Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH:40]=O)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C.C(=O)(O)[O-].[Na+]>>[C:31]([OH:34])(=[O:33])[CH3:32].[O:35]1[C:39]([CH2:40][NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[N:14][C:15]=4[NH2:17])[N:10]([C@H:18]4[CH2:23][CH2:22][C@@H:21]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH2:20][CH2:19]4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:38][C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]1=2
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(N)c4)c4c(N)ncnc43)CC2)CC1
Reactant: O=Cc1cc2ccccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(NCc5cc6ccccc6o5)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.8 %

Procedure:
A mixture of cis-3-(3-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.107 g, 0.263 mmol, 1 equiv), glacial acetic acid (0.06 mL, 1.0 mmol, 3.8 equiv), benzo[B]furan-2-carboxaldehyde (0.1 g, 0.3 mmol, 1 equiv), sodium triacetoxyborohydride (0.212 g, 1.0 mmol, 3.8 equiv), and dichloroethane (2 mL) was stirred at ambient temperature for 4.5 h. Aqueous sodium bicarbonate was added, the organic layer was separated, and the aqueous layer was extracted with two portions of CH2Cl2 (10 mL each). The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford a yellow oil which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give cis-3-{3-[(benzo[b]furan-2-ylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine monoacetate salt as a white solid (0.017 g, 0.031 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.22 (1H, s), 7.51-7.58 (2H, m), 7.22-7.28 (3H, m), 6.98 (1H, s), 6.79-6.84 (2H, m), 6.59-6.62 (1H, m), 4.76-4.81 (1H, m), 4.50 (2H, d, J=5.6 Hz), 2.19-2.24 (14H, m), 2.05-2.07 (2H, m), 1.91 (3H, s), 1.60-1.75 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.99 min. MS: MH+ 537.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH3:14][O:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[CH2:18][NH:19][CH2:20]C(O)=O>CC1C=CC(C)=CC=1>[CH3:14][O:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[CH2:18][N:19]1[C:7](=[O:12])[C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:10][C:9](=[O:11])[CH2:20]1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(Br)cc3C2=O)c(OC)c1
Temperature: 150 °C

Procedure:
A suspension of 6-bromo-2H-3,1-bezoxazine-2,4(1H)-dione (22.0 g, 91 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (22.5 g, 100 mmol) in p-xylene (200 mL) was heated under reflux (150° C.) for 1 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (100 ml). Yield: 33.5 g (91%) m/z 403/405 (M).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[C-:10]#[N:11].[Na+].C(OCC)=O>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: OCc1ccc(O)cc1
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Product: N#CCc1ccc(O)cc1
Yield: 94 %

