Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([S:18][CH:19]3[CH2:24][CH2:23][N:22](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.Br>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([S:18][CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3nc4cncnc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Fc1ccc(Cn2c(SC3CCNCC3)nc3cncnc32)cc1
Yield: 17.4 %

Procedure:
7 A mixture of 24.8 parts of 4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidine and 300 parts of acetic acid, saturated with hydrogen bromide was stirred overnight at room temperature. After evaporation, the residue was taken up in water. The whole was treated with a sodium hydroxide solution and extracted with dichloromethane. The extract was acidified with a hydrochloric acid solution and extracted with water. The aqueous layer was treated with a sodium hydroxide solution and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol. (95:5 by volume)→trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluents. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.0 parts (17.4%) of 9-[(4-fluorophenyl)methyl]-8-(4-piperidinylthio)-9H-purine; mp. 113.5 ° C. (compound 31).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[O:13][CH:14]=2)=[N:6][CH:7]=1.[CH2:27]([N:31]1[CH:35]=[CH:34][N:33]=[N:32]1)[CH2:28][C:29]#[CH:30].C(NC(C)C)(C)C.C(OCC)(=O)C>CN(C=O)C.C1COCC1.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:31]1([CH2:27][CH2:28][C:29]#[C:30][C:2]2[CH:3]=[N:4][C:5]([O:8][CH2:9][C:10]3[N:11]=[C:12]([CH:15]=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[O:13][CH:14]=3)=[N:6][CH:7]=2)[CH:35]=[CH:34][N:33]=[N:32]1
Reactant: C#CCCn1ccnn1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(COc3ncc(Br)cn3)co2)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ncc(C#CCCn4ccnn4)cn3)co2)cc1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine (0.213 g, 0.50 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (0.067 g, 0.55 mmol) and diisopropyl amine (iPr2NH) (2 ml) in DMF (4 ml) and THF (2 ml), copper iodide (CuI) (0.0048 g, 0.025 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min tetrakis(triphenylphosphine)palladium (0.029 g, 0.025 mmol) is added and the mixture is heated at 80° C. for 3 h. Ethyl acetate (150 ml) is added, the resulting mixture is washed with ammonium chloride (NH4Cl) and brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (chloroform (100%)->ethyl acetate (100%)) yielding 5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine as a pale yellow solid. Yield 138 mg (59%).
Reaction SMILES: [O-]CC.[Na+].CO[C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15](=[O:19])[CH2:16][C:17]#[N:18])=[O:8]>C(O)C>[OH:8][C:7]1[C:9]2[S:10][CH:11]=[CH:12][C:13]=2[NH:14][C:15](=[O:19])[C:16]=1[C:17]#[N:18]
Reactant: COC(=O)c1sccc1NC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(O)c2sccc2[nH]c1=O
Yield: 76.4 %

Procedure:
Sodium ethoxide (3.10 g, 45.62 mmol) was added to a solution of 3-(2-cyano-acetylamino)-thiophene-2-carboxylic acid methyl ester (24) (3.10 g, 45.62 mmol) in anhydrous ethanol and refluxed overnight. The solution was cooled and excess solvent was distilled off. The residue was dissolved in water and acidified to pH 2 by cold diluted HCl solution. The solids formed were filtered, washed by cold water, and dried under vacuum at room temperature to yield 6.7 g (84%) of 7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyrdine-6-carbonitrile as white solids. MP>300° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J=5.2 Hz, 1H), 8.04 (d, J=5.2 Hz, 1H), 12.10 (s, 1H) ppm; MS mz=193 amu(M++1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:33]([Si:35]([CH3:38])([CH3:37])[CH3:36])#[CH:34].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:3]=[C:2]2[C:34]#[C:33][Si:35]([CH3:38])([CH3:37])[CH3:36])([O-:13])=[O:12]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of 3-bromo-5-nitro-1-trityl-1H-indazole (4.83 g, 10 mmol), ethynyl-trimethyl-silane (1 g, 10 mmol), copper (I) iodide (91 mg, 0.5 mmol), PdCl2(dppf) (337 mg, 0.5 mmol) and triethylamine (1.2 g, 12 mmol) in DMF (50 mL) was stirred overnight at 80° C. under argon. Then ethyl acetate (100 mL) was added, followed by water. The organic layer was collected and aqueous layer was extracted three times with ethyl acetate. The combined organic fraction was washed with water and then brine. The solvent was removed under vacuum and the product was purified using chromatography (20% hexane in dichloromethane) to give desired product (3.4 g) in 67% yield.
Reaction SMILES: [N:1]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[OH-].[Na+].O>[NH2:1][C:3]1[CH:4]=[C:5]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:6]([OH:13])=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reaction time: 2.5 h

