Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:26])[N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][CH3:22])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:26])[N:19]([CH2:23][CH2:24][O:25][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[N:7]=1)[CH2:20][CH2:21][CH3:22])([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1nc(Br)ccc1[N+](=O)[O-]
Reactant: CCCN(CCO)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCOc1ccc([N+](=O)[O-])c(OC)n1)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
A mixture of 6-bromo-2-methoxy-3-nitropyridine (5 g, 21.46 mmol), (2-hydroxy-ethyl)-propyl-carbamic acid tert-butyl ester (4.36 g, 21.46 mmol) and K2CO3 (2.97 g, 21.46 mmol) in dimethylformamide (DMF) (60 ml) was stirred at room temperature for 24 h and at 40° C. for 4 h. After evaporation of the solvent under reduced pressure the residue was purified by silica gel chromatography with dichloromethane/methanol (10:0; 9:1; 7:3; 0:10) as eluent to provide 2.81 g (36.9%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](S(Cl)(=O)=O)=[CH:4][CH:3]=1.N1C=C[CH:15]=[CH:14][CH:13]=1.[Cl-].[Na+].[OH2:20]>O>[CH2:1]=[C:2]1[CH2:7][C@H:6]2[CH2:5][C@H:4]([CH2:13][C:14](=[O:20])[CH2:15]2)[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Product: C=C1C[C@@H]2CC(=O)C[C@H](C1)C2
Temperature: 69.5 °C
Reaction time: 2.5 h
Yield: 67 %

Procedure:
Commercially available 2-adamantanediol (yl), (500 g, 2.97 mol, Sigma-Aldrich), p-tosyl chloride (624 g, 3.27 mol, Sigma-Aldrich), and pyridine (1.5 L) were combined and stirred under an argon atmosphere. The reaction mixture was heated to a temperature in the range of 68-71° C. and remained at that temperature for 2.5 h. The reaction mixture was cooled to a temperature of about 25° C. and poured into saturated brine (6 L). The resulting mixture was extracted three times with MTBE (4 L for each extraction). The organic portions were combined, dried (MgSO4), filtered, and concentrated onto 1 kg silica gel (pre-treated with hexanes:TEA). The adsorbed material was chromatographed on 1.5 kg silica eluted sequentially with 1:10 EtOAc:hexanes (5 L) then 2:10 EtOAc:hexanes (5 L). All product fractions were combined and evaporated under reduced pressure to provide a residue. The residue was suspended in deionized water (2 L), stirred for 10 min, and filtered under reduced pressure to remove any excess reactants. The remaining solids were taken up in MTBE (2 L), dried (MgSO4), filtered, and evaporated under reduced pressure to provide 301 g of (1R,5S)-7-methylenebicyclo[3.3.1]nonan-3-one (y2) as a white crystalline solid (yield 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 49.5 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (69 mg, 0.24 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (56 mg, 0.24 mmol) and DIPEA (0.21 mL, 1.2 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-7.5% 2M NH3/MeOH in DCM) to afford 270 as a white solid (48 mg, 49%). LCMS (Method K): RT 3.07 min [M+H]+ 405.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.80 (1H, br s), 8.65 (1H, s), 8.16-8.04 (2H, m), 7.98 (1H, s), 7.87-7.81 (1H, m), 7.79 (1H, d, J=8.01 Hz), 7.72 (1H, dd, J=8.82, 4.90 Hz), 7.56-7.49 (1H, m), 7.21-7.10 (2H, m), 6.05 (1H, s), 3.90 (2H, d, J=6.25 Hz), 3.20 (3H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (6.3 g, 21 mmol) in methanol (150 ml) was added ammonium chloride (11.0 g, 209 mmol) followed by deionized water (75 ml). The mixture was heated to 70° C. before the addition of iron (7.0 g, 125 mmol). The reaction mixture was stirred at 70° C. for 2 hours, before being allowed to cool to room temperature and filtered through Kieselgel. The filter pad was washed with MeOH (150 ml) and the filtrate concentrated in-vacuo. The residue was dissolved in saturated NaHCO3 (aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3 (aq) (3×50 ml), dried over MgSO4, filtered and concentrated in-vacuo. The residue was purified by flash column chromatography (50 g silica Isolute cartridge, 5-20% EtOAc:Heptanes) to give the title compound (3.0 g, 51%) as a thick pale yellow oil. LC-MS 87%, 1.89 min (3.5 minute LC-MS method), m/z=243.9, 244.9, 245.9, 246.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.34 (d, J=1.89 Hz, 1H) 6.95 (d, J=1.89 Hz, 1H) 3.88 (s, 3H) 3.80 (br. s., 2H) 2.29 (s, 3H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.N1CCCCC1.CS([C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1)(=O)=O.Cl>O.N1C=CC=CC=1>[C:1]([OH:7])(=[O:6])/[CH:2]=[CH:3]/[C:18]1[CH:25]=[CH:24][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CC(=O)O