Procedure:
A mixture of 4.96 g. para-hydroxybenzyl alcohol 2.4 g. sodium cyanide 12 ml. ethanol and 12 ml. ethyl formate is heated with stirring under reflux for a period of ninety minutes. The reaction product is then subjected to the same isolation process as in Example 1 to give a 94% yield of crude product showing a melting point of 58°-61° C. uncorrected.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1([CH2:26][O:27][CH3:28])[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[CH2:21][C:20]1([CH2:26][O:27][CH3:28])[CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: COCC1(C)CNCCN1Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(C)CN(C(=O)c2cccc(OC)n2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 77.6 mg (507 μmol) 6-methoxy-2-pyridinecarboxylic acid, 125 mg (507 μmol) 1-benzyl-2-methoxymethyl-2-methyl-piperazine, 177 mg (551 μmol) TBTU and 100 μL (581 μmol) DIPEA in 1.5 mL DMF was stirred at RT for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1cccc(-c2cnc3[nH]cc(-c4ccccc4F)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Crude (3-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from last step was dissoled in methanol (1 mL) and potassium hydroxide (50% w/v, 0.038 mL, 0.136 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 30 minutes before being diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was then dissolved in DMSO and purified by mass triggered reverse phase HPLC to afford pure (3-(3-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (5.6 mg, 21% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light brown syrup. 1H NMR (500 MHz, DMSO-d6) δ 3.60 (m, br, 8H), 7.33 (m, 3H), 7.39 (m, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.74 (m, 1H), 7.84 (m, 3H), 8.28 (m, 1H), 8.61 (d, J=2.5 Hz, 1H), 12.17 (s, 1H). MS: m/z 402.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:19])=[O:18])[CH:5]=[C:6]([CH:15]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][NH2:14])[CH2:11][CH2:10]1.[ClH:30].N1C=CC([C:36]([NH2:38])=[NH:37])=N1>CN(C)C=O>[ClH:30].[CH3:1][C:2]1[CH:3]=[C:4]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:19])=[O:18])[CH:5]=[C:6]([CH:15]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][NH:14][C:36]([NH2:38])=[NH:37])[CH2:11][CH2:10]1
Reactant: Cc1cc(OCC2(CON)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(CONC(=N)N)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of N-{1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}amine (3.5 g, 8.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide (30 mL) was added 1H-pyrazole-carboxamidine hydrochloride (3.7 g, 25.0 mmol). The reaction mixture was stirred at ambient temperature overnight. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile (50 mL) was added and the solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was dried under high vacuum. The residue was partitioned between water (100 mL plus 5 mL brine) and diethyl ether (50 mL). The water solution was extracted with diethyl ether (50 mL). The combined diethyl ether solution was extracted with pH 5 water (30 mL). The combined water solution was adjusted to pH 8-9 by using 2N NaOH and extracted into ethyl acetate (3×100 mL). The ethyl acetate solution was washed with pH 7 buffer solution (5×60 mL) and brine (50 mL) and dried over Na2SO4. After removing the solvent, 0.6N HCl methanol (50 mL) was added and the solution was concentrated. The residual oil was crystallized from methanol/ethyl acetate (1:50) to give the title compound as white solid (3.6 g, 86%). 1H-NMR (300 MHz, DMSO-d6) δ11.07 (br s, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.09-8.14 (m, 2H), 7.97 (t, J=7.7 Hz, 1H), 7.65 (br s, 4H), 6.76 (s, 1H), 6.52 (s, 1H), 6.51 (s, 1H), 3.86 (s, 2H), 3.78 (s, 2H), 3.48 (s, 3H), 2.21 (s, 3H), 0.69 (m, 2H), 0.62 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C20H25N3O7S2: 484.1 (M+H), 506.1 (M+Na). Found: 484.0, 506.0.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 172 mg (1 mmole) of n-decanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 217 mg (Yield: 49%) of the title compound having the following structure as a red oil.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([N:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11])[C:7]([F:17])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23].[F-].[K+]>CS(C)=O>[C:4]([C:3]1[C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23])=[N:9][C:8]([N:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11])=[C:7]([F:17])[CH:6]=1)#[N:5]
Reactant: CN(CC(C)(C)C)c1nc(Cl)c(C#N)cc1F
Reactant: CONC(=O)c1ccc(C)c(N)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)c(F)cc2C#N)c1
Temperature: 150 °C
Yield: 4 %

Procedure:
A mixture of 2-chloro-6-[(2,2-dimethyl-propyl)-methyl-amino]-5-fluoro-nicotinonitrile (120 mg, 0.47 mmol), 3-amino-N-methoxy-4-methyl-benzamide (120 mg, 0.66 mmol) and potassium fluoride (30 mg, 0.51 mmol) in DMSO (1 mL) was heated to 150° C. overnight. The reaction mixture was allowed to cool down to room temp and then partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The product (7.5 mg, 4%) was obtained after purification by silica gel chromatography with 30% EtOAc in hexane as eluent. C21H26FN5O2 MS m/e=400 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].C(OC(=O)C)(=O)C.Cl[C:23](Cl)([F:28])[C:24]([O:26][CH3:27])=[O:25]>[Zn].[Cu]Cl.O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:13]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C2(C=O)CC2)cc1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOc1ccc(C2(C=C(F)C(=O)OC)CC2)cc1
Yield: 62.7 %

Procedure:
The method of Example 1 was repeated using zinc powder (4.1 g), copper (I) chloride (0.63 g), molecular sieve 4A (4.2 g), tetrahydrofuran (72 ml), 1-(4-ethoxyphenyl)-1-formylcyclopropane (4.7 g), acetic anhydride (2.6 ml) and methyl dichloro-fluoroacetate (3.3 g) to yield the title compound (3.4 g, 52%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([F:29])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>CN(C)C=O.C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[CH:21][C:22]=1[F:29]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Yield: 55.3 %

Procedure:
7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (190 mg) was dissolved in N,N-dimethylformamide (5 ml) and triethylamine (1 ml). Palladium hydroxide (40 mg) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/methanol (20/1) to give 75 mg (yield 56%) of the title compound.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:20][C:21]1[CH:22]=[C:23]([C:27](F)=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]>C1COCC1.CCOC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([C:27]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:12]=2[F:11])=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C(O)c1cc(Br)ncc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: -78 °C
Yield: 59.3 %

Procedure:
Lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (11.9 ml, 1.00 M, 11.82 mmol) was added to a solution of 2-fluoro-4-iodoaniline (1.40 g, 5.91 mmol) at −78° C. The pale green colored solution was stirred for 1½ h at −78° C. Then, lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (5.45 ml, 1.00 M, 5.45 mmol) was added followed by 2-bromo-5-fluoroisonicotinic acid (1.00 g, 4.55 mmol) in THF (5 ml). The dark colored homogeneous mixture was warmed to room temperature and stirred overnight. The crude was diluted with EtOAc (300 ml). Then, it washed with dilute HCl solution (20 ml), H2O (20 ml), dried and purified on Flashmaster II using a 100 g cartridge to obtain 1.18 g (59%) of 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][O:28][CH2:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Yield: 67.9 %