Procedure:
To 17.6 grams of 4-nitroso-2,6-di-tert-butylphenol dissolved in 60 ml of 5N sodium hydroxide and 120 ml of water was added with stirring over a 30-minute period a solution of 52.2 grams of sodium hydrosulfite in 220 ml of water during which time the temperature rose to 53° C. After the addition was complete, stirring was continued for another 2.5 hours. The product formed was then rapidly collected by filtration, washed with 400 ml of water and dried in a vacuum desiccator over phosphorus pentoxide to yield 4-amino-2,6-di-tert-butylphenol, melting at 105°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].S(=O)(=O)(O)[OH:12]>>[F:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]([NH2:8])=[O:12]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(Br)ccc1F

Procedure:
5-Bromo-2-fluorobenzonitrile (0.370 g) was heated at 110° C. for 1 hour in concentrated sulfuric acid (10 ml). After cooling, the reaction was diluted with ice-cold water and the slurry was extracted into ethyl acetate, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the sub-title compound as a solid (0.328 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>CO.[Pd]>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc(CCN)c1

Procedure:
Nitrile 91a (4.8 g, 27 mmol) was hydrogenated on a Parr shaker at 40 psi H2 in the presence of 10% Pd/C (0.48 g) and p-toluenesulfonic acid (5.2 g, 27 mmol) in methanol (100 mL). The solution was filtered through a Celite pad to remove the catalyst, then solvent was removed in vacuo to give an orange solid (10.7 g). HR-MS: Calc'd. 180.1025. Found 180.1025.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([CH2:16]O)=[C:6]1[CH3:18])(=[O:4])=[O:3].P(Br)(Br)[Br:20]>C(OCC)C.O1CCCC1>[Br:20][CH2:16][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]=1[CH3:18]
Reactant: BrP(Br)Br
Reactant: COc1ccc2c(c1)c(CO)c(C)n2S(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CBr)c(C)n2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-Methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-methanol (1.53 g, 5.68 mmol) in anhydrous ethyl ether (50 ml) and tetrahydrofuran (20 ml) at 0° C. under N2 was added a solution of phosphorus tribromide (7.5 ml, 1 M in dichloromethane). The mixture was stirred at room temperature for 8 hours and concentrated under reduced pressure to give 3-bromomethyl-1-methane sulfonyl-5-methoxy-2-methyl-1H-indole as white solid. 1H NMR (CDCl3) δ:2.57 (s, 3H), 3.04(s, 3H), 3.89 (s, 3H), 4.63 (s, 2H), 6.93 (dd, 1H, J=9.1 Hz, 2.5 Hz), 7.04 (d, 1H, J=2.5 Hz), 7.89 (d, 1H, J=9.1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[C:21]([C:24]1([C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+].Cl>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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:31]2[CH:30]=[C:29]([C:24]3([C:21]([OH:23])=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:34]=[CH:33][CH:32]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: O=C(O)C1(c2cccc(B(O)O)c2)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)O)CCCC3)c2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [330 mg, 0.99 mmol], 3-(1-carboxy-cyclopentyl)-phenylboronic acid [580 mg, 2.48 mmol] and Cs2CO3 (808 mg, 2.48 mmol) in ethylene glycol dimethyl ether (4 mL) and water (1 mL), for a period of 5 minutes. To this mixture is added tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol) and the reaction vessel is sealed and heated to 90° C. After stirring for 8 hours the mixture is diluted with water (30 mL) acidified to pH 1 with concentrated HCl and extracted thrice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 1-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-cyclopentanecarboxylic acid as a solid that is treated with HCl in ethyl acetate. The material is then dissolved in acetone (5 mL) and heptane (15 mL) is added and allowed to stand at ambient temperature for 16 hours. The solvent is decanted from the crystals and dried under high vacuum to provide 1-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-cyclopentanecarboxylic acid hydrochloride [48 mg, 9%, Example 74] as a solid. LCMS RT=2.54 minutes, MS: 486 (M+H). IC50=0.5 nM
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:25])[CH3:24])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:26].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([C:23](=[O:25])[CH2:24][Br:26])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [Br-]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reaction time: 24 h

