Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][C:18](=[O:21])[N:17](CC3C=CC(OC)=CC=3)[C@H:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C@H:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: COc1ccc(CN2C(=O)CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2c2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)N1

Procedure:
cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-6-keto-1-(4-methoxybenzyl)-2-phenyl piperidine (0.17 g, Example 27) was dissolved in acetonitrile (3 ml) and water (1 ml) then cooled to 0° C. and cerium ammonium nitrate (173 mg) was added. The mixture was stirred at 23° C. for 18h, then poured into water (10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with brine (1×10 ml) then dried (MgSO4) and concentrated to leave a pale yellow oil. Purification on silica gel (hexanes/ethyl acetate 1:1 then ethyl acetate then methanol/ethyl acetate 1:9) provided cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-6-keto-2-phenyl piperidine as an oil. 1H NMR (360 MHz, CDCl3) δ7.72 (1H, s), 7.44 (2H, s), 7.37 (5H, m), 5.86 (1H, s), 4.75 (1H, d, J=3.2 Hz), 4.52 (1H, d, J=12.5 Hz), 4.14 (1H, d, J=12.5 Hz), 3.98 (1H, m), 2.65 (1H, ddd, J=6.4, 12.2, 18.2 Hz), 2.48 (1H, m), 2.30 (1H, m), 2.06 (1H, m). m/z (CI+) 418 (MH).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@H:15]([O:29][CH2:30][CH2:31]OS(C)(=O)=O)[C@@H:16]2[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:37]([CH2:31][CH2:30][O:29][C@@H:15]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[C@@H:16]1[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCOS(C)(=O)=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c(F)cccc2[C@H](OCCN=[N+]=[N-])[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Temperature: 70 °C
Yield: 89.9 %

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-(methylsulfonyloxy)ethoxy)methyl)morpholine-4-carboxylate (554 mg, 1.0 mmol) in anhydrous DMF (18 mL), solid NaN3 (230 mg, 3.51 mmol) was added and the reaction mixture was heated to 70° C. for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (110 mL), and water (30 ml). The organic phase was washed with water (3×30 mL), dried over Na2SO4 and evaporated to give (R)-tert-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (423 mg, 90%). MS (E/Z): 471 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 79.2 %

Procedure:
A mixture of 3,4-dinitrophenol (250 mg), 4-(2-chloroethyl)morpholine hydrochloride (252 mg) and potassium carbonate (375 mg) in dimethylformamide (3 ml) was heated at 120° C. for 20 minutes in a Personal Chemistry Smith Creator microwave. The reaction mixture was partitioned between ethyl acetate and water and the organic layer dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 4-[2-(3,4-dinitro-phenoxy)-ethyl]-morpholine (319 mg) as a yellow oil. LC-MS (METHOD B): RT=2.13 minutes, 298 (M+H)+.
Reaction SMILES: C1N=[C:5]2[N:7]([C@@H:10]3O[C@H:13](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@@H:12](O)[CH2:11]3)C=N[C:4]2=[C:3](N)[N:2]=1.P(OC[C@H]1O[C@@H]([N:50]2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.OP(=O)(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)OP(=O)(OP(=O)(O)O)O>>[NH2:50][CH2:13][CH2:12][CH2:11][CH2:10][NH:7][CH2:5][CH2:4][CH2:3][NH2:2]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Product: NCCCCNCCCN

Procedure:
0.2 mM ea dATP, dGTP, dCTP, dTTP
Reaction SMILES: [CH3:1][CH:2]([CH3:69])[CH2:3][CH:4]1[CH2:18][N:17](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][N:14](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]1S(C1C=CC(C)=CC=1)(=O)=O.OS(O)(=O)=O.C(O)C.C(OCC)C>CC#N>[CH3:1][CH:2]([CH3:69])[CH2:3][CH:4]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC(CC(C)C)N(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC#N
Solvent: CCO
Product: CC(C)CC1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 69 h
Yield: 20 %

