Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]2[C:27]([F:28])=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([F:29])[C:18]=2[CH3:30])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]2[C:27]([F:28])=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:29])[C:18]=2[CH3:30])[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cc(F)c(N2C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(C)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(F)c(C(=O)O)cc(F)c1N1C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 1 mol/L aqueous sodium hydroxide solution (15 mL, 15 mmol) was added under cooling with ice to a solution of ethyl 4-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoate (2.51 g, 6.30 mmol) in ethanol (20 mL), followed by stirring at room temperature for 20 hours. The resultant mixture was neutralized with 1 mol/L hydrochloric acid under cooling with ice, and ethanol was removed under reduced pressure. Subsequently, 1 mol/L hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate (200 mL×2), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried under reduced pressure (solvent), to thereby yield the title compound as a yellow oily substance (2.20 g, quantitative amount). The product was employed, without further purification, in the subsequent step.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[C:9]([NH:11][CH:12]([CH:15]([OH:25])[C:16]2[O:17][C:18]3[C:19]([N:24]=2)=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][CH3:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[CH:1]1([CH2:7][CH:8]([CH2:26][C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])[C:9]([NH:11][CH:12]([C:15]([C:16]2[O:17][C:18]3[C:19]([N:24]=2)=[N:20][CH:21]=[CH:22][CH:23]=3)=[O:25])[CH2:13][CH3:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1nc2ncccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1nc2ncccc2o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (237.6 mg, 0.48 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 95 mg of 2-cyclohexylmethyl-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide; H1 NMR(DMSO-d): 8.72–8.68(1H, m), 8.6(111, d, J=5.2 Hz, NH), 8.4–8.34(1H, m), 7.68–7.59(1H, m), 5.2–4.96(1H, m), 3.5–3.45(8H, m), 2.58(1H, m), 2.5–2.4(1H, m), 2.45–2.15(1H, m), 2.05–1.9(1H, m), 1.85–1.65(2H, m), 1.6–1.4(5H, m), 1.3–1.2(1H, m), 1.25–1(4H, m), 0.97(3H, t); MS: 469.6(M−1), 471.4(M+1), 493.2(M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([O:61][CH3:62])[CH:57]=[N:58]2)=[CH:53][CH:52]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:51]4[CH:60]=[C:59]5[C:54]([CH:55]=[C:56]([O:61][CH3:62])[CH:57]=[N:58]5)=[CH:53][CH:52]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]
Reactant: COc1cnc2cc(Br)ccc2c1
Reactant: CCN1CC2(CCN(C(C(N)=O)c3ccc(Br)cc3F)CC2)OCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1CC2(CCN(C(C(N)=O)c3ccc(-c4ccc5cc(OC)cnc5c4)cc3F)CC2)OCC1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (198 mg, 0.46 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (117 mg, 0.46 mmol), and potassium acetate (91 mg, 0.92 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (38 mg, 0.046 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromo-3-methoxyquinoline (110 mg, 0.46 mmol) and 2M aq K2CO3 (0.51 mL, 1.02 mmol) were added. The reaction mixture was purged with nitrogen and was heated with stirring at 100° C. for 1 h. The reaction mixture was diluted with dichloromethane (60 mL) and any salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate and the filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) afforded the racemic title product, which was resolved by chiral HPLC (Chromegachiral CC4, methanol) to afford the title product in >98% ee (45 mg, 19% yield). αD=+56° (c=0.02, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.07 Hz, 3 H) 1.68-1.80 (m, 2 H) 1.90-2.02 (m, 2 H) 2.31-2.41 (m, 1 H) 2.58-2.71 (m, 2 H) 2.72-2.80 (m, 1 H) 3.18 (s, 2 H) 3.41 (d, J=7.33 Hz, 2 H) 4.01 (s, 3 H) 4.02 (d, J=1.77 Hz, 2 H) 4.52 (s, 1 H) 5.65 (d, J=4.55 Hz, 1 H) 7.21-7.33 (m, 1 H) 7.44-7.56 (m, 3 H) 7.61 (dd, J=7.96, 1.89 Hz, 1 H) 7.81-7.94 (m, 2 H) 8.30 (s, 1 H) 8.71 (d, J=3.03 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][CH:34]=1>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][CH:34]=2)[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCCOc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