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1ccccc1
Temperature: 25 °C
Yield: 154 %

Procedure:
Combine 312 g (2.99 mole) of malonic acid, 506 mL of pyridine, 30 mL of piperidine and 300 g (1.49 mole) of p-methylsulfonyl-benzaldehyde and heat the mixture to 95°-100° C. for 4 h. Cool the mixture to room temperature and slowly pour into 3 L of a mixture of HCl, water and ice. Collect the resulting precipitate by filtration and dry the solid to give 340 g (83% yield) of the E-cinnamic acid derivative, m.p.=294°-296° C. 1H NMR (DMSO-d6, ppm): 7.96 (s, 4H); 7.78 (d, J=16 Hz, 1H); 6.71 (d, J=16 Hz, 1H); 3.5 (hr. s, 1H); 3.25 (s, 3H). ##STR15##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.P([O-])([O-])(O)=O.[NH4+:18].[NH4+]>[N+](CCC)([O-])=O.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:18]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: [NH4+]
Agent: O=P([O-])([O-])O
Solvent: CC(=O)O
Solvent: CCC[N+](=O)[O-]
Product: N#Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 5-bromo-indole-3-carboxaldehyde (5 g, 22.3 mmol), diammonium hydrogen phosphate (15.6 g, 31.8 mmol) in 1-nitropropane (66 mL) and acetic acid (22 mL) were heated at reflux for 16 h. After cooling to room temperature, the solvents were removed under reduced pressure and water added to the dark residue. After a short while, 5-bromo-1H-indole-3-carbonitrile precipitated rapidly. The solid was filtered, washed severally with water and dried for several hours to afford 4.3 g (86%) of the desired product. 1H-NMR (CD3OD) δ 7.40 (m, 2H), 7.77 (s, 1H), 7.97 (s, 1H). Mass spec.: 222.95 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])O[C:5](=[O:8])[C:6]=1[CH3:7].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][NH2:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][N:21]1[C:5](=[O:8])[C:6]([CH3:7])=[C:2]([Br:1])[C:3]1=[O:9]
Reactant: CC1=C(Br)C(=O)OC1=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(C)=C(Br)C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
3-bromo-4-methyl-2,5-furandione (prepared as described in Org. and Bimolecular chemistry, pag 1782, 2004; 4.8 g, 25.1 mmol) and {[2,4-bis(methyloxy)phenyl]methyl}amine (3.78 mL, 25.1 mmol) were dissolved in acetic acid (100 mL) and the mixture was stirred at 100° C. overnight. Solvent was then concentrated under reduced pressure, additional acetic acid (100 mL) was added followed by sodium acetate (1.443 g, 17.59 mmol) and the mixture was refluxed for further 3 hours. Solvent was eliminated under reduced pressure and the residue was partitioned between DCM and water. Organic phase was washed with water, dried and solvent was eliminated under reduced pressure providing a crude that was purified by flash chromatography (eluent: Cy to Cy/AcOEt 7:3) affording 1-{[2,4-bis(methyloxy)phenyl]methyl}-3-bromo-4-methyl-1H-pyrrole-2,5-dione (8.55 g, 25.1 mmol, 100% yield) as a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]3[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=3)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)[CH:11]=1.[C:34]([OH:40])([C:36](F)(F)F)=[O:35].C[C:42]#[N:43]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:43][CH2:42][CH2:36][C:34]([OH:40])=[O:35])=[O:28])=[CH:32][CH:33]=3)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)[CH:11]=1
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccn3)cn2)nc1)c1ccc(C(=O)OCC)cc1
Reactant: CC#N
Reactant: O=C(O)C(F)(F)F
