Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:37]3[CH:38]=[N:33][CH:34]=[N:35][CH:36]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OB(O)c1cncnc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3cncnc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow oil. MS: 501.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([O:23][CH3:24])=[N:21][CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.[C:25]1(O)[CH:30]=[CH:29]C=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([O:23][C:24]4[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=4)=[N:21][CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: COc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Product: Cc1noc2c1-c1ccnc(Oc3ccccc3)c1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine (Compound 170) was followed, except that phenol was used instead of methanol. LC/MS m/z 402 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=5.40 Hz, 1H), 7.56 (d, J=5.40 Hz, 1H), 7.41 (s, 4H), 7.31 (tt, J=2.20, 8.00 Hz, 2H), 7.14 (tt, J=1.40, 7.50 Hz, 1H), 6.79 (d, J=8.00 Hz, 2H), 5.31 (d, J=13.3 Hz, 1H), 4.25 (d, J=13.29 Hz, 1H), 2.58 (s, 3H).
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH2:4][F:5].Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[F:1][CH2:2][CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH2:4][F:5]
Reactant: O=[N+]([O-])c1ccc(OC(CF)CF)cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OC(CF)CF)cc1

Procedure:
3.4 g (15.7 mmol) of p-(1,3-difluoro-2-propoxy)nitrobenzene, 17.7 g (78.5 mmol) of SnCl2 ·2H2O and 35 ml of absolute ethanol were heated together at reflux for 1 hour. The reaction mixture was poured over ice, made basic with 50 percent aqueous NaOH and extracted three times into ether. The combined ether extracts were washed two times with water, dried over MgSO4 and filtered. Hydrogen chloride gas was bubbled into the ether solution causing the above-named aniline to precipitate as the hydrochloride salt. The product was collected as a tan solid by filtration (80 percent of theoretical) and decomposed (d) at 240° C. T1 - % C? % H? % N? -Analysis: -Calc. for C9H11F2NO.HCl: 48.33 5.41 6.26 -Found: 48.42 5.41 6.33 -
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[OH:25])[CH:20]=[O:21])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[CH:20]=[O:21])[CH3:15]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (30.0 g), 3-ethoxy-4-hydroxybenzaldehyde (22.9 g), potassium carbonate (21.01 g) and N,N-dimethylformamide (300 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-ethoxy-4-[[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy]benzaldehyde as brown crystals (31.20 g, yield 69%). Recrystallization from ethyl acetate-hexane gave pale-yellow needle. melting point: 159-160° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:8]1
Reactant: N#Cc1ccc2c(c1)C[C@H](NC(=O)NC1CCCCC1)CN2
Reactant: O=Cc1cccc(Cl)c1
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)NC1CCCCC1)CN2Cc1cccc(Cl)c1

Procedure:
The title compound was prepared from (S)-1-[6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-3-cyclohexyl-urea, prepared as described in Example 42A, and 3-chlorobenzaldehyde by procedures analogous to those described in Example 3A. HPLC (method B): retention time=7.50 min. MS (ES): m/z 423 [M+H]+. Chiral HPLC 100% e.e.; retention time=12.2 min; Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in hexanes for 30 min at 1 mL/min.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2>CO>[CH3:1][O:2][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 81 °C
Yield: 233.2 %

Procedure:
Sodium methoxide (571 mg, 1.05 mmol) was added to a solution of 5-chloro-8-nitroquinoline (Intermediate 65) (550 mg, 2.64 mmol) in MeOH (15 ml) and heated to 81° C. for 2 h. After cooling, the mixture was concentrated in vacuo, water was added and the mixture was extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo gave the title compound (500 mg, 93%). The structure was confirmed by 1H NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:39].[K+].[K+].O1CCOCC1>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]3[NH:7][C:2](=[O:39])[N:3]=[CH:4][CH:5]=3)=[CH:17][C:14]=2[C:15]#[N:16])=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(COc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 90.8 %

