Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[O:35][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Oc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1Cl
Temperature: 80 °C
Yield: 66.5 %

Procedure:
To a stirred solution of 4-chloromethyl-1-trityl-1H-imidazole (400 mg; CAS 103057-10-9) at r.t. in DMF (5 ml) under an argon atmosphere were added 2,3-dichlorophenol (273 mg) and K2CO3 (385 mg). The reaction mixture was heated to 80° C. for 5 hours, then cooled to r.t., diluted with EtOAc and washed with 1 N NaOH. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give 4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (360 mg) as white solid. MS (ISP): 243.3 ([Trt]+)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=[CH:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:20][C:18]1[C:19]2[N:11]([CH2:10][CH2:9][OH:8])[CH:12]=[CH:13][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc2ncnc(Cl)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCCn1ccc2ncnc(Cl)c21
Reaction time: 4 h
Yield: 110.2 %

Procedure:
To a solution of 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (560 mg) in tetrahydrofuran (1.7 mL), was added tetrabutylammonium fluoride (1M tetrahydrofuran solution) (2.69 mL) under ice-cooling, and the mixture was stirred for 4 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:ethyl acetate/methanol=10/0→9/1). The object fraction was concentrated under reduced pressure and dried to give the title compound (391 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[C:4]([C:10]#[N:11])=[N:3]1>C(Cl)Cl.[Pd]>[NH2:7][C:5]1[C:4]([C:10]#[N:11])=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cc([N+](=O)[O-])c(C#N)n1
Agent: [Pd]
Solvent: ClCCl
Product: Cn1cc(N)c(C#N)n1
Reaction time: 8 h

Procedure:
1-Methyl-4-nitropyrazole-3-carbonitrile (2.0 g) was dissolved in DCM (30 ml) and 10% Pd/C (0.3 g, 50% wet) added. The mixture was stirred under a hydrogen atmosphere overnight. The catalyst was filtered off and the solution poured on to a silica column (15 g). The product was eluted with 100% EtOAc (100 ml) to yield 4-amino-1-methylpyrazole-3-carbonitrile, 1.277 g. Mass spectrum: MH+ 123
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:40][CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[O:23][N:22]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and tert-butylamine (216 mg, 2.96 mmol) as starting materials.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:26])[CH:11]([C:20]1(O)[CH2:24][CH2:23][CH2:22][CH2:21]1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C=CC=CC=1>[CH2:1]([O:8][N:9]1[C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C1(O)CCCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1C(=O)N(OCc2ccccc2)C12CCCC2
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
To a solution of N-(benzyloxy)-N2 -(t-butoxycarbonyl)-α-(1-hydroxycyclopentyl)glycinamide (0.82 g, 2.16 mmole) in 15 ml of pyridine under argon was added pyridine-sulfur trioxide complex (0.47 g, 29.5 mmole). The reaction mixture was heated at 50°-55° C. After 1.5 hours, an additional amount (0.150 g, 0.9 mmole) of pyridine-sulfur trioxide complex was added and the reaction was heated for an additional hour. The reaction mixture was then concentrated in vacuo and azeotroped three times with acetonitrile. To this residue was added a cold mixture of potassium carbonate solution (3.32 g/9 ml water) and ethyl acetate (25 ml). The reaction was stirred vigorously and refluxed for two hours at which point tlc indicated that the reaction was near completion. After cooling, the reaction mixture was diluted with water and ethyl acetate and the phases separated. The organic phase was washed with 5% potassium bisulfate solution and brine and dried over anhydrous sodium sulfate. After evaporating to a residue, the crude benzyl ether was chromatographed on LPS-1 (hexane:ethyl acetate, 3:1) to give 550 mg of pure material.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[CH:14]2.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[CH:14]2)=[O:31]
Reactant: Cn1ccnc1SCc1cccc2cc(-c3nccs3)[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1ccnc1S(=O)Cc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 7-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-2-(1,3-thiazol-2-yl)-1H-indole (0.087 g) in ethyl acetate was added m-chloroperbenzoic acid (0.070 g) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0) to give the title compound (0.028 g, yield 31%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[Br-].[CH:19]1([Zn+])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:19]1([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]3=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reactant: [Zn+]C1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C1CC2(CCCOC2)Oc2ccc(C3CCCCC3)cc21
Temperature: 160 °C
Yield: 33.1 %

