Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)=[C:40]([C:43]([OH:45])=O)[NH:41][N:42]=2)[CH:37]=1)[CH3:31].[C:56]([NH:63][CH2:64][CH2:65][CH2:66][NH2:67])([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C(Cl)Cl>[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)=[C:40]([C:43]([NH:67][CH2:66][CH2:65][CH2:64][NH:63][C:56](=[O:57])[O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:45])[NH:41][N:42]=2)[CH:37]=1)[CH3:31]
Reactant: CCc1cc(-c2n[nH]c(C(=O)O)c2-c2ccc(OC)cc2)c(O)cc1O
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCc1cc(-c2n[nH]c(C(=O)NCCCNC(=O)OC(C)(C)C)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
HOBT (572 mg, 4.2 mmol), NMM (1.55 ml, 14.1 mmol) and EDAC.HCl (820 mg, 4.3 mmol) were added at 0° C. consecutively to a solution of 5-(5-ethyl-2,4-dihydroxy-phenyl)-4-(4-methoxyphenyl)-2H-pyrazole-3-carboxylic acid (500 mg, 1.4 mmol) in 40 ml of dry DCM. The resulting mixture was stirred at 0° C. for 15 minutes. Then a solution of N—BOC-1,3-diaminopropane (740 mg, 4.3 mmol) in 5 ml of dry DCM was added. The resulting mixture was stirred at 0° C. for one our and at room temperature for 2.5 hours. The reaction mixture was washed with 50 ml of 10% w/v aqueous citric acid solution, 50 ml 20% aqueous KHCO3 solution and 50 ml of distilled water. The organic extracts were dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by automated column chromatography on a 40 g RediSep™ normal phase silica cartridge using an ISCO Companion™ eluting with a mixture of 5% methanol in DCM was used. The fractions containing the desired product were combined and evaporated under reduced pressure go give the title compound as a white solid (450 mg, 63%); 1H NMR Spectrum: δH (400 MHz, DMSO-d6) 0.90 (3H t, J=7.5 Hz), 1.38 (9H, s), 1.56 (2H t, J=6.9 Hz), 2.28 (2H q, J=7.4 Hz), 2.95 (2H d, J=6.1 Hz), 3.15-3.20 (2H, m), 3.72 (3H, s), 6.41 (1H, s), 6.57 (2H, s), 6.72 (1H, s br), 6.78 (2H d, J=7.3 Hz), 7.12-7.14 (2H, m), 7.92-8.02 (1H, m br), 9.28-9.35 (2H, m), 12.89 (1H, s, br);
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:21]([CH2:33][OH:34])[O:20][C@H:10]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:21]([CH2:33][O:34][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[O:20][C@H:10]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Compound 16 (569 mg, 1.20 mmol) was dissolved by addition of pyridine (17 mL). Pivaloyl chloride (188 μl, 1.57 mmol) was added to the solution, and the mixture was stirred at −5° C. for 1 hour. Pivaloyl chloride (188 μl, 1.57 mmol) was further added thereto, and the mixture was stirred at −5° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and filtered through Celite, and the filtrate was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:AcOEt=10:1) to obtain Compound 17 (648 mg, 96.7%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C[Si]([C:21]#[N:22])(C)C.C([O-])(O)=O.[Na+].C(Cl)[Cl:29]>[Ti](Cl)(Cl)(Cl)Cl>[Cl:29][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[C:21]#[N:22]
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[Si](C)(C)C#N
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CC(Cl)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.4 g (20 mmol) of 4,4'-difluorobenzophenone were dissolved in 50 ml of CH2Cl2 under nitrogen gas. 2.7 ml (24 mmol) of titanium tetrachloride and 2.7 ml (20 mmol) of trimethylsilyl cyanide were then added in succession at 0° C. After 30 minutes, the mixture was allowed to warm up to room temperature and was stirred for a further 24 hours. Aqueous NaHCO3 solution was added, after which the mixture was extracted with ether. The ether phase was dried over Na2SO4. The product was obtained in the form of a yellow oil.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:30]=[CH:29][C:13]([O:14][C@@H:15]([CH:26]([CH3:28])[CH3:27])[C@H:16]([OH:25])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:11]=1.O.CCOCC>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([CH:26]([CH3:27])[CH3:28])[CH:16]([O:25][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:29][CH:30]=1
