Azzindani/Open_Reaction_Data huggingface dataset:
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.[OH:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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:39]3[CH:40]=[C:35]([OH:34])[CH:36]=[CH:37][CH:38]=3)[C:10]=12
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(-c4cccc(O)c4)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure J using 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1 g, 0.1785 mmol, 1 eq), 3-hydroxyphenylboronic acid (0.0492 g, 0.357 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (0.0206 g, 0.0178 mmol, 10 mol %), and sodium carbonate (2M aq. sol, 0.535 mL, 1.07 mmol, 6 eq) in DMF (1 mL). After purification, 3-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol was obtained as light gray solid. The gray solid was suspended in CH2Cl2 and filtered to provide 3-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol [PI3Kδ IC50=8 nM] as off-white solid. 1H NMR (DMSO-d6) δ ppm 9.65 (1 H, s), 8.28 (1 H, s), 8.04 (1 H, s), 7.87 (1 H, d, J=7.8 Hz), 7.74-7.80 (1 H, m), 7.64 (1 H, d, J=7.0 Hz), 7.56-7.61 (2 H, m), 7.50-7.56 (1 H, m), 7.34-7.38 (1 H, m), 7.30 (1 H, t, J=7.8 Hz), 6.94-7.02 (2 H, m), 6.80-6.87 (1 H, m), 5.53 (2 H, s), 2.60 (3 H, s). Mass Spectrum (ESI) m/e=527.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]3)[CH2:13][O:14]2)=[C:9]([F:28])[CH:8]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]3)[CH2:13][O:14]2)=[C:9]([F:28])[CH:8]=1
Reactant: CCOC(=O)c1cnn(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnn(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)c1
Yield: 74.9 %

Procedure:
A solution of ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (100 mg) and a 1 M aqueous NaOH solution (0.55 mL) in EtOH/THF (3 mL/1 mL) was stirred at 100° C. for 2 hours, neutralized with 1 M HCl, and extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) and the obtained solid was washed with IPE to obtain 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylic acid (71 mg) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:20][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncnc3)no2)cc1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 4-ethynyl-1,2-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.71 (ddd, J=10.5, 8.3, 8.3 Hz, 1H), 7.77-7.86 (m, 2H), 8.04 (ddd, J=11.4, 7.6, 2.0 Hz, 1 H), 9.31 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18](Cl)=[O:19]>>[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18]([N:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:19]
Reactant: C1COCCOCCOCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13-tetraoxacyclopentadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH:20][C:21](=[O:23])[CH3:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Solvent: c1ccncc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(NC(C)=O)cc3c2c1C
Temperature: 0 °C

Procedure:
0.6 g of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is dissolved in 6 ml of pyridine and 1.5 ml of acetic anhydride and the whole is stirred for 16 hours at room temperature. The mixture is then stirred into 30 ml of ice water and intensely extracted with ethyl acetate. The extracts are washed until neutral with semisaturated common salt solution, dried using sodium sulphate and filtered. The solvent is distilled off in vacuo. The residue (0.78 g) is recrystallized from acetone-diisopropyl ether. 0.49 g of 6-acetamido-4-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 273°-278° C. is obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[C:20]3=[O:28])[CH2:18]2)=[CH:15][CH:16]=1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCN1C(=O)[C@@]2(C[C@H]2c2ccc(Cl)cc2)c2ccccc21

