Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[SiH](OCC)OCC)C>C1C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Solvent: c1ccccc1
Product: c1ccc(Cn2cccc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
N-benzylsuccinimide (0.38 g, 2.0 mmol), triethoxysilane (1.85 mL, 10 mmol), and titanium (IV) isopropoxide (0.06 mL, 0.2 mmol) were dissolved in C6H6 (4.0 mL) and the mixture was heated to 60 ° C. for 16 hours. The solvent was removed in vacuo and the reaction mixture was poured into a mixture of 1 M NaOH (10 mL) and THF (10 mL). This mixture was stirred for 1 hour, poured into ethyl ether (75 mL), and washed with 1 M NaOH (5×50 mL). The ether layer was dried over MgSO4, filtered, and the solvent was removed in vacuo to produce 0.29 g (91% yield) of N-benzylpyrrole as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[O-]S(C(F)(F)F)(=O)=O.[O:50]=[S:51]1(=[O:65])[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=2)[CH2:53][CH2:52]1>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:64][C:61]3[CH:62]=[CH:63][C:58]([CH2:57][N:54]4[CH2:55][CH2:56][S:51](=[O:65])(=[O:50])[CH2:52][CH2:53]4)=[CH:59][CH:60]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ncc2ccc(Br)n2n1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol (100 mg, 0.467 mmol) was dissolved in N,N-dimethylformamide (9.00 mL) at 0° C. and N,N-diisopropylethylamine (244 μL, 1.40 mmol) was added and the reaction was let stir for 30 minutes. N-Phenylbis(trifluoromethanesulphonimide) (184 mg, 0.514 mmol) was added and the reaction was let warm to room temperature. After 100% conversion to the triflate, 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine (140 mg, 0.584 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was taken up in EtOAc (30 mL) and washed three times with water (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-amine as a yellow foam (134 mg, 66%). LCMS (m/e) 301 (M—N(CH2)4SO2); 1H-NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 7.73 (d, 2H, J=8.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 6.92 (s, 1H), 6.81 (d, 1H, J=4.8 Hz), 6.76 (d, 1H, J=4.8 Hz), 3.63 (s, 2H), 3.10-3.03 (m, 4H), 3.03-2.97 (m, 4H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35](O)([CH3:37])[CH3:36]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH:35]([CH3:37])[CH3:36])=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CC(C)O
Product: CC(C)OC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and isopropanol Rf value: 0.4 (aluminium oxide, methylene chloride/isopropanol=30:1) C31H33N3O3
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22]([N:29]1[CH2:33][CH2:32][CH:31](OS(C)(=O)=O)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:3]1([S:9]([C:12]2[CH:21]=[CH:20][C:15]3[N:16]([CH:31]4[CH2:32][CH2:33][N:29]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:30]4)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To a suspension of sodium hydride (0.033 g. of a 60% dispersion in mineral oil, 0.834 mmol) in 3 mL dimethylformamide was added portionwise 7-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.200 g, 0.726 mmol), and the resulting suspension was stirred at room temperature for 10 minutes. Racemic methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester (0.259 g., 1.018 mmol) was added dropwise and the reaction mixture was heated to 65° C. for 21 hours. The reaction mixture was then poured into 100 mL water, and extracted three times with 50 mL ethyl acetate. The organic fraction was washed twice with 50 mL 10% aq. hydrogen chloride and once with 50 mL saturated sodium bicarbonate. The organic fraction was then dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (2%-5% methanol in dichlormethane) to give 0.127 g (0.292 mmol, 40%) of 7-benzenesulfonyl-4-(1-benzyl-pyrrolidin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine as a red oil. MS: 474 (M+ACN)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:18]=[N:19][C:20]([N:24]([CH3:26])[CH3:25])=[CH:21][C:22]=4[CH3:23])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:27]([OH:30])[CH2:28][CH3:29])=[CH:6][CH:5]=1.[CH2:31](I)[CH3:32]>CN(C)C=O.[Cl-].[NH4+]>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([N:24]([CH3:25])[CH3:26])=[N:19][CH:18]=4)[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:27]([O:30][CH2:31][CH3:32])[CH2:28][CH3:29])=[CH:6][CH:5]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
Sodium hydride (60% in oil, 27.1 mg, 0.678 mmol) was added to a stirred solution of 1-{9-chloro-1-[6-(dimethylamino)-4-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (226 mg, 0.565 mmol) in N,N-dimethylformamide (5.0 mL) at room temperature. After stirring 5 min, ethyl iodide (132 mg, 0.848 mmol) was added to the mixture, and the mixture was stirred at room temperature for 6 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate to give the title compound as a colorless crystal (121 mg, 0.283 mmol, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33](=[CH2:35])[CH3:34]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:25][C:23]1[CH:22]=[CH:21][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:24]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:34][C:33]([CH3:35])=[CH2:32])=[CH:18][CH:19]=1)=[CH:7]3
