Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:3])[CH3:2].[Br:13]Br>ClCCl>[Br:13][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: BrBr
Reactant: CC(C)Oc1cccc(C=O)c1
Solvent: ClCCl
Product: CC(C)Oc1ccc(Br)c(C=O)c1
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a suspension of 50.0 g (110 mmol) 3-hydroxybenzaldehyde and 100 g (725 mmol) dry K2CO3 in 100 mL dry DMF, 61.5 g (500 mmol) isopropylbromide was added at room temperature. The reaction mixture was heated for 17 h at 90° C. The solvent was removed under reduced pressure and the residue was partitioned between 2N NaOH and toluene. The collected organic layers were dried (MgSO4), filtered and the solvent removed under pressure. The residue was distilled in vacuo to give 58.8 g (88%) colorless liquid. To a solution of 57.0 g (347 mmol) 3-isopropoxybenzaldehyde in 200 mL dichloromethane 30.5 g (372 mmol) NaOAc was added. After that a solution of 55.5 g (347 mmol) bromine in 50 mL dichloromethane was added dropwise and the reaction mixture was stirred overnight. The reaction mixture was extracted with saturated aqueous Na2SO3 and the combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was distilled in vacuo to give 1 (52.1 g, 62%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([N:13]([CH3:21])[C:14]([NH:16][CH2:17][CH2:18][S:19][CH3:20])=[O:15])=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([N:13]([CH3:21])[C:14]([N:16]([CH3:25])[CH2:17][CH2:18][S:19][CH3:20])=[O:15])=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: CSCCNC(=O)N(C)c1nnc(-c2cncc(F)c2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCN(C)C(=O)N(C)c1nnc(-c2cncc(F)c2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.8 %

Procedure:
An ice-cold solution of 1-[5-(5-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-1-methyl-3-(2-methylsulfanyl-ethyl)-urea (0.132 g, 0.4 mmol) in N,N-dimethylformamide (0.6 mL) was treated with sodium hydride (60% in mineral oil, 0.018 g, 0.4 mmol) and stirred for 5 minutes before addition of a solution of iodomethane (0.063 g, 0.4 mmol) in N,N-dimethylformamide (0.1 mL). The ice bath was removed after 5 minutes. The reaction mixture was stirred at room temperature for 14 hours, diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, purified by normal and reversed phase chromatography to give the title compound as a colorless gum (0.027 g, 20%): IR (KBr thin film) 1658 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.53 (d, J=3.2 Hz, 1H), 8.02 (ddd, J=9.1, 4.5, 1.7 Hz, 1H), 3.66 (s, 3H), 3.59 (t, J=6.8 Hz, 2H), 3.06 (s, 3H), 2.78 (t, J=7.1 Hz, 2H), 2.14 (s, 3H); ESIMS m/z 342 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1B(O)O.C(O)(O)=O>C(#N)C.O.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>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:20]1[CH:19]=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[Cl:14])[C:3]([CH3:13])=[N:4]2
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1cc(F)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 1.0000 g, 4.693 mmol), 2-chloro-5-fluorophenylboronic acid (0.9002 g, 5.163 mmol), tetrakis(triphenylphosphine)palladium (0.2712 g, 0.2347 mmol), and sodium carbonate anhydrous (2.487 g, 23.47 mmol) in acetonitrile-water (3:1) (47.00 mL) was stirred at 100° C. After 3 hs, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline as a red syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1 H, dd, J=8.4, 1.4 Hz), 8.03 (1 H, dd, J=7.6, 1.4 Hz), 7.88 (1 H, dd, J=8.4, 7.6 Hz), 7.75 (1 H, dd, J=9.0, 5.1 Hz), 7.61 (1 H, dd, J=8.6, 3.1 Hz), 7.46-7.53 (1 H, m), 2.54 (3 H, s); LC-MS (ESI) m/z 307.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12].[CH:15](=O)[CH3:16].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:15][CH3:16]
Reactant: CON(C)C(=O)c1ccc(F)cc1N
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNc1cc(F)ccc1C(=O)N(C)OC
Reaction time: 1.5 h