Procedure:
To a stirred solution of 1-[3,5-bis(benzyloxy)phenyl]ethanone (5 g, 15.04 mmol) in tetrahydrofuran (60 mL) and methanol (35 mL) was added tetrabutylammonium tribromide (7.25 g, 15.04 mmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred for 24 hours and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to afford the desired compound as a yellow oil in quantitative yield.
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1)=[O:2].[CH3:45][Mg]Br.C([SiH](CC)CC)C>C1COCC1>[OH:2][CH:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][NH:11][C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:38])=[O:35])[N:4]=1)[CH3:45]
Reactant: C[Mg]Br
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C=O)c12
Agent: CC[SiH](CC)CC
Solvent: C1CCOC1
Product: COc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C(C)O)c12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(R)-1-(4-Formyl-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (114 mg, 0.196 mmol) was dissolved in THF (3 mL), cooled to −78° C., and charged with methylmagnesium bromide (0.196 mL, 0.588 mmol). The reaction was allowed to warm to 0° C. and stirred for 10 min. The reaction mixture was quenched with saturated ammonium chloride (3 mL), extracted with EtOAc (10 mL, ×2), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in TFA (0.8 mL), charged with triethylsilane (0.031 mL, 0.196 mmol), and stirred at room temperature for 10 min. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM (2 mL) and TEA (1 mL) to free-base the product. The solvents were removed in vacuo and the residue was purified by flash chromatography (10-100% EtOAc/DCM) to give 1-(4-(1-hydroxyethyl)-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-((R)-1-phenylethyl)urea. MS ESI calc'd. For C18H21N5O3 [M+1]+ 356. found 356.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[C:21]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][S:23][CH:24]=1>>[Br:19][C:20]1[C:21]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][S:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1cscc1Br
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cscc1Br

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 4-bromothiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.48 (br m, 2H), 7.39 (dd, J=1.8 & 10.5 Hz, 1H), 7.28 (ddd, J=2.4, 4.8 & 9.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.02 (m, 1H), 6.02 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.68 (br s, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:3]=1[CH:4]=[O:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)(=O)C>[N:15]1([C:2]2[CH:9]=[CH:8][C:7]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=Cc1cc(-c2cccs2)ccc1F
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2cccs2)ccc1N1CCCC1
Yield: 32 %

Procedure:
Ex-63A: A solution of 2-fluoro-5-thiophen-2-yl-benzaldehyde (1.42 g, 6.89 mmol) in pyrrolidine was refluxed (10 mL). After 4.5 days the reaction mixture was cooled and diluted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0.5M) sodium carbonate (2M) and saturated solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (20%, v/v, in hexane) afforded 2-pyrrolidin-1-yl-5-thiophen-2-yl-benzaldehyde (0.5 g, 32%). 1H NMR (CDCl3) δ 10.14 (s, 1H), 7.94 (d, J=2 Hz, 1H), 7.62 (dd, J=2.7, 9 Hz, 1H), 7.22–7.20 (m, 2H), 7.07–7.04 (m, 1H), 6.86 (d, J=9 Hz, 1H), 3.41 (m, 4H), 2.01 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[N+:19]([O-])([O-:21])=[O:20].[Na+]>>[NH2:1][C:2]1[C:11]([N+:19]([O-:21])=[O:20])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2.0 g (13.3 mmol) of 6-amino-3H-benzoxazol-2-one [J. Chem. Soc., 321 (1938)] in 20 ml of trifluoroacetic acid 1.2 g (14.1 mmol) of sodium nitrate is added below 20° C. The reaction mixture is stirred at room temperature overnight, then concentrated. The residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent to yield. 2.50 g (96%) of the title compound. Mp.: 198° C. (toluene-methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH:15][CH2:16][CH:17]([CH2:19]O)[OH:18]>>[OH:18][CH:17]1[CH2:16][O:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][CH2:19]1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Product: OC1COC(c2ccc(Cl)cc2)OC1

