Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].C(Br)(C)(C)C.[CH3:34][S:35]([CH3:37])=O>C(OCC)(=O)C>[CH3:34][S:35][CH2:37][O:17][C:16](=[O:18])[CH:15]([O:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)[CH3:19]
Reactant: CS(C)=O
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Agent: CC(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CSCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 g (0.03 mol) of 2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenoxy]-propionic acid and 252 g (3.0 mol) of sodium bicarbonate are suspended in 2.5 liters of dimethyl sulphoxide and thereafter treated slowly with 336.5 ml (3.0 mol) of tert.butyl bromide. The mixture is stirred at room temperature overnight. The mixture, including the separated thick precipitate, is subsequently taken up in 5 liters of ethyl acetate. The ethyl acetate solution is washed twice with 1 liter of water, dried over sodium sulphate and evaporated. The residue is chromatographed on a 10-fold amount of silica gel with hexane/ethyl acetate (7:1) and the eluate is evaporated. There is obtained 2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenoxy]-propionic acid [(methylthio)methyl]ester in the form of an oil.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:9])=[N:15][CH:14]=2)=[CH:37][CH:38]=1)[CH3:29]
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(NCc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)cc1
Yield: 28.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.298 mmol), acetic acid (17 μL, 0.29 mmol), (4-amino-phenyl)-acetic acid ethyl ester (14 mg, 0.45 mmol) and sodium triacetoxyborohydride (101 mg, 0.48 mmol) to afford 43 mg (30%) of the desired product after purification.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH3:16][N:17]([CH3:25])/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[Na+]>CC1CCCO1.CN(C)C1C=CN=CC=1.C(OC)(C)(C)C>[CH2:23]([O:22][C:20](=[O:21])[C:19](=[CH:18][N:17]([CH3:25])[CH3:16])[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:24]
Reactant: CCOC(=O)/C=C/N(C)C
Reactant: CCOC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Temperature: -5 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
Ethyl 2-chloro-2-oxoacetate (99 g, 725 mmol) was dissolved in 2-methyltetrahydrofuran (800 ml) and 4-(dimethylamino)-pyridine (1.25 g, 10.0 mmol) was added. The mixture was cooled to −5° C. and a solution of triethylamine (76.2 g, 753 mmol) and (E)-ethyl 3-(dimethylamino)acrylate (106 g, 740 mmol) in 2-methyltetrahydrofuran (70 ml) was added via dropping funnel. The mixture was stirred for 3 h at ca. 0° C. After that, 5% (m/m) aqueous sodium chloride solution (250 mL) was added, the mixture was concentrated in vacuo to remove the 2-methyltetrahydrofuran. Ethyl acetate (800 mL) and 5% (m/m) aqueous sodium chloride solution (250 mL) were added, the organic phase was washed with 5% (m/m) aqueous sodium chloride solution (4×250 mL), the combined aqueous layers reextracted with ethyl acetate (2×300 mL) and the combined organic extracts concentrated in vacuo. The residue was filtered over silica gel (500 g, eluting with ethyl acetate/n-heptane 3:2 (v/v)) and the combined filtrates concentrated in vacuo to afford 146 g crude product as an orange oil. The crude product was dissolved at room temperature in tert-butylmethylether (1 L) and cooled to 1° C. Crystallization started at ca. 13° C. The suspension was filtered and washed with few cold tert-butylmethylether to afford 116.6 g of the title compound as light yellow crystals (66%, purity 99.9% by HPLC). MS (GC-split): m/z=243 [M]+. 1H NMR (CDCl3, 600 MHz); δ 1.26 (t, J=7.1 Hz, 3H), 1.36 (t, J=7.1 Hz, 3H), 3.03 (s, 3H), 3.36 (s, 3H), 4.17 (q, J=7.1 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 7.85 (s, 1H). The product was isolated as single isomer.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17](O)=[O:18])[CH2:14][N:15]=1)=[CH:7]2.[NH4+].O[N:33]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([NH2:33])=[O:18])[CH2:14][N:15]=1)=[CH:7]2
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) in N,N-dimethylformamide (12 mL) were added 1-hydroxybenzotriazole ammonium salt (154 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give pale-yellow crystals. The obtained crystals were recrystallized from methanol-ethyl acetate to give the title compound (224 mg, yield 75%) as colorless crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[C:32]([O:27][C:25]2[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2cc(F)cc(F)c2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 22.3 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (202 mg, 0.5 mmol), 3,5-difluorophenylboronic acid (156 mg, 1.0 mmol), copper (II) acetate (182 mg, 1.0 mmol), triethylamine (252 mg, 2.5 mmol) and freshly activated 4 Å molecular sieves (1.5 g) in DCM (10 mL) was stirred at ambient temperature and under ambient atmosphere for 64 hours. The reaction mixture was filtered, washed with DCM (2×10 mL), evaporated in vacuo and the residual oil partitioned between ethyl acetate (25 mL) and 1M hydrochloric acid (10 mL). The ethyl acetate layer was separated, washed sequentially with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant to give the title compound (45 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:31]1[O:33][CH2:32]1>CO>[CH3:30][CH:2]([CH3:1])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH3:27])[CH2:20][N:19]1[CH2:31][CH2:32][OH:33])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: C1CO1
Reactant: CCC(F)(F)CCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Solvent: CO
Product: CCC(F)(F)CCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CCO)C1
Temperature: 4 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of the title compound of Example 39 (17.9 mg, 0.039 mmol) in MeOH (2 mL) at 0° C. was added ethylene oxide (0.4 mL). The reaction mixture was stirred at 4° C. overnight. The reaction mixture was concentrated and purified by chromatography to give the title compound as a white solid (8.2 mg, 42%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[CH:17]C(=O)[C:15]([C:20](=O)[CH:21]=[CH:22][N:23](C)C)=[N:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:35][OH:36]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:18]=[CH:17][C:35](=[O:36])[C:15]([C:20]4[N:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=[CH:22][CH:21]=4)=[N:14]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CO
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(C3CCCCC3)cc2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2ccc(C3CCCCC3)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 30 %