Procedure:
To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.20 g, 1.01 mmol), acetaldehyde (86 μL, 1.53 mmol), and AcOH (87 μL, 2.1 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (430 mg, 2.03 mmol) at 5° C. The mixture was stirred for 90 minutes at the same temperature and then 40 minutes at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide quantitatively.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH2:21].CC1C=CC=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1CCC(=Nc2c(Cl)cccc2Cl)CC1

Procedure:
A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 parts of 2,6-dichlorobenzenamine, 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid is stirred and refluxed with water-separator. The reaction mixture is evaporated, yielding 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate as a residue.
Reaction SMILES: [N+]([O-])(O)=O.[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[CH2:8][O:9][C@@H:10]1[O:15][C@@H:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:13][CH2:12][CH2:11]1>C(OCC)C>[Cl:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:6]([Cl:5])[C:7]=1[CH2:8][O:9][CH:10]1[O:15][CH:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cccc(Cl)c1CO[C@H]1CCC[C@H](Cn2ccnc2)O1
Solvent: O=[N+]([O-])O
Solvent: CCOCC
Product: Clc1cccc(Cl)c1COC1CCCC(Cn2ccnc2)O1
Yield: 97803.5 %

Procedure:
When 0.2 ml of 69% w/v aqueous nitric acid was added to a solution of 865 mg of trans-1-[6-(2,6-dichlorobenzyloxy)tetrahydropyran-2-ylmethyl]imidazole in 10 ml of diethyl ether, the solution became turbid and an oily layer separated. After decanting off the ethereal layer, more diethyl ether was added to the residue to aid crystallization and the precipitated crystals were filtered, to give 846 g of the title product. Further recrystallization of these crystals from a mixture of acetone and ethyl acetate gave the title product in the form of colourless crystals melting at 117° C.
Reaction SMILES: [CH:1]([N:3](C)[CH:4]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=O.[ClH:21]>CO>[ClH:21].[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH:4]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[NH:3][CH3:1]
Reactant: COc1ccccc1CC(c1sccc1C)N(C)C=O
Agent: Cl
Solvent: CO
Product: CNC(Cc1ccccc1OC)c1sccc1C

Procedure:
A solution of 1.83 g of N-formyl-2-methoxy-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, 25 ml of methanol, and 25 ml of 3N hydrochloric acid solution was heated for 3 hr under reflux. Methanol was added to clear the solution. The solution was concentrated, the residue was diluted with water, and extracted with ether. The aqueous phase was basified with 2.5N sodium hydroxide solution and extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. An ether solution of the residue was treated with excess ethereal hydrogen chloride. Recrystallization from acetonitrile gave 0.83 g of product, mp 201°-203.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>CN(C)C=O>[CH2:27]([C@:25]1([OH:26])[C:15]2[CH:14]=[C:13]3[N:18]([C:17](=[O:21])[C:16]=2[CH2:22][O:23][C:24]1=[O:29])[CH2:19][C:20]1[C:8]([CH2:7][CH2:6][Si:5]([CH2:4][CH2:3][CH2:2][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)([CH3:34])[CH3:35])=[C:9]2[CH:33]=[CH:32][CH:31]=[CH:30][C:10]2=[N:11][C:12]3=1)[CH3:28]
Reactant: c1c[nH]cn1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCn1ccnc1
Yield: 77 %