Procedure:
The title compound was prepared in analogy to Example 70 starting from 2-Chloro-N,N-diethylethaneamine hydrochloride (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)Spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C22H25ClN20: 368, observed (M+H)+: 369.1 1H NMR (400 MHz, MeOD-d4) δppm 1.41 (t, J=7.20 Hz, 6 H) 2.21-2.31 (m, 2 H) 3.32 (t, J=8.59 Hz, 1 H) 3.39-3.55 (m, 4 H) 3.60 (t, J=6.44 Hz, 2 H) 4.23-4.42 (m, 2 H) 6.16 (d, J=7.58 Hz, 1 H) 6.85 (t, J=7.45 Hz, 1 H) 7.19 (d, J=7.83 Hz, 1 H) 7.24-7.32 (m, 3 H) 7.33-7.40 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46]Cl.[Na+].[Cl-]>C(Cl)Cl>[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(OCOCC[Si](C)(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of thioglycoside 78 (1.40 g, 3.10 mmol) in 15 mL of methylene chloride is added N,N-diisopropylethylamine (0.64 mL, 3.70 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.60 mL, 3.40 mmol). The mixture is stirred at room temperature for 2 h, poured into saturated NaCl (50 mL) and extracted with CH2Cl2 (2×50 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (40% EtOAc/hexane) to give 1.60 g (89%) of 1-deoxy-1-{4-[2(trimethylsilyl)ethoxymethoxy]phenylthio}-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 79 as a colorless oil: Rf 0.4 (33% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.46 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 5.40 (d, J=3.3 Hz, 1H, H-4), 5.22 (s, 2H, SEM), 5.20 (dd, J=9.9, 9.9 Hz, 1H, H-2), 5.02 (dd, J=3.3, 9.9 Hz, 1H, H-3), 4.58 (d, J=9.9 Hz, 1H, H-1), 4.18 (dd, J=6.6, 11.2 Hz, 1H), 4.10 (dd, J=6.6, 11.2 Hz, 1H), 3.89 (dd, J=6.6, 6.6 Hz, 1H, H-5), 3.75 (t, J=8.4 Hz, 2H, SEM), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.04 (s, 3H, OAc), 1.98 (s, 3H, OAc), 0.94 (t, J=8.4 Hz, 2H, CH2 --TMS), 0.01 (s, 9H, SiMe3).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[O:10][C:11]([CH2:14][CH3:15])=[CH:12][N:13]=2)=[CH:5][N:6]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([C:11]1[O:10][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][CH:5]=2)=[N:13][CH:12]=1)[CH3:15]
Reactant: CCc1cnc(CSc2cnc(N)s2)o1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cnc(CSc2cnc(NC(=O)c3ccccc3)s2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
A mixture of 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (48.2 mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) and triethylamine (35 mg, 0.35 mmol) in methylene chloride (0.5 mL) was stirred at rt for 10 min. The organic solution was washed with water and concentrated. The residue was purified by a flash column (SiO2 ; hexanes: ethyl acetate/2:1) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzamide (41 mg, 59%) as a solid, mp 122-123° C. 1H NMR (CDCl3) δ12.65 (s, 1 H), 7.96 (m, 2 H), 7.61 (m,, 1 H), 7.49 (m, 2 H), 6.88 (s, 1 H), 6.56 (s, 1 H), 3.93 (s, 2 H), 2.61 (q, J=7.6 Hz, 2 H), 1.20 (t, J=7.6 Hz, 3 H); MS m/e 346 (M+H)+ ;
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10]>C1COCC1.[Cu]I>[Cl:6][C:7]1[C:8]([C:9](=[O:10])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:13]=[CH:14][N:15]=1
Reactant: [Li]C(C)(C)C
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cccnc1Cl
Temperature: -40 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of copper(I) iodide (1.18 g, 6.2 mmol) in 5 mL of THF was cooled to -40° C. and then tert-butyllithium (8.85 mL, 1.4M, 12.4 mmol) was added. The mixture was stirred for 1 hour and 2-chloronicotinic acid chloride (2 g, 11.3 mmol) was added dropwise. The mixture was stirred at -40° C. for 1.5 hours and then allowed to warm to room temperature. The mixture was quenched with water and then diluted with ethyl acetate. The mixture was filtered, washed with water (2×10 mL) and brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with hexanes/ethyl acetate (85:15) to give 1-(2-chloro-3-pyridyl)-2,2-dimethylpropan-1-one (1.735 g, 8.8 mmol) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH:14]([F:16])[F:15])=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O>[F:15][CH:14]([F:16])[CH2:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:17])=[N:3][CH:4]=1
Reactant: [F-]
Reactant: FC(F)COc1cnc(Cl)c2ccccc12
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ncc(OCC(F)F)c2ccccc12
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-4-(2,2-difluoroethoxy)isoquinoline (630 mg, 2.59 mmol) in DMSO (10 mL) was added CsF (786 mg, 5.17 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-50% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give it the desired product 4-(2,2-difluoroethoxy)-1-fluoroisoquinoline (310 mg, 52.8% yield). MS: MS m/z 228.1 (M++1).
Reaction SMILES: [O:1]([C:8]1[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OO)(=[O:18])C.C(O)(C)C>C(O)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[N+:10]([O-:18])[C:9]=1[C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Oc1ccccc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: N#Cc1c(Oc2ccccc2)ccc[n+]1[O-]
Temperature: 95 °C