Procedure:
A mixture of 5-{[(2-chloro-4-pyrimidinyl)oxy]methyl}-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzo-nitrile (2.30 g, 2.61 mmol), DABCO (0.147 g, 1.31 mmol) and potassium carbonate (1.08 g, 7.84 mmol) in a mixed solvents of 1,4-Dioxane (10 mL) and water (10 mL) was heated at 70° C. for 3 h, then concentrated and diluted with ethyl acetate (100 mL) and water (100 mL). Separated organic part was washed with water and brine, dried over sodium sulfate, concentrated. Purification via mass-directed autopreparation afforded the title product (1.0 g). LC-MS (ESI): m/z 420 [M−H]+; 3.89 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11](C(OC)=O)[C:12]([O:14][CH3:15])=[O:13].[Na+].[Cl-]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a stirred solution of dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (5.0 g, 18.5 mmol, 1.0 eq) in DMSO (30 mL) was added NaCl (1.07 g, 18.5 mmol, 1.0 eq) and water (0.5 mL) and stirred at 120° C. for 3 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (50 mL×2), washed with brine, dried over Na2SO4 and the solvent evaporated. The crude residue was purified by CC using PE/EtOAc (19:1) to get methyl 2-(2-fluoro-4-nitrophenyl)acetate (2.5 g, 64%) as a viscous oil (TLC system: EtOAc/PE (1:4), Rf: 0.55).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=O)[O:7]CC)[CH3:4].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.O>CCCCCC.C1COCC1.C(O)(=O)C>[CH2:3]([O:5][C:6]([CH:18]1[C:17](=[O:20])[CH2:16][CH2:15][C:14]2([O:13][CH2:12][CH2:11][O:21]2)[CH2:19]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2(CCC1=O)OCCO2
Temperature: 0 °C

Procedure:
Sodium hydride (60% dispersion; 45 g, 1.17 mol) was washed with 500 ml of hexane (2×), suspended in 750 mL of THF and treated with diethylcarbonate (112.5 g, 0.94 mol). The suspension was heated to reflux and treated drop-wise with a solution of 1,4-cyclohexanedione mono-ethylene ketal (60.0 g , 0.384 mol) in THF (250 mL). After the addition was complete the suspension was heated to reflux for an additional 4 hours. The mixture was cooled in an ice bath to 0° C. and then poured, while vigorously stirring, into a mixture of ice (1 L), water (100 mL) and acetic acid (100 mL). The resulting mixture was extracted with hexane (2 L total) and the extracts washed with water and brine. The hexane extract was dried over Na2SO4, filtered and concentrated to give 8-Oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid ethyl ester as a pale yellow oil. This was used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][CH:40]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of compound 5g (0.26 g, 0.49 mmol) in DCM (8 mL) was added TFA (2 mL). The solution was stirred at rt for 3 h, and concentrated to obtain a residue that was washed with Et2O (3×20 mL) and isolated as a yellow solid, compound 40. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.52-8.63 (m, 1H), 8.11-8.24 (m, 4H), 8.01-8.11 (m, 2H), 7.79-7.98 (m, 5H), 7.61-7.75 (m, 1H), 6.49 (d, J=5.6 Hz, 1H), 4.11 (br. s., 4H), 3.83-3.96 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H23N5O3: 478.2 (M+H). Found 478.1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.O1CCOCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([NH2:18])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCCN(C(N)=O)C1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Product: NCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)piperidine-1-carboxamide (150 mg, 0.583 mmoles) (prepared as described in Preparative Example 241, Step A above) was dissolved in methanol (3 mL). 10% conc. sulfuric acid in 1,4-dioxane (7.9 mL) was added and the mixture was stirred at 25° C. for 1 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the pH was basic. The resin was filtered off, washed with methanol, evaporated to dryness and chromatographed on a silica gel column (15×2 cm) using dichloromethane followed by 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give the 3-(aminomethyl)piperidine-1-carboxamide (80 mg, 87%): FABMS: m/z 158.1 (MH+); HRFABMS: m/z 158.1294 (MH+). Calcd. for C7H16N3O: m/z 158.1293; δH (CDCl3+drop CD3OD) 1.20 (1H, m, CH2), 1.48 (1H, m, CH2), 1.60 (1H, m, CH), 1.68 (1H, m, CH2), 1.83 (1H, m, CH2), 2.64 (bm, 2H, —CH2NH2), 2.82 (1H, m, CH2), 3.02 (1H, m, CH2), 2.98 (2H, m, CH2), 3.70 (1H, m, —CH2NH2), 3.78 (1H, m, —CH2NH2) and 5.24 ppm (1H, bs, NH); δc (CDCl3+drop CD3OD) CH2: 24.1, 28.6, 44.0, 44.8, 47.9; CH: 38.3; C: 159.0.
Reaction SMILES: CN(C)C(=O)C.[C:7]([O:16]CC)(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].C(=O)([O-])[O-].[K+].[K+].S(O[CH2:30][CH:31]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)(=O)C>C(OCC)(=O)C.O>[CH2:40]([CH:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30][O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]([OH:16])=[O:15])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCCCCCCCC(CCCCCC)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)O
Reaction time: 2 h