Procedure:
Pd(PPh3)2Cl2 (60 mg) in a 40 mL tube under Ar was treated sequentially with 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (600 mg, 2.01 mmol) in THF (20 mL*3), CuI (600 mg) and cyclohexylzinc(II) bromide (8.1 mL, 4.02 mmol). The mixture was heated under microwave at 160° C. for 10 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by column chromatography to give 6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (200 mg, 30%). 1H-NMR (CDCl3): 1.31 (t, 4H), 1.48 (m, 1H), 1.62 (m, 5H), 1.76 (d, 4H), 1.89 (m, 1H), 2.06 (d, 1H), 2.49 (s, 1H), 2.61 (m, 2H), 3.49 (m, 2H), 3.79 (m, 2H), 6.88 (d, 1H), 7.29 (d, 2H), 7.61 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][N:21]1[CH:25]=[C:24]([CH:26]=O)[N:23]=[CH:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:26][C:24]3[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Cn1cnc(C=O)c1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1cn(C)cn1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 93 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-methyl-1H-imidazole-4-carbaldehyde using standard reductive amination conditions. The resulting crude material was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-1H-imidazol-4-ylmethyl)-amine as a solid (93% yield).
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[O:7][C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:34][CH:2]([F:1])[C:3]1[O:7][C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:10])=[O:9])=[CH:5][CH:4]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C(F)F)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(C(F)F)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of tert-butyl {[1-{[5-(difluoromethyl)-2-furyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (154 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solution of ethyl acetate-ethanol to give the title compound as a white solid (yield 96.3 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(#N)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
18.7 g of 2-chlorobenzoylisocyanate were added to 150 ml of a solution of 17.7 g of 4-trifluoromethylaniline in dry acetonitrile. After stirring at room temperature for a few hours, the crystalline precipitate was sucked off, washed with successively acetonitrile, ethanol and petroleum ether and dried in air. The desired product was obtained in a yield of 29.0 g; melting point 214° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:64][C:65]1[CH:66]=[C:67]([CH:70]=[C:71]([C@H:73]2[CH2:77][C@H:76]([F:78])[CH2:75][NH:74]2)[CH:72]=1)[C:68]#[N:69]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:68]([C:67]1[CH:70]=[C:71]([C@H:73]2[CH2:77][C@H:76]([F:78])[CH2:75][N:74]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[CH:3]=2)[CH:72]=[C:65]([F:64])[CH:66]=1)#[N:69]
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)cc(C#N)c3)cc12
Temperature: 140 °C

Procedure:
A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (36 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg, 2 μmol), xantphos (6 mg, 8 μmol), cesium carbonate (61 mg, 0.19 mmol), 1,4-dioxane (0.5 mL) and 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15) (28 mg, 0.13 mmol). The contents were heated to 140° C. for 25 minutes under microwave irradiation. Upon cooling to room temperature the reaction was partitioned with EtOAc and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield ethyl 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-7). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H), 8.21 (d, J=7.6 Hz, 1 H), 7.39 (s, 1 H), 7.31-7.27 (m, 1 H), 7.26-7.21 (m, 1 H), 6.94 (d, J=2.4 Hz, 1 H), 6.24 (dd, J=2.8, 7.6 Hz, 1 H), 5.40 (d, J=52.4 Hz, 1 H), 5.07 (dd, J=7.2, 9.6 Hz, 1 H), 4.35-4.26 (m, 2 H), 4.23-4.08 (m, 1 H), 4.05-3.93 (m, 1 H), 2.97-2.85 (m, 1 H), 2.17-1.99 (m, 1 H), 1.35 (t, J=7.2 Hz, 3 H). MS m/z 397.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][N:40]2[C:39](=[O:41])[C:38]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]3[C:36]2=[O:46])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC(CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
1-(tert-Butoxycarbonyl)perhydroazepin-3-yl methanol (1.13 g, 4.93 mmol) was dissolved in tetrahydrofuran (10 mL). To this solution, triphenylphosphine (1.60 g, 5.92 mmol) and phthalimide (871 mg, 5.92 mmol) were added and the mixture was stirred at room temperature for 5 min. A 40% toluene solution of diethyl azodicarboxylate (3.23 mL, 7.40 mmol) was then added and the mixture was stirred at room temperature for 4 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine and was dried over magnesium sulfate, followed by evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 1.27 g (72%) of the desired compound as a colorless powder.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([OH:15])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>C(OCC)C>[OH:15][CH:11]([CH3:10])[CH2:12][C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#CCC(C)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(CC(C)O)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chlorooximidoacetate (4 g, 26.4 mmol) and 4-pentyn-2-ol (10.00 ml, 107 mmol) were dissolved in diethyl ether (30 ml). A solution of triethylamine (3.68 ml, 26.4 mmol) in diethylether (20 ml) was added dropwise to the reaction mixture. After 1 h of stirring at RT the reaction mixture was washed with brine and water, dried with MgSO4 and evaporated to dryness. The residue was purified with flash chromatography using a gradient of methanol in methylene chloride affording 2.51 g (48%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ, 1.11 (d, 3H), 1.31 (t, 3H), 2.82-2.94 (m, 2H), 3.93-4.03 (m, 1H) 4.35 (q, 2H), 4.89 (d, 1H), 6.67 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]1[CH3:16].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:7]2[C:8]3[CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=3[C:14]3[C:2]([CH3:17])([CH3:1])[N:3]([CH3:16])[CH2:4][CH2:5][C:6]2=3)=[CH:24][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(C)(C)N(C)CC3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C1(C)C