To a stirred solution of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)-carbamate (1.76 g, 5.9 mmol) in DMF (10 mL) was added cesium carbonate (4.0 g, 12.0 mmol). The reaction mixture was then stirred at room temperature for 20 minutes. 4-(2-Bromoethoxy)benzenecarboxaldehyde (1.35 g, 5.9 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine (×3), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 50% ethyl acetate/iso-hexane to afford the title compound (1.6 g, 61%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:28]=1)[C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[O:13].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:72]([NH2:76])([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:72]([NH:76][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH:23]([CH3:25])[CH3:24])[C:12](=[O:13])[C:11]1[CH:26]=[C:27]([O:29][CH2:30][CH2:31][NH:32][C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH:28]=[C:9]([Cl:8])[CH:10]=1)=[O:21])([CH3:75])([CH3:74])[CH3:73]
Reactant: CC(C)N(CCCCCC(=O)O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reactant: CC(C)(C)N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCCCCC(=O)NC(C)(C)C)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6-({3-chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-isopropyl-amino)-hexanoic acid trifluoroacetate (0.02 g) and PyBroP® (0.021 g) in DMF (1 ml) was added DIPEA (0.016 ml) followed by tert-butylamine (0.005 ml), after 1 min. The reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.0094 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Br[C:20]1[S:24][C:23]([C:25]2([C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:20]3[S:24][C:23]([C:25]4([C:31]5[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=5)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:22][CH:21]=3)=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C2(c3ncc(Br)s3)CCOCC2)cc1
Reactant: CC1(C)OB(c2ccc(C3CC3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(C2(c3ncc(-c4ccc(C5CC5)nc4)s3)CCOCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (490 mg, 2.00 mmol), methyl 4-(4-(5-bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (382 mg, 1.00 mmol), potassium carbonate (276 mg, 2.0 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf), 146 mg, 0.20 mmol) in toluene/ethanol/water (2 mL/1 mL/1 mL) was heated in microwave (Emry's Optimizer) at 110 C for 20 minutes. The reaction mixture was cooled to room temperature and then diluted with EtOAc and filtered. The filtrate was concentrated and purified by Flash Chromatography (SiO2, 95% EtOAC: 5% MeOH) to give methyl 4-(4-(5-(6-cyclopropylpyridin-3-yl)thiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate. MS found for C24H24N2O3S as (M+H)+ 421.42. To the above ester in MeOH/THF/dioxane (1:1:1) (9 mL) was added 3N NaOH (5.0 mL) and stirred at 55° C. After 14 hours, the reaction mixture was concentrated, diluted with water, and neutralized with 6N HCl. The formed solids were filtered and washed with water and dried. MS found for C23H22N2O3S as (M+H)+ 407.04. The acid was used further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].[F-].[K+]>CN(C=O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([N:8]3[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:7]=2)=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: CC(=O)Nc1cc(N)cc(-n2cccc2)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(I)cc2[N+](=O)[O-])cc(-n2cccc2)c1
Yield: 49 %

Procedure:
A solution of N-(3-amino-5-pyrrol-1-yl-phenyl)acetamide of Example 87(d) (5.0 g, 18.72 mmol), 1-fluoro-4-iodo-2-nitrobenzene (4.02 g, 18.72 mmol, 1.0 eq.) and potassium fluoride (1.08 g, 18.72 mmol, 1.0 eq.) in DMF (30 ml) was heated at 130° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 49% yield (4.3 g).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C@H:16]2[NH:21][C:20](=[O:22])[CH2:19][O:18][CH2:17]2)=[CH:13][CH:12]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[I:8][C:24]1[CH:23]=[C:14]([CH:13]=[CH:12][C:11]=1[O:10][CH3:9])[CH2:15][C@H:16]1[NH:21][C:20](=[O:22])[CH2:19][O:18][CH2:17]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(C[C@@H]2COCC(=O)N2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C[C@@H]2COCC(=O)N2)cc1I