Procedure:
Using the method of Example 21, 42 g 4-chlorobenzaldehyde, 27.6 g glycerol and 4 ml 40 percent sulfuric acid were reacted to form 5-hydroxy-2-(4-chlorophenyl)-1,3-dioxane. The reaction mixture was dissolved in benzene and washed successively with two 50 ml volumes of 5 percent aqueous sodium bicarbonate, two 50 ml volumes aqueous sodium bisulfite and two 100 ml volumes of water. The benzene solution was dried with magnesium sulfate, filtered and evaporated under reduced pressure to form an oil which crystallized, m.p. 95°-100° C (recrystallized from benzene-ligroin).
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[N:6]1[N:7]=[C:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[C:18]([O:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29])[CH:19]=[CH:20][CH:21]=3)[N:16]=2)[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:6]1[N:7]=[C:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[C:18]([O:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH:29][C:3](=[O:4])[CH2:2][F:1])[CH:19]=[CH:20][CH:21]=3)[N:16]=2)[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: O=C(Cl)CF
Reactant: CC(C)(CN)COc1cccc2ccc(-c3nnc4ccccn34)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)CF)COc1cccc2ccc(-c3nnc4ccccn34)nc12
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
2-Fluoroacetyl chloride (12 mg, 0.13 mmol) was added to a stirred solution of 3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine (prepared according to Example 18; 30 mg, 0.086 mmol) and diisopropylethyl amine (45 μL, 0.26 mmol) in DCM (2 mL) at 0° C. After 30 minutes, the reaction was quenched with saturated aqueous bicarbonate (5 mL), extracted into EtOAc, washed with water, dried over Na2SO4 followed by concentration in vacuo. The resulting oil was purified by flash column chromatography (silica gel), eluting with 100% EtOAc (Biotage) to give the desired product (12 mg, 0.029 mmol, 34% yield) as a white solid. MS ESI (+) m/z 408.2 (M+1) detected.
Reaction SMILES: [CH2:1]([SiH:5]([CH2:7][CH:8]([CH3:10])[CH3:9])Cl)[CH:2]([CH3:4])[CH3:3].[F:11][C:12]([F:18])([F:17])[S:13]([OH:16])(=[O:15])=[O:14].Cl>>[F:11][C:12]([F:18])([F:17])[S:13]([O:16][Si:5]([O:16][S:13]([C:12]([F:18])([F:17])[F:11])(=[O:15])=[O:14])([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC(C)C[SiH](Cl)CC(C)C
Agent: Cl
Product: CC(C)C[Si](CC(C)C)(OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F
Yield: 72.7 %

Procedure:
An oven-dried 250 mL-RB flask is charged with diisobutylchlorosilane (17.9 g, 0.10 mol). Then trifluoromethanesulfonic acid (45 g, 0.30 mol) is added dropwise. The mixture is heated at 60° C. until no HCl evolves (about 6 hours). The residue is distilled to yield 32 g (73%) of the product as a clear liquid. 1H NMR (500 MHz, CDCl3, in ppm) δ 2.06 (theptat, 2H, J=6.5 Hz, 7.0 Hz), 1.26 (d, 4H, J=7.0 Hz), 1.09 (d, 6H, J=6.5 Hz).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:11](O)([CH3:13])[CH3:12].S(=O)(=O)(O)O>C1C=CC=CC=1>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:11]([CH3:13])[CH3:12])=[O:5]
Reactant: O=C(O)c1ccccc1S
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)c1ccccc1S

Procedure:
Using a procedure similar to Example I, a mixture of 50.0 g (0.32 mole) of 2-mercaptobenzoic acid, 60 g (1.0 mole) of anhydrous isopropanol, 200 ml of benzene and 1.0 g of sulfuric acid (98%) was heated at reflux for 22 hours and yielded isopropyl 2-mercaptobenzoate: 13.2 g (20.1% of theory), bp 92°-93°C/0.7 mm.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=O.CCOCC>ClCCl>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Fc1ccccc1-c1nc2ccccc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
N-phenyl-1,2-phenylenediamine (3.68 g, 20 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 5 ml of triethylamine was then added, and the mixture was cooled to 0° C. 2-Fluoro-benzoyl chloride (3.16 g, 20 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2-fluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=4.32 g, 75%).