Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[C:22][Si](C)(C)C)[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-]>CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[CH:22])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C#C[Si](C)(C)C)c2c(N)ncnn12
Agent: O=C([O-])[O-]
Solvent: CO
Product: C#Cc1cc([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)n2ncnc(N)c12
Yield: 27.9 %

Procedure:
a solution of Compound 16 (2.0 mg, 5.3 μmol) in methanol (0.20 mL) was stirred with MP-carbonate (2.9 mmol/g, 18 mg, 53 μmol) for 30 min. The solution was decanted from the resin and concentrated in vacuo, affording rendering Compound 17 (0.45 mg, 28%) as a white solid: ESI-MS m/z 305.2 ([M+H]+); 1H NMR (d6-DMSO) δ 7.92 (s, 1H), 6.97 (s, 1H), 5.35 (s, 1H), 4.91-4.73 (m, 3H), 4.38 (s, 1H), 3.76-3.57 (m, 4H), 0.80 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[C:37](=O)([O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[O:38]N1C(=O)CCC1=O>O1CCOCC1.C(Cl)Cl>[CH3:50][Si:49]([CH3:52])([CH3:51])[CH2:48][CH2:47][O:46][C:37]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCN(C(=O)OCC[Si](C)(C)C)CC4)sc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (450 mg, 1.083 mmol) in dioxane (10 mL) was added Et3N (0.45 mL, 3.25 mmol) followed by 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (281 mg, 1.083 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (30 mL), washed with water (30 mL) and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 35% EtOAc) to afford tert-butyl 4-(2-(1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (555 mg, 0.991 mmol, 92% yield) as a white solid. LCMS (m/z)=560 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Yield: 75.2 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (360 mg, 0.97 mmol), ethyl isonipecotate (460 mg, 2.91 mmol), diisopropylethyl amine (0.51 mL, 2.91 mmol) and a catalytic amount of DMAP in dioxane (15 mL) was heated at 120° C. in a sealed tube until consumption of the limiting reagent, as judged by TLC. The reaction mixture was then cooled and partitioned between EtOAc and water. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified with a silica gel column and 0-50% EtOAc in hexanes gradient to afford the product (360 mg, Yield 75%). HRMS m/z calcd for C21H24N3O3I [M+H]+: 494.0935. Found: 494.0935.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>O1CCCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(N)cc1-c1nnn[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(NC(=O)c2ccccc2)cc1-c1nnn[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 3-trifluoromethylphenyl-4-amino-2-(5-tetrazolyl)phenyl urea (0.36 g, 5 1.0 mmol) in tetrahydrofuran (40 mL) was added triethylamine (0.17 mL, 1.2 mmol). The solution was cooled on an ice bath and benzoylchloride (0.14 mL, 1.2 mmol) was added. The reaction was stirred at 0° C. for another 30 min. The reaction was poured into water. The precipitate was filtered off and re-crystallised from 96% ethanol to give 0.28 g of the desired material. M.p. 271-272° C.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:27])[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17][CH2:16]1.Cl>S(Cl)(Cl)=O.CN(C)C=O>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:25][C:21]2[CH:22]=[CH:23][C:24]3[C:15]([CH3:14])([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[C:19]=3[CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: CC1(C)CCC(=O)c2cc(N)ccc21
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of monomethyl terephthalate (VIIIa) (2.86 g, 15.89 mmoles) in thionylchloride (50 mL) with 2 drops of N,N-dimethylformamide was allowed to stir at room temperature. The mixture became homogeneous within 30 minutes and was then concentrated in vacuo. The residue was then taken up in 30 mL of anhydrous pyridine and treated with 4,4-dimethyl-7-amino-1-tetralone (3.00 g, 15.9 mmoles). After 16 hours at room temperature 1N HCl was added to the mixture. It was extracted with ethyl acetate, washed with 1N HCl (4×200 mL) and washed with saturated sodium bicarbonate (2×200 mL). The organic phase was then separated, dried over magnesium sulfate, and concentrated in vacuo to give 5.07 g (Y: 91% ) of the title compound; 1H-NMR (CDCl3): δ8.27 (dd, J=8.7, 2.5 Hz, 1H), 8.19 (bs, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 2.70 (t, J=7.0 Hz, 3H), 2.00 (t, J=7.0 Hz, 3H), 1.38 (s, 6H); MS (DCI) m/e: 352 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].Cl[CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>CN(C)C=O>[OH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[O:4][CH2:3][CH2:2][OH:1]
Reactant: OCCOCCCl
Reactant: Nc1ccccc1OCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCCOCCNc1ccccc1OCCO
Temperature: 90 °C
Reaction time: 96 h
Yield: 53 %