Reaction time: 0.67 h

Procedure:
A solution of NIS (559 mg, 2.49 mmol) in DCM (3 mL) was added dropwise to a RT solution of (R)-5-(4-methoxy-benzyl)-morpholin-3-one C-6 (500 mg, 2.26 mmol) and trifluoromethanesulfonic acid (220 μL, 2.49 mmol) in DCM (3 mL) under argon and the resulting mixture was stirred for 40 min. The reaction was quenched with sat. aq. NaHCO3 and the layers were separated. The organic layer was washed with water (2×), dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the title compound as a pale yellow solid. LC-MS B: tR=0.62 min; [M+H+MeCN]+=388.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=C(C=CC=2)C(O)=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1CC[O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][CH:13]2[CH2:14][O:27][CH2:26][CH2:25][NH:24]2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Product: COC1=C(OC)C(=O)C(CC2COCCN2)=C(C)C1=O
Yield: 55.6 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41 and morpholine (0.036 ml, 0.41 mmol) were used, and a method similar to that described in Example 42 was employed to obtain the title compound (57 mg, 0.15 mmol, yield 54%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:34])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].N12CCCN=C1CCCCC2.[C:46]([O:50][CH2:51][CH3:52])(=[O:49])[CH:47]=[CH2:48]>C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:34])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][N:29]([CH2:48][CH2:47][C:46]([O:50][CH2:51][CH3:52])=[O:49])[CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: C=CC(=O)OCC
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a suspension of 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (Example 10; 90 mg; 0.18 mmol) in acetonitrile (3 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.16 ml; 1.09 mmol). Ethyl acrylate (0.03 ml; 0.27 mmol) was added to the solution and the resulting mixture stirred at 70° C. for 0.5 h. The mixture was cooled to room temperature and the solvent removed. The residue was partitioned between ethyl acetate and brine, and the aqueous layer further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (90 mg).
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH2:23])=[NH:22])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][CH3:8]>CO>[CH2:4]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[N:23]=[CH:14][C:9]([CH2:4][CH2:5][CH3:6])=[CH:10][N:22]=3)=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCc1ccc(-c2ncc(C(=N)N)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCc1ccc(-c2ncc(-c3ncc(CCC)cn3)cn2)cc1
Reaction time: 2 h
Yield: 120 %

Procedure:
To a solution of NaOH (0.8 g, 0.02 mol) dissolved in dry methanol (30 ml) were added 2-(p-pentylphenyl)-5-pyrimidinecarboxamidine hydrochloride (3.0 g, 0.01 mol) and α-propyl -β-dimethylaminoacrolein (1.4 g, 0.01 mol), followed by boiling with stirring for 2 hours and then distilling off methanol. Water (100 ml) and toluene (100 ml) were added to the reaction residue to extract the product, followed by washing the extraction liquor with water, drying the toluene layer over anhydrous sodium sulfate, distilling off toluene and three times recrystallizing the residual solids from ethanol to obtain the objective 2-(p-pentylphenyl)-5'-propyl-5,2'-bipyrimidinyl (2.0 g, 0.006 mol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[CH2:15]1[O:17][C@H:16]1[CH2:18][Cl:19]>C(O)(C)C>[Cl:19][CH2:18][C@H:16]([OH:17])[CH2:15][NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:2]([F:1])[CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Solvent: CC(C)O
Product: O[C@@H](CCl)CNc1ccc(N2CCOCC2)c(F)c1
Yield: 99.3 %

Procedure:
