+H)+, 0.86 min (ret time).