Procedure:
6 g (39.17 mmol) 2-(2-hydroxyethoxy)aniline A3, 5 ml (5.85 g, 47 mmol) 2-(2-chloroethoxy)ethanol and 8.19 ml (5.95 g, 58.75 mmol) triethylamine were dissolved in 20 ml dimethylformamide and stirred for 4 days at 90° C. After cooling, the solution was filtered, the precipitate washed with dichloromethane and the filtrate concentrated in vacuo. The residue was taken up in chloroform and washed twice with a small quantity of water. The chloroform solution was then dried over sodium sulfate and concentrated. The viscous crude product was purified by column chromatography on silica gel 60 with toluene/acetone 1:2 as the mobile phase. 5 g of brown, viscous oil were obtained; yield 53%.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:5]([CH3:14])=[N+:6]([O-:13])[C:7]([N+]([O-])=O)=[CH:8][CH:9]=1.[CH3:15][OH:16]>>[CH3:2][O:3][C:4]1[C:5]([CH3:14])=[N+:6]([O-:13])[C:7]([O:16][CH3:15])=[CH:8][CH:9]=1
Reactant: COc1ccc([N+](=O)[O-])[n+]([O-])c1C
Reactant: CO
Agent: [Na]
Product: COc1ccc(OC)[n+]([O-])c1C

Procedure:
1.15 g (50 mmol) of sodium were dissolved in 100 ml of anhydrous methanol, and after that 7.4 g (40 mmol) of 3-methoxy-2-methyl-6-nitropyridine N-oxide were added at 20° C. and while stirring. The mixture was then heated to reflux for 3 h and, after having been cooled down, concentrated in vacuo; the residue was taken up in water and this mixture was extracted with dichloromethane; the organic phase was dried and concentrated and the residue was crystallized using diisopropyl ether. 7 g of product were obtained, m.p. 63°-65° C.
Reaction SMILES: C(OC([NH:8]OS(C1C(C)=CC(C)=CC=1C)(=O)=O)=O)(C)(C)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH2:30][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][N:32]=2)=[CH:25][CH:24]=1>C(O)(C(F)(F)F)=O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][N:32]3[N:8]=2)=[CH:25][CH:24]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Reactant: N#Cc1ccc(CC(=O)c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2cc(-c3ccc(F)cc3)nn2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine (13.0 g 41.8 mmol)1 was added portionwise with stirring to TFA (40 ml) over 10 min then stirred for a further 30 minutes. The solution was poured onto ice (250 ml) and left until the ice melted. The resulting white solid was filtered off, washed with water, and dissolved in DCM (300 ml). The solution was dried over 4 Å mol. sieves for 1.5 hours, filtered and 6-[2-(4-fluorophenyl)-2-oxoethyl]nicotinonitrile (3.32 g 13.8 mmol) was added. The reaction was stirred at room temperature for 4 days, washed with water (100 ml), dried and purified by column chromatography. Elution with cyclohexane/ethyl acetate (3:1) gave the title compound as a yellow solid (0.6 g 18%). NMR: (CDCl3): δ 6.87 (1H, s) 7.15-7.20 (3H, m) 7.57 (1H, dd) 7.95 (2H, m) 8.84 (1H, d). Ref 1 Josef G Krause, Synthesis, 1972, 140.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.53 g, 4.77 mmol) in DMF (10 mL) was added NIS (1.18 g, 5.24 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h at ambient temperature, the reaction was quenched with saturated NH4Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL×3) and brine (30 mL) successively, dried over Na2SO4 and concentrated in vacuo to give the desired product (yellow solid, 1.90 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=10.3 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.64 (dd, J=14.3, 8.3 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2ccc(Br)cc2)cc1
Yield: 73.1 %

Procedure:
Methyl 4-hydroxybenzoate (1.09 g, 7.14 mmol), 2-(4-bromophenyl)ethanol (1.44 g, 7.14 mmol), and triphenylphosphine (2.06 g, 7.86 mmol) were dissolved in THF (44 mL), and then diethyl azodicarboxylate (3.57 mL, 40% toluene solution, 7.86 mmol) was added thereto while stirring under ice-cooling. The mixture was further stirred at room temperature for 2 days, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 19:1 to 9:1, v/v) to give 1.75 g of the title compound (white powder, yield: 73%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.C(Cl)(Cl)[Cl:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH:37]=O)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[ClH:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH2:37][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: ClC(Cl)Cl
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 40 %