Procedure:
A mixture of 2-(2-methylpropyl)-1,4,7,10, 13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 5C (14.1 g, 0.0135 mole) and concentrated H2SO4 (50 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 69 h. To the resulting brown solution ethanol (70 mL) was added dropwise with stirring at 0° C., followed by ethyl ether (1 l). The brown solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution washed with ethyl ether. A small amount of solid was removed by filtration, the pH was adjusted to 10-11 with 10N NaOH and the solvent was removed in vacuo. Ethanol (2×250 ml) was then added and removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and filtered at room temperature. The filtrates were combined, the solvent was removed in vacuo and the residue was dissolved in THF and filtered. The solvent was removed in vacuo to give the crude product as a tan oil which was then dissolved in CH3CN and filtered to remove insoluble impurities. Crystallization occurred upon cooling the filtrate to -20° C. Recrystallization from cold (-20° C.) CH3CN gave 715 mg (20% yield) of the product as a white crystalline solid: mp 70°-6° C.; 1H NMR (CDCl3) δ 0.89 (d,J=6.5 Hz, 3 H), 0.90 (d, J=6.6 Hz, 3 H), 1.13 (m, 1 H), 1.39 (m, 1 H), 1.64 (sept, J=6.3 Hz, 1 H), 2.05 (br s, 5 H), 2.34 (m, 1 H), 2.75 (m, 18 H); Exact mass (M+Li)+ : calcd. 278.2896; found, 278.2919 (C14H33N5Li).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CC[N+](CCCN(C)C)=C=N>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13])[C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: CNCc1c(C)oc2ccccc12
Reactant: O=C(O)C=Cc1cnc2c(c1)OCC(=O)N2
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a solution of methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (152 mg, 0.87 mmol) in DMF (5 mL) were added in sequential order 3-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (175 mg, 0.79 mmol), 1-hydroxybenzotriazole (121 mg, 0.87 mmol), diisopropylethylamine (412 uL, 2.37 mmol), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (174 mg, 0.87 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (125 mg, 42%) as a light brown solid and as a mixture of amide rotamers. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.50-7.59 (m, 3H), 7.19-7.26 (m, 3H), 4.74 (s, 2H), 4.70 (s, 2H), 3.06 (s, 3H), 2.52 (s, 3H); MS (ESI) m/e 378 (C21H19N3O4+H)+.
Reaction SMILES: [CH:1](=[CH:7][C:8](=O)C)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:11]C(C)=O>>[CH3:11][C:5]1[O:6][C:2](=[C:1]=[CH:7][CH3:8])[CH2:3][CH:4]=1
Reactant: CC(=O)C=Cc1ccco1
Reactant: CC(C)=O
Product: CC=C=C1CC=C(C)O1

Procedure:
furfurylidene acetone, 5-methyl-2-furfurylidene, acetone,
Reaction SMILES: [Si]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C@H:28]5[O:31][C@H:29]5[CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[O:31]1[C@H:29]2[CH2:30][C@:20]34[C@H:26]([C:27]([CH3:33])([CH3:32])[C@@H:28]12)[CH2:25][CH2:24][C@H:23]([CH3:34])[C@@:21]3([CH3:35])[CH2:22][C:10]1[C:9]([OH:8])=[CH:17][C:16]2[C:15](=[O:18])[NH:14][CH2:13][C:12]=2[C:11]=1[O:19]4
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@H]3O[C@H]3C[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@H]3O[C@H]3C[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of the above Compound (43b) (28 mg, 0.056 mmol) in 2.0 ml of THF was added dropwise 75 μl (0.075 mmol) of 1M tetrabutylammonium fluoride under ice-cooling, and the mixture stirred for 2 hours at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution, and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=10:1) to give 16 mg (74%) of Compound (43a).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:42][CH:43]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(C)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(C)c3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogencarbonate (2.8 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxy-3-methylphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.94 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.4 g, 38%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
4-Trifluoromethylaniline (0.258 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.60 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.123 g, 0.238 mmol, 44%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]2[C:15]([F:33])=[N:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:6]([C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]2[C:15]([F:33])=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][CH:25]=3)[CH:19]=2)[CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cc(-c2cc(-c3ccc(CN4CCCCC4)cc3)cnc2F)c(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cc(-c2cc(-c3ccc(CN4CCCCC4)cc3)cnc2F)c(N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6′-((trimethylsilyl)ethynyl)-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine (90 mg, 0.2 mmol) and potassium carbonate (150 mg, 1.1 mmol) in methanol (2 mL) was stirred at ambient temperature for 1 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a brown residue that was taken to the next step without purification.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][C:5]([O:7]CC)=O.Cl[C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH2:13]>CCO.CCOC(C)=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:11]2[S:3][CH2:4][C:5](=[O:7])[NH:13][C:12]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CSc2ccc([N+](=O)[O-])cc2N1

Procedure:
A solution of 2.44M aqueous NaOH (24 mL, 58 mmol) was added to a stirring solution of ethyl 2-mercaptoacetate (19 mL, 174 mmol) in EtOH (150 mL). The mixture was added to the stirring solution of 2-chloro-5-nitroaniline (10 g, 58 mmol) in EtOH (68 ml). The resulting mixture was heated at reflux overnight. After this time the reaction was diluted with EtOAc and washed with water. The separated organic layer was dried over Mg2SO4, filtered and evaporated in vacuo. The crude residue was triturated with EtOAc to give 6-nitro-2H-benzo[b]-[1,4]thiazin-3(4H)-one. Mass Spectrum (ESI) m/e=257 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]([NH:7][C:8]([CH:10]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)[C:11]([CH3:19])([CH3:18])[CH2:12]OS(C)(=O)=O)=[O:9])([CH2:5][CH3:6])[CH3:4]>C1COCC1.CO>[C@@H:3]([N:7]1[CH2:19][C:11]([CH3:18])([CH3:12])[C@@H:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=2)[C:8]1=[O:9])([CH2:5][CH3:6])[CH3:4]
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)N1CC(C)(C)[C@@H](Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 22.5 °C
Reaction time: 90 h