Procedure:
300 ml of N,N-dimethylacetamide was added to 17.5 g of ethyl salicylate, and 34.6 g of potassium carbonate and then 32.1 of 2-hexyldecyl mesylate were added dropwise over about 30 min with stirring on a steam bath. After the addition the stirring was continued for 2 hours further under heating, and then the reaction mixture was cooled and transferred into a separately funnel. Then 300 ml of ethyl acetate and 1l of water were added for extraction. The ethyl acetate solution was washed with dilute hydrochloric acid, and then with an aqueous sodium hydrogencarbonate solution, and it was concentrated. 300 ml of ethanol was to the coil concentrate, to dissolve the concentrate, and a solution, of 12 g of sodium hydroxide in 50 ml of water was added dropwise thereto over about 10 min at room temperature with stirring. After the addition the stirring was continued for 1 hour further and 30 ml of concentrated hydrochloric acid diluted with 300 ml of water was added dropwise. The reaction liquid was transferred into a separately funnel, and 500 ml of water and 300 ml of ethyl acetate were added for extraction. The ethyl acetate solution was washed with 500 ml of water twice and then concentrated, to obtain 36.0 g of 2-(2-hexyldecyloxy)benzoic acid in the form of an oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:53]([Se:54][CH3:55])=[CH:52][N:13]([C@@H:14]2[O:44][C@H:18]([CH2:19][O:20][C:21]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22]3[CH:27]=[CH:26][C:25]([O:30][CH3:31])([O:28][CH3:29])[CH2:24][CH:23]=3)[C@@:16]([Si](C(C)(C)C)(C)C)([OH:17])[CH2:15]2)[C:12](=[O:56])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CO>ClCCl>[C:1]([NH:9][C:10]1[C:53]([Se:54][CH3:55])=[CH:52][N:13]([C@@H:14]2[O:44][C@H:18]([CH2:19][O:20][C:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])([O:30][CH3:31])[CH2:26][CH:27]=3)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:56])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(NC(=O)c4ccccc4)nc3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccccc2)=CC1
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)=CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
4-N-benzoyl-5-methylseleno-3′-t-butyldimethylsilyl-5′-O-(4,4-dimethoxytrityl)-2′-deoxycytidine (compound 3) 280 mg (MW 8553, 0.33 mmol) was placed in a flask and dried under high vacuum before it was dissolved in anhydrous THF. The solution was placed in an ice-water bath under dry argon tetra-Butylammonium fluoride 0.44 ml (1M solution in THY, 1.2 eq.) and acetic acid 0.03 ml (1.2 eq.) were injected dropwise simultaneously to make solution pH keep about 7. The reaction mixture was stirred for overnight before it was completed (monitored on TLC, 3% methanol in dichloromethane, Rf=0.35). The crude product was extracted by EtOAc and NaCl solution (sat.) three times, and the combined organic layer was dried over anhydrous MgSO4, followed by filtration and solvent evaporation. The residue was purified on a silica gel column (equilibrated with CH2Cl2) and eluted with a methanol/dichloromethane gradient (0.5-5%) to afford the desired product compound 4225 mg. (yield=91%). 1H-NMR (400 MHz, DMSO) δ: 2.04 (s, 3H, SeCH3), 2.21-2.26 and 2.69-2.76 (2×m, 2H, H-2′), 3.34-3.47 (2×m, 2H, H-5′), 3.79 (s, 6H, 2×OMe), 4.15-4.17 (m, 1H, H-3′), 4.46-4.48 (m, 1H, H-4′), 6.14-6.17 (t, J=6.4 Hz, 1H, H-1′), 6.84-7.79 (m, 18H, arom-H), 8.48 (s, 1H, H-6). 13C NMR (100 MHz, DMSO) δ: 11.02 (SeCH3), 41.99 (C-2′), 55.27 (OMe), 63.11 (C-5′), 72.41 (C-3′), 86.67 (C-4′), 86.94 (arom-C), 87.87 (C-1′), 102.39 (C-5), 113.31 (arom-C), 127.07 (arom-C), 128.04 (arom-C), 128.07 (arom-C), 128.29 (arom-C), 129.68 (arom-C), 129.45 (arom-C), 130.00 (arom-C), 130.92 (arom-C), 132.70 (arom-C), 134.22 (arom-C), 135.47 (NHCO), 144.41 (arom-C), 144.32 (C-2), 150.83 (C-6), 158.69 (C-4), 172.28 (arom-C).
Reaction SMILES: [C:1]1(=[O:12])[O:11][C@@H:5]2[C@@H:6]([C:8]([O:10][C@@H:4]2[C@H:2]1[OH:3])=[O:9])[OH:7]>O>[O:9]=[CH:8][C@@H:6]([C@H:5]([C@@H:4]([C@@H:2]([CH2:1][OH:12])[OH:3])[OH:10])[OH:11])[OH:7]
Reactant: O=C1O[C@H]2[C@H](OC(=O)[C@@H]2O)[C@@H]1O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 5 h