Procedure:
A solution of Compound 11 (60 mg) and imidazole (37 mg) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 16 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel column using 3% ethanol in dichloromethane to obtain the required product in 77% yield (45 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7]C2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](C=O)=[CH:33][CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:31]=[CH:32][CH:33]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1ccnc2ccccc12
Product: C[C@@H]1CN(Cc2ccnc3ccccc23)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting quinoline-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.68 (brs, 1H), 8.83 (d, J=4.1 Hz, 1H), 8.25-8.22 (m, 1H), 8.12-8.08 (m, 1H), 7.98 (s, 1H), 7.75-7.72 (m, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 5.21 (m, 1H), 4.77 (m, 1H), 4.13-4.06 (m, 3H), 3.59-3.52 (m, 2H), 3.32 (d, J=8.7 Hz, 1H), 3.03 (d, J=9.9 Hz, 1H), 2.88-2.86 (m, 1H), 2.72-2.69 (m, 1H), 2.36-2.28 (m, 3H), 2.04-2.00 (m, 1H), 1.89-1.84 (m, 2H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 445.1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@@H](NC(=O)OCc1ccccc1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C1CC1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-oxobutanoate (1.526 g, 4.778 mmol) was dissolved in anhydrous ethanol (15 ml), and the solution was mixed with sodium borohydride (94.6 mg, 2.50 mmol)under ice-cooling and stirred at the same temperature for 1 hour. Under ice-cooling, the reaction solution was mixed with water (20 ml) and then ethanol was evaporated under a reduced pressure. The thus obtained residue was mixed with chloroform (50 ml) and stirred, and then the thus separated chloroform layer was washed with saturated sodium chloride aqueous solution (30 ml) and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness under a reduced pressure, thereby obtaining 1.509 g (98.3%) of the title compound as a colorless oil. This product was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl (trans-4-{5-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridin-2-yl}cyclohexyl)acetate (Example 406, 355 mg, 0.725 mmol) in THF (5 mL) and MeOH (25 mL) was added a 2M solution of NaOH (1.8 mL). The resulting yellow solution was allowed to stir at ambient temperature for 16 hr then a further 1.8 mL of 2M NaOH was added and stirring was continued at ambient temperature for 16 hr. The volatile organics were removed by evaporation and residue adjusted to pH ˜1 with 2M HCl and the suspension was filtered and dried to leave 410 mg of a solid. This was suspended in acetic acid (4 mL) and heated to 120° C., giving an incomplete solution. This was allowed to cool, filtered and washed with water then dried overnight, to give the title compound (167 mg, 48%) as a solid; 1H NMR (CDCl3) δ 1.10-1.19 (m, 2H), 1.56-1.65 (m, 2H), 1.72-1.79 (m, 1H), 1.85-1.94 (m, 4H), 2.17 (d, 2H), 2.79-2.85 (m, 1H), 7.67-7.76 (m, 2H), 8:12-8.19 (m, 1H), 8.44 (d, 1H), 9.01 (s, 1H), 11.14 (s, 1H), 11.58 (s, 1H), CO2H not seen; MS m/e MH+ 476.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.P(Br)(Br)[Br:22].CCOC(C)=O>C(Cl)Cl>[Br:22][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Cc2ccc(OC(F)(F)F)cc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Cc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A solution of alcohol 95 (0.18 g, 0.64 mmol) in CH2Cl2 (4 mL) was treated with PBr3 (115 μL 1.2 mmol). The reaction mixture was stirred at room temperature for 2 h, then EtOAc (150 mL) was added. The organic layer was washed with water (100 mL), the aqueous layer was re-extracted with EtOAc (100 mL), and the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with petroleum ether/EtOAc (9:1), to give 1-(bromomethyl)-4-[4-(trifluoromethoxy)benzyl]benzene (96) (0.14 g, 64%) as a white solid: mp (EtOAc/hexane) 33-35° C.; 1H NMR (CDCl3) δ 7.34-7.30 (m, 2H), 7.20-7.10 (m, 6H), 4.48 (s, 2H), 3.97 (s, 2H); HREIMS calcd for C15H1279BrF3O m/z (M+) 344.0024, found 344.0033; calcd for C15H1281BrF3O m/z (M+) 346.0003, found 346.0011.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:5]([F:13])=[CH:4][C:3]=1[F:14].[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:17][CH:16]=[CH2:15])[CH2:9][N+:10]([O-:12])=[O:11])[C:5]([F:13])=[CH:4][C:3]=1[F:14]
Reactant: O=[N+]([O-])/C=C/c1cc(F)c(F)cc1F
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Temperature: -20 °C
Yield: 88.9 %