Reactant: CC(C)[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)C(Oc1ccc(Br)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.3 %

Procedure:
Solid tert-butyldimethylsilyl chloride (0.46 g) was added to a solution of (3R, 4S)-4-(4-bromophenoxy)-5-methyl-1-pyridin-3-yl-3-hexanol (0.93 g) andimidazole (0.26 g) in dry dimethylformamide (12 ml) and the resulting solution stirred at room temperature for 3 days. Water (100 ml) and ether (100 ml) were added. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with dichloromethane then dichloromethane: hexane (1:1) to give the sub-title compound as an oil (0.70 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].C1COCC1>O.C(O)(=O)C>[CH2:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2ccc(C(=O)c3cccc(NCc4ccccc4)c3)cc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A dry round bottom flask was charged with 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.100 g, 0.397 mmol), benzaldehyde (0.042 g, 0.397 mmol) and acetic acid (0.1 mL). The mixture was allowed to stir for 5 hours at room temperature. A 1M solution of sodium cyanoborohydride in THF (1.19 mL, 1.19 mmol) was then added, and the mixture was allowed to stir for 45 minutes. Subsequently the reaction mixture was poured into H2O (˜30 mL) and allowed to stir for 15 minutes. The suspension was filtered and the filtrate was extracted with EtOAc (3×˜10 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford a brown oil. The brown oil was then chromatographed over silica (97/3, chloroform/methanol w/0.5% NEt3) to afford 6-[3-(benzylamino)benzoyl]-1,3-dihydro-2H-indol-2-one in 26% yield (0.035 g, 0.103 mmol).
Reaction SMILES: [K].[C:2]1(=[O:19])[N:6]([CH2:7][CH2:8][CH2:9][S:10]([O-])(=[O:12])=[O:11])[C:5](=[O:14])[C:4]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[C:2]1(=[O:19])[N:6]([CH2:7][CH2:8][CH2:9][S:10]([Cl:21])(=[O:12])=[O:11])[C:5](=[O:14])[C:4]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:3]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)[O-]
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)Cl
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
Potassium-3-phthalimidopropane-1-sulfonate (6.0 g) was suspended in dry toluene (25 ml) under a nitrogen atmosphere and heated to reflux. Then 4.11 g of PCl5 was added in portions and the mixture was heated at reflux for 60 minutes. A second portion of 4.11 g of PCl5 was added and heating was continued for 90 minutes. The reaction mixture was evaporated to dryness and crushed ice was added to the residual solid. When the ice had just molten, the solid was filtered off and dried in vacuo to yield 5.64 g (87%) of a solid. 1H-NMR (CDCl3) δ (ppm) 7.88-7.81 (m, 2H), 7.78-7.71 (m, 2H), 3.87 (t, J=6.5 Hz, 2H), 3.77-3.69 (m, 2H), 2.48-2.34 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:38])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CN(Cc1ccc(CO)cc1)C1CCOCC1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(Cc1ccc(CBr)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
Into a solution of N-methyl-N-(tetrahydropyran-4-yl)-4-(hydroxymethyl)benzylamine (0.68 g) and triphenylphosphine (0.91 g) in dichloromethane (10 ml) was added under ice cooling carbon tetrabromide (1.44 g), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with an aqueous solution of sodium bicarbonate under ice cooling and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/hexane 1/9) and further to washing with diethyl ether/hexane to obtain N-methyl-N-(tetrahydropyran-4-yl)-4-(bromomethyl)benzylamine (687 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:27]([NH2:29])=[O:28])[CH:3]=1.C=O.[OH-].[Na+].[C:34](=O)([O-])[O-:35].[Na+].