Procedure:
To a 150-mL sealed tube containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.72 g, 2.0 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.33 g, 2.2 mmol) in ethanol (20 mL) was added triethylamine (1.0 mL, 2.2 mmol). The mixture was heated with a heat gun until all solid material was dissolved, then mixture was allowed to cool, at which time a precipitate was formed. The solid was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide 8-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a pale yellow solid (0.59 g, 68%). MS (ES+): 435.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[CH3:37][NH:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][C:29]1([CH3:33])[O:28][C:27]2[CH:34]=[CH:35][C:24]([C@H:22]3[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]4[CH:3]=[C:2](/[CH:43]=[CH:42]/[S:39]([NH:38][CH3:37])(=[O:41])=[O:40])[CH:7]=[CH:6][CH:5]=4)[CH2:23]3)=[CH:25][C:26]=2[CH2:31][O:30]1
Reactant: C=CS(=O)(=O)NC
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(Br)c4)C(=O)O3)ccc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)/C=C/c1cccc(CCCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Yield: 20.5 %

Procedure:
A stirred mixture (5R)-3-{6-[4-(3-bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.0 g), N-methylethenesulphonamide (WO 95/09166), (462 mg), tri-o-tolylphosphine (200 mg), palladium acetate (165 mg) and triethylamine (5 ml) in dry DMF (15 ml) was heated at 90° C. for 18 h. The mixture was cooled and filtered. The filtrate was poured into water (200 ml) and extracted into ethyl acetate (3×50 ml). The combined extracts were washed with water (100 ml) and (Na2SO4) and evaporated in vacuo. The residual oil was purified by chromatography on Biotage (40 g) eluting with diethyl ether-ethyl acetate (9:1) to give the title compound (220 mg). LCMS RT=3.70 min.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[N:4]([CH:19]2[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[N:3]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: OC1CCC2(CC1)OCCO2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 3-bromo-4-chloropyrazolo[3,4-d]pyrimidine (Intermediate B) (7.5 g, 32 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (15.17 g, 96 mmol), triphenylphosphine (16.86 g, 64 mmol) in THF (275 mL) was added diethylazodicarboxylate (11.14 g, 64 mmol) in THF (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature and then stirred at room temperature for 3 hrs. The reaction mixtures was concentrated in vacuo and dissolved in hot heptane/EtOAc/DCM (5:1:5). Flash silica gel column chromatography using heptane, heptane/EtOAc (5/1) then heptane/EtOAc (4/1) gave a solid which was triturated with heptane and the solids removed by filtration to furnish 8.2 g of 3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (69%) [Rf in 1:1 heptane:EtOAc=0.5]1H NMR (400 MHz, d6-DMSO): 8.89 (1H, s), 4.92 (1H, m), 3.90 (4H, m), 2.16 (2H, m), 1.96 (2H, m), 1.81 (6H, m) HPLC: Tr=17.11 mins, 96.6%
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:22])=[CH:13]/[C:14]3[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[C:12](/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH2:4][CH2:3][C:2]3([CH3:23])[CH3:1])\[CH3:22])=[CH:21][CH:20]=1)(=[O:26])[CH3:25]
Reactant: C/C(=C\c1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCO2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1

Procedure:
By treating p-[(E)-2-(4,4-dimethyl-6-chromanyl)propenyl]benzyl alcohol with acetyl chloride and pyridine there is obtained p-[(E)-2-(4,4-dimethyl-6-chromanyl)propenyl]benzyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([CH3:10])[CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1CO
Reactant: O=S(Cl)Cl
Product: Cc1cc(Cl)ccc1CCl
Temperature: 100 °C
Yield: 93 %

Procedure:
Step A A mixture of 4-chloro-2-methylbenzyl alcohol (Aldrich) (5 g, 32 mmol) in thionyl chloride (20 mL) was heated at refluxing (100° C.) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 4-chloro-2-methylbenzyl chloride as a light yellow oil (5.2 g, 93%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[O:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[O:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1ccc(Br)o1
Product: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)o1

Procedure:
1-(5-(4-(Trifluoromethyl)phenyl)fur-2-yl)ethanone is prepared from 4-trifluoromethylbenzeneboronic acid and 5-bromo-2-acetylfuran according to general procedure A.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[NH:31][CH:32]=[CH:33][N:34]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1ncc[nH]1
Product: CCN(Cc1ncc[nH]1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(1H-imidazol-2-ylmethyl)-amine