Procedure:
A solution of 9.6 g of 3-phenoxy-2-pyridinecarbonitrile, [J. Med. Chem. 18, 1 (1975)] in 25 ml of glacial acetic acid is treated with 25 g of 40% peracetic acid in acetic acid. The mixture is heated at 95° C. for 16 hours. One hundred ml of isopropanol is added and the mixture is concentrated at reduced pressure. The residue is dissolved in 250 ml of dichloromethane and the organic layer is washed with excess dilute sodium hydroxide solution and is dried over anhydrous MgSO4.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26])[CH:17]=[CH:18][C:19]=1[F:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]2[NH:27][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=3[N:26]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1ccc(F)c(Cl)c1
Agent: Cl
Product: O=c1[nH]c(COCCc2ccc(F)c(Cl)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 82.2). Off-white solid. MS: m/e=352.2 [M+H+].
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[CH:26]=[CH:25][C:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=2)=[O:13])=[N:9][C:7]1=[O:8])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:15]([O:14][C:12]([NH:11][C:10]1[CH:25]=[CH:26][N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:7](=[O:8])[N:9]=1)=[O:13])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1
Reactant: CCOC(=O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a suspension of [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid ethyl ester (6.40 g, 17 mmol) in tetrahydrofuran (30 mL) and water (60 mL) was added lithium hydroxide monohydrate (1.6 g) at room temperature. After stirring 20 min, the reaction mixture was acidified by adding 1 N HCl (40 mL). The precipitated solid was filtered off, washed with water (20 mL) and ethyl alcohol (20 mL), and dried in vacuo to give the desired product (5.8 g, 98%). 1H-NMR (500 MHz; DMSO-d6) δ 7.94 (d, 1H), 6.93 (d, 1H), 6.90 (s, 1H), 6.82 (s, 2H), 5.93 (s, 2H), 4.99 (s, 2H), 4.43 (s, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1.[CH2:35](N(CC)CC)C.CI.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH3:35])[CH2:19][CH2:20]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1
Reactant: CON=C1C[C@@H](c2noc(CN3CCNCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Product: CON=C1C[C@@H](c2noc(CN3CCN(C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A solution containing 1 equivalent of (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime (Example 48), dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine, was reacted with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction was hydrolyzed and then made basic with sodium carbonate solution (10%) and extracted with DCM. The organic phase was then dried with magnesium sulfate, and concentrated in vacuo to give a residue which was purified by flash-chromatography using dichloromethane/methanol as eluent to give the expected product, (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime, as a mixture of E-/Z-isomers, in 50% yield (99.9% purity by HPLC). The pure Z-isomer could be separated by flash-chromatography, and was obtained in 31% yield (98.9% purity by HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]#[N:10])[C:3]=1[O:11][CH3:12].[H-].[Na+].[CH2:15](I)[CH3:16]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:15][CH3:16])[C:9]#[N:10])[C:3]=1[O:11][CH3:12]
Reactant: CCI
Reactant: COc1c(Cl)ccnc1CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C#N)c1nccc(Cl)c1OC
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
2-(4-Chloro-3-methoxy-2-pyridinyl)-acetonitrile (7.06 g) is dissolved in THF (40 ml) and 60% sodium hydride (1.62 g) is added followed by 3.25 ml of ethyl iodide. The reaction is allowed to stir at 45° C. for 1.5 hour then the reaction mixture is diluted with water and extracted with ethyl acetate. The desired product is purified by chromatography using hexane/ethyl acetate 4/1 as solvent.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:12]([CH3:14])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][N:5]=[C:6]([C:12]([CH2:14][Br:1])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: BrBr
Reactant: CCOC(=O)C(=NOC)C(C)=O
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=NOC)C(=O)CBr