Procedure:
To a solution of 1-(4-cyclohexylphenyl)-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude, 500 mg, 1.42 mmol) in 20 mL of methanol was added phenylhydrazine (615 mg, 5.70 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-cyclohexylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (170 mg, 30% for two steps) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.N1C=CC=CC=1.O>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1O
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of titanium (IV) chloride (11.1 g) in THF (50 mL) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.26 g) and 3-hydroxy-4-methoxybenzaldehyde (3.00 g) in THF (50 mL) at 0° C., and then a solution of pyridine (4.00 g) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 1 hr, and water was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.50 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[C:9]2[C:31]([O:33]CC)=[O:32])=[CH:5][CH:4]=1.[Li+].[OH-].Cl>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[C:9]2[C:31]([OH:33])=[O:32])=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1c(OCCOc2cccc3ccccc23)c2ccccc2n1Cc1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(C(=O)O)c(OCCOc3cccc4ccccc34)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 101C (80 mg) in tetrahydrofuran (2 ml), methanol (1 ml) and water (1 ml) was added LiOH (100 mg). The mixture was stirred at room temperature overnight. The mixture was then acidified with 5% HCl and extracted with ethyl acetate (200 ml). The organic layer was washed with water, brine and dried over Na2SO4. After concentration of the solvent, the residue was dissolved in DMSO/methanol (1:1, 1.5 ml) and purified via reverse phaseHPLC. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.99 (m, 1H), 8.01 (m, 1H), 7.86 (m, 1H), 7.73 (m, 1H), 7.46 (m, 6H), 7.27 (m, 1H), 6.98 (m, 3H), 6.74 (m, 2H), 5.70 (s, 2H), 4.64 (m, 2H), 4.48 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1.I[CH2:21][CH3:22].O>CN(C=O)C>[CH2:21]([O:3][C@H:4]1[C@H:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][CH2:7][N:6]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:5]1)[CH3:22]
Reactant: CC(C)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(C)C
Reaction time: 0.42 h