Product: CCCC(Nc1ccc(-n2cc(-c3ccccn3)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Example 163, Steps B-D, using (+/−)-ethyl 4-(1-(6-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H20/5% MeCN linear to 5% H20/95% MeCN over 4.0 min, Hold at 5% H20/95% MeCN to 5.0 min. Flow: 2.0 mL/min. Retention time: 2.20 min. MS (M+1): 485.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH3:10])=[N:13][NH:12][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)c1cc(Br)cnc1Cl
Reactant: NN
Product: Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Starting material 1-(5-bromo-2-chloropyridin-3-yl)ethanone (5.8 g, 24.7 mmol) and 100 ml anhydrous hydrazine was charged into 500 ml round bottom flask and the resulting mixture was allowed to stir at room temperature for overnight. After removing the excess hydrazine via rotatory evaporation under reduced pressure, the remaining residue was diluted with distilled water and solid was appeared. After filtering the water, the resulting solid was taken up in ethylacetate and saturated aqueous sodium bicarbonate and was extracted by ethylacetate twice. The combined organic layer was washed with water and brine and dried over sodium sulfate. The crude product was eluted through a short silica gel column (3 inch in length) with ethylacetate as a white solid (4.0 g, y=77%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: Cc1ccsc1-c1nc2c(C(=O)O)cccc2o1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccsc1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
A mixture of 2-(3-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (87 mg, 0.34 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (93 mg, 0.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.68 mmol) and 1-hydroxybenzotriazole (92 mg, 0.68 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.24 mL, 1.7 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide (92 mg, 69%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=7.0 Hz, 1H), 8.19 (dd, J=8.0, 1.0 Hz, 1H), 7.66 (dd, J=8.5, 1.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 4.55-4.51 (m, 1H), 3.18-3.09 (m, 2H), 2.79 (s, 3H), 2.68-2.60 (m, 2H), 2.55 (s, 3H), 2.08-1.98 (m, 3H), 1.65-1.42 (m, 3H), 1.16-1.11 (m, 2H); MS (ESI+) m/z 396 (M+H); HPLC=98.4% (AUC), tR=12.84 min.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:19][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C(O)c1ccc(OCc2ccc(F)cc2)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOC(C(=O)OC)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-hydroxyacetate (0.507 g, 1.75 mmol) was dissolved in tetrahydrofuran (9 ml), and sodium hydride (0.09 g, 2.27 mmol) was added thereto while being cooled with ice. The mixture was stirred for 30 minutes at room temperature, and 2-methoxyethoxymethylchloride (0.26 ml, 2.27 mmol) was added thereto while being cooled with ice. After being stirred for 62 hours at room temperature, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was dried over MgSO4, and then the solvent was evaporated out. The obtained residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetate (0.421 g, 64%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1.C(N(CC)CC)C>[N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:37][C:38]5[CH:47]=[CH:46][C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[N:39]=5)=[O:26])=[CH:28][CH:29]=4)[CH:15]=3)[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Reactant: Nc1ccc2ccccc2n1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2ccccc2n1)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
Triethylamine (0.22 ml) was added to THF suspension (6 ml) of 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate (300 mg). Further, trimethylacetyl chloride (0.095 ml) was added dropwise to under ice-cooling, which was stirred for 30 minutes. The temperature of the reaction mixture was raised to room temperature, which was stirred for 1 hour. THF solution (1.0 ml) of 2-aminoquinoline (170 mg) was added dropwise to the reaction mixture under ice-cooling, which was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: THF), and recrystallized (ethyl acetate-diisopropyl ether) to give the titled compound (45 mg).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=[CH2:11].C>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O-:13])(=[O:12])[CH:10]=[CH2:11].[CH:5]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:14][C:15]=1[CH:16]=[CH2:17])=[CH2:6]