Procedure:
Bromine (100 g.) was dropwise added over 40 minutes under reflux to a solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (100 g.) in a mixture of carbon tetrachloride (300 ml.) and acetic acid (300 ml.). The mixture was stirred at 70° to 80° C. until the evolution of hydrogen bromide ceased. The reaction mixture was washed twice with water (300 ml.), a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solution was treated with activated charcoal (2 g.) and concentrated under reduced pressure to give ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (120.8 g.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]=1[CH3:19])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:6]=1[CH2:19][Br:21])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc(Oc2ccc(F)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(Oc2ccc(F)cc2)c1CBr
Temperature: 25 °C
Yield: 101.5 %

Procedure:
A mixture of 3-(4-fluoro-phenoxy)-2-methyl-benzoic acid ethyl ester (2.63 g, 9.60 mmol), N-bromosuccinimide (1.79 g, 10.08 mmol) and benzoyl peroxide (116 mg, 0.48 mmol) in carbon tetrachloride (35 mL) was refluxed for 4 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (3.44 g): 1H NMR (CDCl3, 200 MHz): δ=7.67 (m, 1H), 7.27 (m, 2H), 7.01 (m, 4H), 5.09 (s, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:3]=1.[C:25]1([O:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[C:34]([CH3:47])[CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:47][C:34]1[CH:33]=[C:32]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:37]=[CH:36][C:35]=1[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(N)ncnc43)CC2)CC1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccccc2)ccc1-c1cn([C@H]2CC[C@H](N3CCN(C)CC3)CC2)c2ncnc(N)c12
Temperature: 80 °C

Procedure:
A mixture of trans-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.347 g, 0.000788 mol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl phenyl ether (0.27 g, 0.000867 mol), tetrakis(triphenyl-phosphine)palladium(0) (0.054 g, 0.000047 mmol), and sodium carbonate (0.209 g, 0.00197 mol) in N,N-dimethylformamide (15 mL) and water (10 mL) was heated at 80° C. under an atmosphere of nitrogen for 16 hours. The mixture was allowed to cool to ambient temperature and the solvent removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine/dichloromethane (5:95) followed by methanol/triethylamine/ dichloromethane (3:5:92) as mobile phase to yield trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.376 g, 0.000757 mol). Trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.376 g, 0.000757 mol) was dissolved in refluxing ethanol (10 mL) and a preheated solution of maleic acid (0.264 g, 0.00227 mol) in ethanol (5 mL) was added. The mixture was refluxed for 15 minutes, cooled to ambient temperature and the precipitate collected by filtration, washed with cool ethanol and dried to give trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate (0.153 g, 0.000181 mol): 1H NMR (DMSO-d6, 400 MHz) 8.22 (s, 1H), 7.42 (m, 3H), 7.25 (d, 1H), 7.17 (t, 1H), 7.09 (d, 2H), 7.02 (s, 1H), 6.89 (d, 1H), 6.16 (s, 6H), 4.58 (m, 1H), 3.3 (br, 9H), 2.68 (s, 3H), 2.22 (s, 3H), 2.01 (br, 6H), 1.57 (br, 2H) RP-HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 23 min with 0.1 M ammonium acetate, 1 mL/min) Rt 7.30 min. MS: MH+497.