Procedure:
To a cooled (−40° C.) solution of (E)-1,2,4-trifluoro-5-(2-nitrovinyl)benzene (250 g, 1.23 mol) in THF (490 mL), allylmagnesium chloride (800 mL, 1.6 mol, 2 M in THF) was added at such a rate as to maintain the internal temperature below −20° C. The solution was stirred at −20° C. for thirty minutes and then carefully quenched by the addition of 2M HCl (1 L), while maintaining the temperature below −5° C. Methyl t-butyl ether (500 mL) was added, and the biphasic solution was allowed to warm to >10° C. The layers were separated, and the organic was washed with H2O (1×500 mL), saturated aqueous NaHCO3 (1×500 mL), and brine (1×500 mL). The organic layer was concentrated to dryness, and the crude product was filtered through a 450 g plug of silica gel (eluting with 5% ethyl acetate in hexane at a flow rate of 90 mL/min). The first 100 mL of eluent was discarded, and the subsequent 2 L were collected and concentrated to dryness to give the title compound as an oil (268 g, 89%). 1H NMR (300 MHz, CDCl3) δ ppm 7.05-6.90 (m, 2H), 5.65 (dddd, J=7.5, 7.5, 9.5, and 16.6, Hz, 1H), 5.12-5.06 (m, 2H), 4.63 (d, J=7.5 Hz, 2H), 3.75 (p, J=7.5 Hz, 1H), and 2.48 (t, J=7.5 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=3)[N:8](C3CCCCO3)[N:7]=2)=[CH:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.Cl>CO>[O:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2
Reactant: N#Cc1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Reaction time: 4 h
Yield: 7.3 %

Procedure:
To a flask containing 3-benzo[b]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (278 mg, 0.8 10 mmol) was added 6N HCl (12 mL) and methanol (12 mL). The solution was brought to 60° C. for 4 hours. The resulting precipitate was filtered and washed with water to provide the title compound (189 mg, 90%). ES-MS (m/z) 260[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10](I)[C:3]=12.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([NH:44][C:45]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:54])=[C:29]([O:28][CH3:27])[CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2nc(I)c3c(N)ncnc32)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OCc1ccccc1
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: O
Solvent: COCCOC
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 85 °C
Yield: 29.8 %

Procedure:
A mixture of tert-butyl 4-[(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-4-hydroxy-1-piperidinecarboxylate (0.27 g, 0.00057 mol), benzyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.26 g, 0.00068 mol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.000034 mol) and sodium carbonate (0.15 g, 0.0014 mol) in ethylene glycol dimethyl ether (7 mL) and water (3 mL) was heated at 85° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under the reduced pressure. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with water and brine, and dried over magnesium sulfate. The organic layer was filtered through silica gel twice to remove the catalyst, and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl 4-{[4-amino-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.1 g, 0.00017 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.9 min. MS: MH+ 604.
Reaction SMILES: [N+:1]1([O-])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc2c1CCCC2
Product: CC(=O)OC1CCCc2cccnc21
Temperature: 90 °C
Reaction time: 7 h
Yield: 33 %

Procedure:
5,6,7,8-Tetrahydroquinoline N-oxide (1.6 g, 11 mmol) was mixed with acetic anhydride (9.2 ml) and stirred at 90° C. for 7 hours. After removing the solvent by evaporation under a reduced pressure, the residue was neutralized with sodium hydroxide aqueous solution (1 N) and the reaction product was extracted with chloroform. The extract was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 690 mg (3.6 mmol, 33%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ncc(Sc2ncccn2)s1
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 2-acetamido-5-chlorothiazole (14.3 g), 2-mercaptopyrimidine (10 g) and potassium carbonate anhydrous (22.4 g) in N,N-dimethylformamide (280 ml) was stirred at 150° C. an hour. The reaction mixture was poured into water with stirring under ice cooling. The mixture was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give solid. The solid was triturated with water, and the precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetamido-5-(2-pyrimidinylthio)thiazole (12.30 g, yield: 60.2%). mp: 225° C. (dec.) IR (Nujol): 3170, 1645, 1555, 1310 cm-1