Reactant: C=C(C)CBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) (1.0 equiv.) in dimethylformamide (0.10 M) was added anhydrous potassium carbonate (1.5 equiv.) followed by methallyl bromide (1.2 equiv.). The resulting mixture was allowed to stir for 18 hours at 100° C. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and water. The biphasic layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-60% ethyl acetate in hexanes to provide 8-methyl-2-(4-(2-methylallyloxy)phenethyl)benzo[f][1,7]naphthyridin-5-amine as a solid. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.68 (s, 1H), 8.27 (d, 1H), 7.41 (s, 1H), 7.12-7.19 (m, 3H), 6.87 (d, 2H), 6.60 (br, 2H), 5.06 (s, 1H), 4.93 (s, 1H), 4.43 (s, 2H), 3.20 (t, 2H), 3.05 (t, 2H), 2.45 (s, 3H), 1.79 (s, 3H). LRMS [M+H]=384.2
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[C:47]([Cl:49])[CH:48]=1>C(#N)C>[Cl:49][C:47]1[CH:46]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:44]=[C:43]([Cl:42])[CH:48]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc(Cl)cc(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 44 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0332 g, 0.0719 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0600 mL, 0.432 mmol) and 3,5-dichlorobenzenesulfonylchloride (0.0530 g, 0.216 mmol) to obtain 4-(3,5-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0212 g, yield 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([F:26])[C:17]([O:24][CH3:25])=[C:18]([F:23])[CH:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([O:24][CH3:25])[C:16]=3[F:26])=[O:11])=[CH:6][CH:7]=1
Reactant: COc1c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(COCC[Si](C)(C)C)c2c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1c(F)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1F
Temperature: 85 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-oxo-6,7,8-trifluoro-1-(2-(trimethylsilyl)ethoxy) methyl-3-quinolinecarboxamide (1.00 g) from Preparation No. 13 and methanol (163 μL) are dissolved in DMF (20 mL). Sodium hydride (60% dispersion, 80 mg) is added and the mixture is heated to 140° C. for 1 h. The mixture is allowed to cool to rt, is poured into sat. aq. ammonium chloride (100 mL), and is extracted with ethyl acetate (3×50 mL). The organic layer is washed with brine (10 mL), dried (MgSO4), and concentrated. The crude product is purified by column chromatography (heptane/ethyl acetate, 4/1; 3/1) to afford N-((4-chlorophenyl)methyl)-6,8-difluoro-7-methoxy-4-oxo-1-(2-(trimethylsilyl)ethoxy)methyl-3-quinolinecarboxamide. The resulting crude amide is suspended in ethanol (15 mL), heated to 85° C., and to the mixture is added 50% aq. hydrochloric acid (5 mL). The mixture is heated an additional 1.5 h and allowed to cool to rt. The reaction mixture is neutralized with solid sodium bicarbonate and filtered. The solids are washed with ethanol (10 mL) followed by ethyl acetate (20 mL), and the combined filtrates are concentrated to afford a tan solid. The crude product is purified by recrystallization from acetic acid/water followed by column chromatography (heptane/2-propanol, 95/5) to afford 27 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([NH:16][OH:17])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:21]([CH:23]=[O:24])C.C(O)(=O)C.[O-]C#N.[K+]>O>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([N:16]([OH:17])[C:23]([NH2:21])=[O:24])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: ON[C@@H]1COc2cc(OCc3ccccc3)ccc21
Agent: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N(O)[C@@H]1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred solution of (S)-N-(6-benzyloxy-2,3-dihydrobenzofuran-3-yl)hydroxyamine of Example 7(b) above, (10.0 kg, 38.9 moles), DMF (50.0 L), and acetic acid (3.34 L) cooled to 5° C. was added in one portion, a cooled (0° C.) solution of potassium cyanate (4.73 kg, 58.3 moles) in water (9.0 L). This was added at such a rate that the internal temperature did not exceed 10° C. The resultant suspension was stirred for 30 min at room temperature. Water (213 L) was added and the mixture stirred for 1 hour at ambient temperature. The product was collected by centrifugation and the wet cake washed with water (425 L) and 95% ethanol (40 L). The product was isolated an dried at 45°-50° C. under vacuum to afford the crude product (11.4, 97%) as an off white solid. The crude product (11.0 kg) was recrystallized from DMF/TBME (110 L/233 L)) and washed with TBME (89 L) to afford the desired compound (9.1 kg, 83%) as a white solid after drying at 45°-50° C. under vacuum. The product was greater than 99% e.e. as determined by chiral HPLC.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Cl[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(Cl)Cl.CC(=O)OCC>CN(C=O)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([CH2:25][CH2:24][S:7][C:8]2[N:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]([NH:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:11])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: O=S(=O)(CCCl)c1ccc(F)cc1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1cccs1)c1cccnc1SCCS(=O)(=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