Procedure:
Solid NaH (60 wt % dispersion in mineral oil, 16.6 g, 416 mmol) was added portion wise over 25 min to a cold (0-5° C.) sol'n of methanesulfonic acid 3-sec-butylcarbamoyl-3-(4-cyano-3-trifluoromethylphenoxy)-2,2-dimethylpropyl ester (104 g, 208 mmol) in 400 mL dry THF under an N2 atmosphere. The reaction mixture was allowed to warm to 20-25° C. and then stirred at this temp. for 90 h. The reaction mixture was quenched by adding it to 500 mL cold (5-10° C.) sat'd aq. NH4Cl. The phases were separated and the aqueous was extracted with ethyl acetate (“EtOAc”) (2×500 mL). The pale yellow organic was conc'd under vac (40-45° C.) to an orange-yellow oil/gum (83 g). The crude product was purified by extensive silica gel (230-400 mesh) column chromatography (EtOAc/Heptane) followed by crystallization (EtOAc/Heptane). The pure desired diastereomer was isolated as a white granular solid MS+: 355. m.p. 101-102° C. Optical rotation [α]58925=+180.10(in methanol) Elemental analysis results: Obsv'd (Theor.): C, 61.03 (61.01); H, 6.02 (5.97); N, 7.88 (7.91); F, 15.98 (16.08). HPLC analysis: Chiral purity: 100%.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15]([Li])CCC.IC>O1CCCC1>[CH3:15][CH:9]1[CH2:8][CH2:7][CH2:6][CH:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]1=[O:3]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCC(C)C1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (5.0 g, 0.125 mol) in tetrahydrofuran (250 mL) was added a solution of ethyl 2-oxocyclohexanecarboxylate (19.9 mL, 0.125 mol) in tetrahydrofuran (30 mL) whilst maintaining the temperature of the mixture between 10° C. and 15° C. by means of an ice bath. After stirring at 5° C. for 1 hour, butyl lithium (52.5 mL, 2.5 M solution in hexanes, 131 mmol) was added dropwise while maintaining the temperature below 12° C. After stirring at 5° C. for 30 minutes, iodomethane (7.8 mL, 125 mmol) was added. The reaction mixture was stirred at 5° C. for 1.5 hours and then quenched with a saturated solution of ammonium chloride. The mixture was diluted with ethyl ether, washed with water. The organic extracts were dried over magnesium sulfate and concentrated. The resulting residue was distilled (100–110° C., 0.1 torr) to obtain the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([N:14]=[C:15]=[S:16])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([NH:14][C:15]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[S:16])[C:10]([Cl:12])([Cl:13])[Cl:11])=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(NC(N=C=S)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reactant: Nc1cccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC(NC(=S)Nc1cccnc1)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A solution of Example 45A (239mg, 0.695 mmol) and 3-aminopyridine (65 mg, 0.69 mmol) in THF (4 mL) at ambient temperature was treated with triethylamine (1.66 mL, 1.18 mmol). The mixture was stirred for 3 hours, diluted with ethyl acetate (20 mL), and washed with water (2×10 mL) and brine (10 mL). The organic portion was dried (MgSO4), filtered, and concentrated to provide an oily residue which was purified by flash chromatography (elution with 5% ethanol/hexanes) to provide 158 mg of the desired product as an off-white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][O:8][C:9]=1[CH2:10][CH3:11])=[O:4].O[Li].O>C1COCC1.O>[CH2:10]([C:9]1[O:8][N:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[C:3]([OH:4])=[O:2])[CH3:11]
Reactant: CCc1onc(-c2ccccc2)c1C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCc1onc(-c2ccccc2)c1C(=O)O
Yield: 85.6 %

Procedure:
8.0 g (34 mmol) of 5-Ethyl-3-phenyl-isoxazole-4-carboxylic acid methyl ester (prepared according to: Synthesis 2003; 1347-1356) was dissolved in 50 mL of THF, to which 7.2 g (170 mmol) LiOH.H2O in 25 ml of H2O was added in one portion. The reaction mixture was refluxed for 12 h. After evaporation of THF, the aqueous solution was acidified with 2N HCl to pH=2. After extraction with ethyl acetate (3×100 mL), the combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 5-Ethyl-3-phenyl-isoxazole-4-carboxylic acid (6.32 g) in 72.3% yield as a red solid. (m/e): 216.2 (M−; 100%).
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[NH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]1>CC(N(C)C)=O>[C:52]([N:49]1[CH2:50][CH2:51][N:46]([CH2:45][CH2:44][NH:43][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])[CH2:47][CH2:48]1)(=[O:54])[CH3:53]
Reactant: CC(=O)N1CCN(CCN)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(CCNC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 1-[4-(2-amino-ethyl)-piperazin-1-yl]-ethanone (55 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3, water, concentrated and triturated with methanol to give the titled compound as a yellow solid.