Procedure:
Isolation of crystalline D-glucaro-1,4:6,3-dilactone--The syrup was transferred with a few mL of water to a large 1 L round-bottom flask and then concentrated under reduced pressure to a tacky solid. The flask was placed in a vacuum desiccator set at <0.1 torr and 50° C. for 5 hours. As a result of this treatment, the solid swelled into a white foam filling the flask. The flask was removed from the desiccator and the foam was broken up within the flask and stirred to a powder using a spatula. The powder in the flask was returned to the vacuum desiccator where it remained for 36 hours at <0.1 torr and approximately 45° C. A sample of the resultant beige colored powder was subjected to 1H NMR analysis. The analysis indicated that virtually all of the glucaric acid present had been converted to D-glucaro-1,4:6,3-dilactone. 40 mL of dioxane was added to the flask and the powder dissolved with vigorous shaking. When this solution was transferred to a smaller 250 mL round-bottom flask, D-glucaro-1,4:6,3-dilactone crystals (which is a direct crystalline form of glucaric acid) began to form spontaneously. The 250 mL flask was placed in a desiccator and crystallization was allowed to continue overnight. The crystal mass was stirred to a slurry, and the mother liquor was removed by suction in a Buchner funnel. The crystals were washed once with approximately 15 mL of a cold 3:1 (v/v) mixture of dioxane:CH2Cl2 and placed in a desiccator for 24 hours at 45° C. The weight of the crystals was 5.83 g which is 24.1% of the theoretical yield from glucose.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]([F:19])([F:18])[C:13](=[CH2:17])[C:14]([OH:16])=[O:15].C1(O)C=CC(O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][CH2:17][CH:13]([C:12]([F:19])([F:18])[F:11])[C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2ncsc2c1
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)C(CNc1ccc2ncsc2c1)C(F)(F)F
Yield: 19.7 %

Procedure:
Benzothiazol-6-ylamine (1 g, 6.66 mmol) was reacted with 2-trifluoromethyl-acrylic acid (1.39 g, 9.99 mmol), benzene-1,4-diol (51.3 mg, 0.46 mmol) and toluene (10 mL) to afford the crude product. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) afforded 380 mg of the product (19.67% yield).
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C[Si](C)(C)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[CH:9]([OH:11])[CH:5]1[CH:4]2[CH2:3][CH2:2][N:1]([CH2:7][CH2:6]2)[CH2:8]1
Reactant: CCOC(=O)C12CCCN(CC1)C2
Reactant: C[Si](C)(C)c1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1nccs1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (±) 3-formyl-1-azabicyclo[2.2.2]octane (D32) (2 5g, 0.018 moles) and 2-trimethylsilyl-1,3-thiazole (2.7g, 0.017 moles) was stirred together without solvent at room temperature for 3h. The mixture was diluted with tetrahydrofuran (100ml) and then treated with tetrabutylammonium fluoride trihydrate (5.4g, 0.017 moles). After 1h the mixture was concentrated in vacuo and the residue partitioned between saturated potassium carbonate solution and chloroform. The organic layer was dried (Na2SO4) and evaporated to dryness. The residue was subjected to column chromatography on TLC alumina eluting with 0.5% methanol/chloroform. This gave an oil which was triturated with diethylether/methanol to yield the title compound (D33) as a buff solid (0.5g, 13%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17](OCC)=O)=[CH:15][S:14][C:13]1=[N:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:46][NH:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1>O1CCCC1.O>[Cl:55][C:52]1[CH:53]=[CH:54][C:49]([CH2:48][N:47]([CH2:17][C:16]2[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:13](=[N:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=3)[S:14][CH:15]=2)[CH3:46])=[CH:50][CH:51]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCNC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(Cl)cc1)Cc1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 23.1 %

Procedure:
The compound (300 mg) obtained in Example 208 (2) and triethylamine (101 mg) were dissolved in tetrahydrofuran (30 ml), and thereto was added dropwise methanesulfonyl chloride (115 mg) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hour, and thereto was further added N-methyl-4-chlorobenzylamine (1.04 g), and the mixture was further stirred for one hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (2:1)] to give the title compound (83 mg) as oil. (2)N-[3-(3-Aminopropyl)-4-{[(4-chlorobenzyl)(methyl)amino]methyl}thiazol-2(3H)-ylidene]-4-(trifluoromethoxy)aniline