303 mg (2.2 mmol) of K2CO3 were added to a solution of 500 mg (2.0 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (5 ml), and stirring was carried out for 30 min at RT. 445 mg (2.0 mmol) of 1-(2-chloroethylsulfonyl)-4-fluorobenzene were then added and stirring was continued for a further 2 days at RT. The mixture was then concentrated in vacuo, the residue was taken up in EA, and 1M aqueous NaHCO3 solution was added. The phases were separated and the aqueous phase was extracted with EA. The combined organic phases were dried over MgSO4, filtered through silica gel and concentrated in vacuo. CC (DCM/EA 4:1) of the residue yielded 365 mg (0.84 mmol, 48%) of 2-[2-(4-fluorophenyl)sulfonylethylthio]-N-(2-thienylmethyl)-nicotinamide. MS: m/z 437.0 [M+H]+
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.[H][H]>ClCCl.[Pd]>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Agent: [Pd]
Solvent: ClCCl
Product: Nc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.5 %

Procedure:
To a solution of the crude 4-(2,2,2-trifluoroethoxy)nitrobenzene (1.6 g, 7.2 mmol, 1.0 equiv) in 40 mL of dichloromethane was added 0.4 g of a 5% palladium on activated carbon (0.19 mmol, 0.026 equiv). Hydrogen gas was introduced using a balloon while the mixture was stirred vigorously for 48 h at room temperature. After all starting material had been consumed, the mixture was filtered through a pad of Celite to remove the palladium catalyst. The filtrate was evaporated in vacuo to give a crude product as a brown liquid. This crude product was purified by distillation at reduced pressure to give 1.3 g of pure 4-(2,2,2-trifluoroethoxy)aniline as a colorless liquid, which solidified upon cooling to 0° C. b.p. 81-83° C. at 0.5 torr;. 1H NMR (DMSO-d6) δ4.53 (q, J=9.1 Hz, 2H), 4.76 (br s, 2H), 6.52 (d, J=7.6 Hz, 2H), 6.76 (d, J=7.6 Hz, 2H) ppm.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C.C(O)C>[CH2:1]([NH:4][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=Cc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCNCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 130.8 %

Procedure:
Propylamine (4.13 g) was slowly added to 4-hydroxybenzaldehyde (11.2 g, 91.80 mmol) in 50 mL of isopropanol at ambient temperature. The reaction was stirred for 1 hour and then cooled in an ice bath to 0° C. The imine was then reduced with sodium borohydride (1.74 g, 46 mmol) for 1 hour. The reaction was diluted with 100 mL of ethanol and acidified with acetic acid. The resulting solid was filtered and recrystallized from ethanol/isopropanol to give 15.1 g (99%) of the title compound. TLC (3:1 ethyl acetate/ethanol, trace triethylamine) Rf =0.37.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCCCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 201.4 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and piperidine (9.2 ml) is added thereto at the temperature within 20 min. The above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.8 g). The yield is about 75.2%.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17]([NH:19][OH:20])=[O:18])[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:7]1([CH2:16][C:17]([NH:19][OH:20])=[O:18])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1
Reactant: O=C(CC1(c2ccccc2)Oc2ccccc2O1)NO
Solvent: CCOC(C)=O
Product: CC1(CC(=O)NO)Oc2ccccc2O1

Procedure:
(2-Phenyl-1,3-benzodioxol-2-yl)acetohydroxamic acid (m.p. 120°-21°C. from ethyl acetate can be similarly prepared).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH2:6])[CH:3]=[N:2]1.[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:20][C:16]=2[C:17](O)=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.CC#N.O>[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[CH:20][C:16]=2[C:17]([NH:6][C:4]2[CH:5]=[N:1][NH:2][CH:3]=2)=[O:18])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cn[nH]c1
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1cn[nH]c1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat 1H-pyrazol-4-amine (49.0 mg, 0.59 mmol) was added in one charge to a stirred solution of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 150 mg, 0.49 mmol), EDC (283 mg, 1.47 mmol) and HOBT (226 mg, 1.47 mmol) in dimethylformamide (4 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. 30 ml water was added, and the mixture was extracted with ethyl acetate (70 ml×2). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was further purified by pre-HPLC (Gilson GX-281; Shimadzu 15 μm 250*20 mm; A: 10 mMol NH4HCO3/Water; B: CH3CN) to yield the title compound as a white solid. 50 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Sc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Br)CC1
Temperature: 80 °C
Yield: 98 %

Procedure:
To a stirred solution of 2-bromobenzenethiol (1.0 g, 0.00529 mole) in DMF (10 mL) was added cesium carbonate (2.063 g, 0.0063 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.478 g, 0.00529 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with hexane to afford 1.93 g (98%) of 4-(2-bromo-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 372.06 (M+1)+, 92.78%. A solution of 4-(2-bromo-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (1.93 g, 0.0052 mole) in dioxane.HCl (3 mL), was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 1.38 g (99%) of 4-(2-bromo-phenylsulfanyl)-piperidine hydrochloride. 1H NMR (DMSO-d6): δ 9.1-8.9 (bs, 1H), 7.7-7.64 (d, 1H), 7.56-7.52 (d, 1H), 7.46-7.36 (t, 1H), 7.24-7.16 (t, 1H), 3.7-3.6 (m, 1H), 3.34-3.2 (bd, 3H), 3.1-2.94 (q, 2H), 2.16-2.04 (d, 2H), 1.84-1.66 (q, 2H).