Procedure:
Racemic 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (50 mg, 0.166 mmol) was stirred in 9:1 v:v chloroform:methanol (2 ml) with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d)) (28 mg, 1.0 equivalent) at room temperature for 30 minutes, then the mixture was treated with sodium triacetoxyborohydride (105 mg, 3.0 equivalents) with vigorous stirring. After a further 25 minutes stirring, the reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (2 ml), diluted with dichloromethane and stirred vigorously at room temperature for 20 minutes. The organic phase was separated (hydrophobic fit) and evaporated under reduced pressure to give an orange gum; this was purified by column chromatography on silica (eluting with 0-12% (2M NH3 in MeOH) in DCM). Appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a cream amorphous solid (30 mg, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nc1
Yield: 110.3 %

Procedure:
A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 1 of Example 2 in 6000 mL of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g (173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3 δ4.42 (s, 2H), 7.48 (d, J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H).
Reaction SMILES: [C:1]([O:20][CH2:21][C:22]([OH:24])=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)O.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:22](=[O:24])[CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of 2-(trityloxy)acetic acid (7.2 g, 22.62 mmol) in DCM (250 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (7.92 g, 18.85 mmol), EDC (4.34 g, 22.62 mmol), and DMAP (4.60 g, 37.7 mmol) were added at RT. The solution was stirred at the same temperature overnight. A sat. sol. of K2CO3 was added, and the organic phase was separated, washed with HCl 2N and brine, dried over Na2SO4 and evaporated under vacuum. The resulting brown crude was purified by flash chromatography on silica gel (DCM 100% as eluent). (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(trityloxy)acetoxy)ethyl)pyridine 1-oxide was obtained (8.53 g, 11.84 mmol, 62.8% yield, MS/ESI+ 720.1 [MH]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.Cl[CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]=1[CH3:38]>>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[C:7]2([CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:37]=1[CH3:38])[CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]=1[CH3:38]
Reactant: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2(Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C

Procedure:
Following the same procedure as described in example 14A, the reaction of the title compound of 13A (0.191 g, 0.49 mmol) and 4-chloromethyl-5-methyl-1-trityl-1H-imidazole (0.55 g, 1.48 mmol) yielded the title compound of 15A (282.2 mg, 71% yield).
Reaction SMILES: C1(N2C=NC3C2=NC(OCC)=NC=3N)CCCC=C1.[CH:20]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N:30][C:31]=3[NH2:35])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>>[CH2:37]([O:36][C:29]1[N:28]=[C:27]2[C:32]([N:33]=[CH:34][N:26]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:31]([NH2:35])[N:30]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Product: CCCCCCOc1nc(N)c2ncn(C3CCCCC3)c2n1
Yield: 90 %

Procedure:
The procedure of Example 8 was repeated except that the 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine used therein was replaced by an equivalent weight of 9-(2-cyclohexenyl)-2-n-hexyloxy-9H-adenine. There was produced the title product in 90% yield; m.p. 57°-60° C. IR(neat): 3500, 1635, 1595, 1500, 1465, 1420, 1400 cm-1. UV: λmaxEtOH 253 nm(ε 7200), 270 nm(ε 10900). NMR(CDCl3): 1.5(21H, m), 4.25(2H, t, J=6.5 Hz), 4.40(1H, m), 6.07(2H, s), 7.54(1H, s).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:10][C:4]=2[N:3]=1.[Cl-].Cl[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][NH+:21]=1.O>C(O)C.[OH-].[Na+]>[CH3:27][O:26][C:24]1[C:23]([O:28][CH3:29])=[CH:22][N:21]=[C:20]([CH2:19][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:10][C:4]=3[N:3]=2)[CH:25]=1
Reactant: FC(F)(F)COc1ccc2[nH]c(S)nc2c1
Reactant: COc1c[nH+]c(CCl)cc1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cnc(CSc2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1OC
Reaction time: 20 h

Procedure:
1.0 g of 2-mercapto-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole is dissolved in 15 ml of ethanol and 8.5 ml of 1N sodium hydroxide solution, 0.90 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride are added and the mixture is stirred for 20 hours. After addition of 30 ml of water, the mixture is extracted three times with 30 ml of methylene chloride each time, the methylene chloride phase is washed once with 5 ml of 0.1N sodium hydroxide solution, the combined organic phases are dried over magnesium sulfate and, after the drying agent has been filtered off, the filtrate is completely concentrated. 1.51 g (94% of theory) of the title compound are obtained as an amorphous solid residue of m.p. 55°-57° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:18])([F:19])[F:17])[CH2:12][C:11]([C:5]2[C:6]3[O:10][CH2:9][O:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c2c1OCO2
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3ccc(Cl)c4c3OCO4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 70 mg (0.21 mmol) of 4-(7-chlorobenzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 50 mg (0.25 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 0.5 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%), 60 mg (55% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH2:1]([N:9]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:13][CH2:14]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(CCc4ccccc4)CC3)nn12

Procedure:
A mixture of 1-phenethylpiperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-(4-phenethylpiperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.