[Na+]>COCCOC>[OH:35][CH2:34][NH:29][C:27]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:28]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 4-methyl-5-[(phenylsulfonyl)(2,3,6-trifluorophenyl)methyl]pyridine-2-carboxamide (215 mg, 0.51 mmol) in ethylene glycol dimethyl ether (6 ml), an aqueous solution of formaldehyde (37%, 0.2 ml) and 5% aqueous sodium hydroxide (0.8 ml) were added at 0° C., and the mixture was stirred for 1 hour at room temperature. Sodium carbonate (40 mg) was added to the reaction mixture, and the mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure, and then the residue was dissolved in chloroform, dried over magnesium sulfate, and filtered. Subsequently, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:2 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, and then was collected by filtration, to obtain the title compound (90 mg, 0.20 mmol, 39%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)c(C)c1

Procedure:
To a solution of 4-bromo-3-methylbenzoic acid (commercially available) (1.0 eq.) in EtOH (0.3 M) was added thionyl chloride (1.5 eq.) and heated to reflux for 2 hours. The solvent was concentrated en vaccuo, and the residue was diluted in ether and neutralized with saturated aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo to give ethyl 4-bromo-3-methylbenzoate.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.O(C)[Na].[CH2:21]1COC[CH2:22]1>>[C:12]1([CH:16]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:22]=[CH:21][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccco1
Reactant: O=C(CO)c1ccccc1
Reactant: C1CCOC1
Agent: CO[Na]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 71 %

Procedure:
2.27 g (16.7 mmol) of 2-hydroxyacetophenone, 1.52 g of furan-2-carbaldehyde (15.8 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 2.4 g (71%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.90 (s, 1H), 7.94 (d, d, J=1.5, 8.1 Hz, 1H), 7.71 (d, J=15.0 Hz, 1H), 7.58 (d, J=15.0 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.51 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H), 7.04 (d, d, J=0.9, 8.4 Hz, 1H), 6.96 (d, d, J=8.1, 8.1 Hz, 1H), 6.79 (d, J=3.3 Hz, 1H), 6.56 (d, d, J=1.5, 3.3 Hz, 1H).
Reaction SMILES: [CH:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCC(C)S(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)C(C)CC)n1

Procedure:
A mixture of 9.5 g. 3-sec.butylsulphonyl-1,2,4-triazole, 8.2 g. dipropylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from a mixture of toluene and petroleum ether (b.p. 60° - 80°C.) to give 1-dipropylcarbamoyl-3-sec.butylsulphonyl-1,2,4-triazole, m.p. 80° - 81°C. Elemental analysis satisfactory.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)[CH2:11][CH2:10]1>C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:7])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of 2,2′-azobis(isobutyronitrile) (0.122 g), N-bromosuccinimide (3.19 g) and 4-(2-cyclopropylethoxy)-1-methyl-2-nitrobenzene (3.30 g) in ethyl acetate (100 mL) was refluxed for 8 hr. The reaction mixture was allowed to cool to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was filtered with a short silica gel pad, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (150 mL), and molecular sieves 4A (10 g) and 4-methylmorpholine N-oxide (2.02 g) were added thereto at 0° C. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.90 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[C:25]([CH2:26][NH2:27])=[CH:24][C:23]2[C:18](=[C:19]([Cl:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[C:25]([CH2:26][NH:27][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][NH:34]3)=[CH:24][C:23]2[C:18](=[C:19]([Cl:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1OCc1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OCc2ccccc2)c(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)methanamine (0.021 g, 0.053 mmol), 6-chloropurine (0.012 g, 0.06 mmol, 1.5 eq) and DIEA (0.1 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=31 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.38 (s, 1 H), 8.12 (s, 1H), 8.07 (s, 1 H), 7.90 (s, 1 H), 7.88 (s, 1 H), 7.52-7.59 (t, 1 H), 7.21-7.25 (m, 2 H), 7.19 (m, 4 H), 7.06-7.12 (m, 2 H), 5.05-5.10 (m, 2H), 4.90-4.96 (s, 2H), Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: C(OC[C:5]([CH2:27]OCC)([OH:26])[CH:6]([NH:18]C(OC(C)(C)C)=O)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[ClH:31]>>[ClH:31].[NH2:18][C@H:6]1[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C@H:27]([Cl:31])[C@@H:5]1[OH:26]