Reactant: C=CC(=O)OCCCC
Agent: C
Solvent: C=Cc1ccccc1
Product: C=CC(=O)[O-]
Product: C=Cc1ccccc1C=C

Procedure:
83 parts of styrene and 17 parts of n-butyl acrylate as monovinyl monomers (calculated Tg of copolymer to be obtained=60° C.), 7 parts of carbon black (product name: #25B; manufactured by Mitsubishi Chemical Corporation) as a black colorant, 1 part of a charge control resin having positively charging ability (product name: FCA-207P; manufactured by Fujikura Kasei Co., Ltd.; a styrene/acrylate resin) as a charge control agent, 0.6 part of divinylbenzene as a crosslinkable polymerizable monomer, 1.9 parts of t-dodecyl mercaptan as a molecular weight modifier and 0.25 part of polymethacrylic acid ester macromonomer (product name: AA6; manufactured by Toagosei Co., Ltd.; Tg of copolymer to be obtained=94° C.) as a macromonomer were agitated by means of an agitator to mix followed by uniform dispersion by means of a media type dispersing machine. Thereto, 5 parts of dipentaerythritol hexamyristate as a release agent was added, mixed and dissolved. Thus, a polymerizable monomer composition was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:16]=[C:15]([N:17]2[CH:21]=[CH:20][NH:19][CH2:18]2)[CH:14]=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>>[N+:6]([CH:18]1[N:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:10])[CH:16]=2)[CH:21]=[CH:20][NH:19]1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(N2C=CNC2)ccn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(N2C=CNC2[N+](=O)[O-])ccn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
To a stirred solution of sulfuric acid (14 ml, 95-97%) and HNO3 (10 ml, fum.) was added at 0° C. 3-(2-methyl-4-pyridinyl)-1H-imidazole (4.0 g, 25.1 mmol). The reaction mixture was stirred at room temperature for 50 min, at 100° C. for 2.5 h and at 110° C. for 10 h and poured into ice-water (70 ml). Solid NaHCO3 was added to the stirred mixture until the pH reached 5. The solution was extracted with THF (4×200 ml), the combined organic layers were dried (MgSO4) and evaporated to give 2-nitro-3-(2-methyl-4-pyridinyl)-1H-imidazole (3.4 g, 66%) as a light yellow solid; MS (ISP) 205.2 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>N1C=CC=CC=1>[C:6]([OH:46])(=[O:7])[CH3:37].[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@H:24]3[CH2:29][CH2:28][C@@H:27]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:47])=[O:46])=[CH:38][CH:37]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CN)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CNS(=O)(=O)c6ccccc6)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
Cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.051 g, 0.0001 mol) was dissolved in anhydrous pyridine (1 mL), benzenesulfonyl chloride (0.018 g, 0.0001 mol) was added and the resulting solution was stirred at ambient temperature for twenty hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N1-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]-1-benzenesulfonamide acetate (0.042 g, 0.000048 mol) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][NH:26]1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:27][N:26]=1
Reactant: OB(O)C1(Cl)C=CC=CN1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccnc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 46.4 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (120 mg, 0.3 mmol) and 2-chloropyridine-2-boronic acid (71 mg, 0.45 mmol) gave 4-(2-Chloro-pyridin-4-yl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (58 mg, 46.4%) as a white solid. MS 417 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and morpholine to afford an off-white solid. UPLC-MS (Condition 3) tR=1.20 min, m/z=445.9 [M+H]+, m/z=443.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.37-3.46 (m, 4H) 3.69-3.81 (m, 4H) 7.39 (d, J=8.78 Hz, 2H) 7.86 (d, J=9.16 Hz, 2H) 8.47 (d, J=2.13 Hz, 1H) 8.80 (d, J=2.13 Hz, 1H) 10.44 (s, 1H).