Procedure:
Add sodium hydride (69 mg, 1.73 mmol) to a solution of trans-tert-butyl 3-hydroxy-4-isopropyl-piperidine-1-carboxylate (300 mg, 1.23 mmol) in anhydrous DMF (2.5 mL) at ambient temperature. Stir the mixture for 25 minutes and then add iodoethane (112 μL, 1.48 mmol). Stir the mixture overnight. Add additional iodoethane (59.3 μL, 0.74 μmol) and stir the mixture for 3 h, then add water. Extract the aqueous layer with EtOAc, combine the organic layers. Sequentially wash the combined organic layers with water then brine; dry over anhydrous sodium sulphate; filter; collect the filtrate; and then remove the solvent under vacuum. Purify the compound by silica gel chromatography eluting with hexane:ethyl acetate (0%, 2%, 4% and 6% ethyl acetate) to obtain the title compound as a waxy solid (260 mg, 78%). MS (m/z): 216 (M-tBu+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]=[C:10]=[O:11])[CH:3]=1.[Br:12][C:13]1[C:22]2[CH:21]=[N:20][CH:19]=[CH:18][C:17]=2[C:16]([NH2:23])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:10]([NH:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:11])=[C:17]2[C:22]=1[CH:21]=[N:20][CH:19]=[CH:18]2
Reactant: Nc1ccc(Br)c2cnccc12
Reactant: O=C=NCc1cccc(F)c1
Product: O=C(NCc1cccc(F)c1)Nc1ccc(Br)c2cnccc12

Procedure:
The title compound was prepared using 1-fluoro-3-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73 (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.39 (d, 5.8, 2H), 7.09 (m, 1H), 7.17 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 8.01 (d, J 6.1, 1H), 8.23 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.93 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.64; H, 3.33; N, 11.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=2)[N:9]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cc(F)ccc2nc1-c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc2nc(-c3ccccc3Cl)c(CNc3ncnc4[nH]cnc34)cc2c1

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-6-fluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-6-fluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=1683 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.44 (s, 1 H), 8.14 (s, 1 H), 8.07-8.11 (m, 2 H), 7.66-7.71 (m, 1 H), 7.59-7.66 (m, 1 H), 7.49-7.55 (m, 2 H), 7.40-7.46 (m, 1 H), 7.34-7.40 (m, 1 H), 4.05-4.17 (m, 2 H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](O)[CH:17]=2)[N:6]=1.OCCNC1N=C(NCCO)N=C(N[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2Cl)N=1.O[CH2:46][CH2:47]NC1N=C(NCCO)N=C(NC2C=CC=C(Cl)C=2)N=1.OCCNC1N=C(NCCO)N=C(NC2C=CC(Cl)=CC=2)N=1.OCCNC1N=C(NCCO)N=C(NC2C=CC=C(OC)C=2)N=1>>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:46][CH2:47][CH2:38][CH2:43][CH2:42][CH2:41][CH2:40][CH3:39])=[CH:18][CH:17]=2)[N:6]=1
Reactant: OCCNc1nc(NCCO)nc(Nc2cccc(O)c2)n1
Reactant: OCCNc1nc(NCCO)nc(Nc2ccccc2Cl)n1
Reactant: OCCNc1nc(NCCO)nc(Nc2cccc(Cl)c2)n1
Agent: COc1cccc(Nc2nc(NCCO)nc(NCCO)n2)c1
Agent: OCCNc1nc(NCCO)nc(Nc2ccc(Cl)cc2)n1
Product: CCCCCCCCc1ccc(Nc2nc(NCCO)nc(NCCO)n2)cc1