Reactant: CCOCC(O)(COCC)C(Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Product: N[C@H]1Cc2c(ccc3ccccc23)[C@H](Cl)[C@@H]1O
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
A suspension of α, α-diethoxymethyl-β-tert-butoxycarbonylamino-1-naphthalenepropanol (250 mg), isomer A was stirred in 37% aqueous hydrochloric acid at 0° C. for 1 hour. The resulting emulsion was then stirred at 100° C. for 3 minutes and the flask was immediately cooled in an ice-water bath. The precipitate was filtered, washed with water and dried in vacuo to yield the title compound (152 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Temperature: 60 °C
Yield: 99.2 %

Procedure:
To a solution of 5-chlorosalicylaldehyde (5 g, 32 mmol) (Aldrich) in N,N-dimethylformamide (40 mL) was added K2CO3 (20 g, 145 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (10 g, 42 mmol, Aldrich). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, concentrated, and the residue was purified by chromatography (EtOAc:Hexanes=1:8, then 1:4) to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde as a white solid (Yield 10 g, 99%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Product: CC(C)(C)C(=O)Nc1cccc(COCc2cccc(F)c2)n1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(6-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.73 g) and 3-fluorobenzyl bromide as a yellow solid(0.66 g). MS (ESI): 317.1 (MH+).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=C(C)[N+:20]=1[O-])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(O)(=O)C>[C:5]([O:4][CH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:20]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCOc1cccc(C)[n+]1[O-]
Solvent: CC(=O)O
Product: CCCCCCOc1cccc(COC(C)=O)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
An amount 40 ml of acetic anhydride was stirred at about 115° C. and a solution of 5.50 g of 6-hexyloxy-α-picoline N-oxide in 20 ml of glacial acetic acid was dropwise added over about one hour. After the dropwise addition, the mixture was stirred at 130° C. for 5 hours, acetic acid and acetic anhydride were removed by concentration under a reduced pressure, the reaction mixture was dissolved in ether, and the remaining acetic acid was neutralized with a sodium hydrogen carbonate solution. After extraction with ether and concentration under a reduced pressure, the residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:9) to give 6.85 g of the desired product (yield 100%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cccc(C(C)O)n1
Temperature: -10 °C
Yield: 100 %

Procedure:
To a −60° C. solution of 6-methyl-pyridine-2-carbaldehyde (25 g, 206 mmol) in tetrahydrofuran (200 mL) was added methyl magnesium bromide (200 mL, 1.4 M in tetrahydrofuran/toluene, 1.36 equiv) over 40 minutes. The reaction mixture was slowly warmed to −10° C. over 90 minutes, and then slowly quenched with saturated aqueous ammonium chloride (75 mL). The liquid phase was decanted from the solids and concentrated in vacuo. The resulting residue was dissolved in methylene chloride, dried over magnesium sulfate, and concentrated in vacuo to yield 1-(6-Methyl-pyridin-2-yl)-ethanol (28 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.O.NN>CO.O.[Ni]>[Br:1][C:2]1[CH:16]=[C:6]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1cccc(F)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(Br)cc1NCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To suspension of Example 2A (700 mg, 2.153 mmol) in methanol (10 mL) was added hydrazine monohydrate (0.2 mL, 4.08 mmol) followed by 50% Raney® nickel in water (100 mg). The mixture was stirred at 50° C. for 2 hours, filtered through diatomaceous earth with dichloromethane and concentrated. Purification by flash chromatography (Isco®, Redi-Sep® column) eluting with 100% dichloromethane gave the title compound.