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-1,1,2,8-tetramethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCBr)cc1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
1-(4-hydroxyphenyl)ethanone (8.2 g, 60.2 mmol), potassium carbonate (15.2 g, 110.1 mmol), and KI (1.0 g, 6.0 mmol) in 100 DMF was stirred for 5 min, then 1,2-dibromoethane (60 ml, 696.2 mmol) was added. The mixture was stirred overnight, evaporated, diluted with EtAc/Hexane (1:1), washed with 0.1 M HCl/NaCl (conc), dried over MgSO4, filtered, evaporated and purified by SiO2 chromatography eluted with EtAc/Hexane (1:3 to 2:3) to afford 12.41 g (85.2%) of the title compound. 1H NMR (CDCl3) 7.87 (ddd, 2H, J=2.8, 4.9, 9.7 Hz), 6.88 (ddd, 2H, J=2.8, 4.9, 9.6 Hz), 4.29 (t, 2H, J=6.2 Hz), 3.59 (t, 2H, J=6.2 Hz); 13C NMR 196.88, 162.11, 131.15, 130.54, 113.80, 68.06, 29.50, 26.62; MS m/z+ 264.80 (M+Na), 266.80 (M+2+Na).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C1COCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:30]([C:20]45[CH2:29][CH:24]6[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]6)[CH2:27]4)[CH2:21]5)=[O:31])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a stirring solution of nitro amine 8 (0.240 g, 0.94 mmol) in dry THF-Pyridine (15 ml/0.400 ml), adamantane carbonyl chloride (0.280 g, 1.41 mmol) was added and the mixture stirred at room temperature for 3 h. The reaction was quenched by addition of water and the resulting yellow solid was filtered and passed through a SiO2 gel using EtOAc as a eluent to give 13 (0.265 g, 67%). 1H NMR (DMSO-d6, 500 MHz): δ 13.51 (1H, brs, NH), 9.60 (1H, brs, NH), 8.78 (1H, s), 8.45-8.40 (4H, m), 8.32 (1H, s), 2.00-1.60 (15H, m); EIMS m/z: 418.5 (M+1) and 416 (M−1).
Reaction SMILES: [Na].[CH2:2]([OH:6])[CH2:3][CH2:4][CH3:5].[O:7]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]1>>[OH:7][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:6][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCCCC1CO1
Reactant: CCCCO
Agent: [Na]
Product: CCCCCCCCC(O)COCCCC
Temperature: 100 °C
Yield: 87 %

Procedure:
0.46 gm (0.02 gm-atom) of sodium were added to 185 gm (2.5 mols) of n-butanol. After dissolution of the sodium, the temperature was raised to 100°C, and an amount of 78.2 gm (0.5 mol) of 1,2-epoxy decane was added in drops within 30 minutes while stirring. The reaction mixture was maintained at 100°C for 4 hours. Then the excess alcohol was distilled, and by subsequent vacuum distillation at 100° to 120°C and 0.06 Torr . the 2-hydroxy-decyl-n-butyl ether was separated from the higher boiling by-product. In this manner the intermediate product 2-hydroxydecyl-n-butyl ether (refractive index nD20 = 1.4392) was obtained in a yield of 87%.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:3]=[C:2]([C:38]#[C:37][C:35]([CH3:36])([OH:39])[CH3:34])[C:10]=12
Reactant: C#CC(C)(C)O
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc2cc(Cn3nc(C#CC(C)(C)O)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.0569 g, 0.102 mmol) and copper(i) iodide (0.00387 g, 0.0203 mmol, 0.2 eq) in DMF (2 mL) was treated with 2-methyl-3-butyn-2-ol (0.0984 mL, 1.02 mmol, 10 eq), triethylamine (0.0282 mL, 0.203 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.0117 g, 0.0102 mmol, 10 mol %) under Ar. The mixture was stirred under Ar at rt for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol [PI3Kδ IC50=116 nM] as a tan solid. 1H NMR (DMSO-d6) δ ppm 8.21 (1 H, s), 8.02 (1H, s), 7.87 (1 H, d, J=7.8 Hz), 7.77-7.82 (1 H, m), 7.65 (1 H, d, J=6.7 Hz), 7.57-7.62 (2 H, m), 7.51-7.57 (1 H, m), 7.26-7.32 (1 H, m), 5.76 (1 H, s), 5.44 (2 H, s), 2.60 (3 H, s), 1.46 (6 H, s). Mass Spectrum (ESI) m/e=517.2 (M+1).