Procedure:
2,4-bis-(2-Hydroxyethylamino)-6-(3-hydroxyanilino)-1,3,5-triazine, 2,4-bis-(2-hydroxyethylamino)-6-(2-chloroanilino)-1,3,5-triazine, 2,4-bis-(2-hydroxyethylamino)-6-(3-chloroanilino)-1,3,5-triazine, 2,4-bis-(2-hydroxyethylamino)-6-(4-chloroanilino)-1,3,5-triazine and 2,4-bis-(2-hydroxyethylamino)-6-(3-methoxyanilino)-1,3,5-triazine are particularly preferred.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][N:25](C=O)C>O1CCOCC1.[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:24]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:9]2)=[CH:4][CH:3]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Reactant: CN(C)C=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#N)cc2)CC2(C1)OCCO2
Temperature: 120 °C

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]carbamate (1-5) (21.3 g, 55.5 mmol) in dioxane (100 mL) and DMF (100 mL) was added zinc cyanide (6.52 g, 55.5 mmol) and bis(tri-t-butylphosphine)palladium(0) (2.84 g, 5.55 mmol) and the reaction was heated to 120° C. under N2 for 1 hour. The reaction mixture was cooled to rt, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 1-60% EtOAc/Hexane. The appropriate fractions were combined and the solvent removed in vacuo to give tert-butyl [2-(4-cyanophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]carbamate (1-6). MS (M+H)+: 331.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:6]=1[C:7]([OH:9])=[O:8])=[O:4].[CH2:17]=[C:18]1[O:22][C:20](=O)[CH2:19]1.C(OC(=O)C)(=O)C>CO.O1CCCC1.[C].[Pd]>[O:8]=[C:7]1[C:6]2=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=[CH:12][CH:11]=[C:10]2[N:14]=[C:20]([CH2:19][C:18](=[O:22])[CH3:17])[O:9]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: C=C1CC(=O)O1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2nc(CC(C)=O)oc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 2-methoxycarbonyl-6-nitrobenzoic acid (22.5 g, 0.1 mol) in methanol (100 mL) was added 10% palladium-carbon (2.0 g, 50% hydrate), and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was dissolved in acetone (100 mL). To the solution was added dropwise diketene (23 mL, 0.30 mol) at room temperature. After the mixture was stirred at room temperature for 16 hours, the solution was concentrated under reduced pressure. The resulting crude crystals were collected by filtration, washed with acetone and diethylether, and air dried (15.4 g). The crude crystals were suspended in a mixture of acetic anhydride (10.4 mL, 0.11 mol) and tetrahydrofuran (60 mL), and the suspension was heated under reflux for 12 hours. The suspension was allowed to cool to room temperature, and the solvents were evaporated under reduced pressure to give crude crystals. The crystals were collected by filtration, washed with diethylether, and air dried to give the title compound (8.03 g, 31% yield).
Reaction SMILES: FC1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH:34](O)[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1>>[OH:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccc(C2CC(O)c3cc(O)ccc3O2)c1
Agent: Oc1ccc2c(c1)CCC(c1ccc(F)cc1)O2
Product: Oc1cccc(C2CCc3cc(O)ccc3O2)c1

Procedure:
2-(3-Hydroxyphenyl)chroman-6-ol was prepared as described for 2-(4-fluorophenyl)chroman-6-ol in Example 2(c) but starting from 2-(3-hydroxyphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.38 (s, 1H), 8.77 (s, 1H), 7.17-7.13 (m, 1H), 6.82-6.79 (m, 2H), 6.70-6.67 (m, 1H), 6.62 (d, 1H, J 8.6 Hz), 6.52-6.47 (m, 2H), 4.89 (dd, 1H, J 2.1, 9.9 Hz), 2.86-2.82 (m, 1H), 2.65-2.59 (m, 1H), 2.09-2.04 (m, 1H), 1.91-1.85 (m, 1H).
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCCC1.[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28]N=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]([F:43])[CH:37]=1.C1(C)C=CC=CC=1>C(O)C>[CH:10]1([C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:10]1([C:16]([NH:18][C:19]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][CH:1]=3)=[CH:37][C:38]=2[F:43])=[S:20])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C(N=C=S)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCCC4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
1-Cyclohexanecarbonyl isothiocyanate was prepared using commercially available 1-cyclohexanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclohexanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 61%).