3-Fluoro-4-morpholinyl aniline (39 g) is mixed with R-epichlorohydrin (18.5 g), isopropyl alcohol (200 ml) is added and heated for 16 hours at reflux temperature. The solvent is distilled to give 57 gm of N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:36]=[CH:35][O:34][N:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].NC1C=C[O:40]N=1.C(C1C2C(=NC=CC=2C2C=NC3C(C=2)=CC=CC=3)N(C2C(NC3C=CON=3)=C(C=CC=2)C#N)N=1)(C)C>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:40])=[C:25]([NH:31][C:32]3[CH:36]=[CH:35][O:34][N:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccon1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccon3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: CC(C)c1nn(-c2cccc(C#N)c2Nc2ccon2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccon3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 40 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isoxazol-3-ylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 3-aminoisoxazole instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (32) (the second stage yield: 40%) was prepared as a white solid using 4-{(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isoxazol-3-ylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1C=C(C#CC2CC3(CCNC3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:25]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Product: CCOC(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 112 but replacing Compound 22c for Compound 27d. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 8:2) giving the title compound as a white solid. Yield: 55.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>C(O)(=O)C.Cl.O>[N:1]([C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5])=[N+:27]=[N-:28]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 0 °C

Procedure:
6,65 G (0.025 mol) of 2-amino-5,2'-dichlorobenzophenone are dissolved in a mixture of 25 ml of glacial acetic acid and 6.25 ml of concentrated hydrochloric acid and diazotised with 5 ml (0.025 mol) of 5 M sodium nitrite solution at 20°C. The mixture is then diluted with 100 ml of ice-cold water and neutralised by addition of 10 g (0.075 mol) of crystalline sodium acetate, and the turbid solution is clarified by filtration, using active charcoal. A solution of 5 g (0.077 mol) of sodium azide in 50 ml of water is added to the filtrate. The reaction product which hereupon precipitates is filtered off and washed with water. After drying over potassium hydroxide and calcium chloride in a desiccator, 2-azido-5,2'-dichlorobenzophenone of decomposition point 100°C is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13].BrCC1C(C2C=CC=CC=2C)=NC2C(C=1)=CC=CC=2C.[N:41]1[C:49]([NH2:50])=[C:48]2[C:44]([N:45]=[CH:46][NH:47]2)=[N:43][CH:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[C:3]([CH2:2][N:45]2[CH:46]=[N:47][C:48]3[C:44]2=[N:43][CH:42]=[N:41][C:49]=3[NH2:50])=[CH:12][C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cccc2cc(CBr)c(-c3ccccc3Cl)nc12
Reactant: Nc1ncnc2nc[nH]c12
Agent: Cc1ccccc1-c1nc2c(C)cccc2cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3cnc4c(N)ncnc43)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(bromomethyl)-2-(2-chlorophenyl)-8-methylquinoline (66 mg, 0.19 mmol), {prepared in a similar way as 3-(bromomethyl)-8-methyl-2-o-tolylquinoline, example 9} adenine (39 mg, 0.29 mmol), and cesium carbonate (124 mg, 0.38 mmol) in DMF (0.7 mL) was stirred at rt for 2 h. The crude mixture was evaporated onto silica gel and purified by flash chromatography (Biotage Si 25+M) eluting with MeOH/CH2Cl2 (5% to 10%). The resulting white solid was further purified by HPLC (Berger SFC) eluting with i-PrOH/CO2/DEA to provide a white solid [PI3Kδ IC50=2130 nM]. MS (ESI+) m/z=401.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([CH3:19])[N:9]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=1
Reactant: CCOC(=O)c1cnc(C)nc1-c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(CBr)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
820 mg (2.96 mmol) of ethyl 4-(2-chlorophenyl)-2-methylpyrimidine-5-carboxylate and 633 mg (3.55 mmol) of N-bromosuccinimide were dissolved in 18 ml of carbon tetrachloride and, with stirring, heated to the boil. At boiling point, 49 mg (0.29 mmol) of 2,2′-azobis-2-methylpropionitrile were added a little at a time over a period of 5 hours, followed by refluxing for a further hour. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. The desired product was isolated by chromatographic purification.