Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([O:35][Si](C(C)(C)C)(C)C)[CH:34]=1)[CH2:12][C@@H:13]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([OH:35])[CH:34]=1)[CH2:12][C@@H:13]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(OCc2ccccc2)cc(O[Si](C)(C)C(C)(C)C)c1)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(O)cc(OCc2ccccc2)c1)C(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 12I from 1.30 g (2.2 mmol) of benzyl 3-(benzyloxy)-N-(tert-butoxycarbonyl)-5-{[tert-butyl(dimethyl)silyl]oxy}-L-phenylalaninate (Example 5J) and 4.4 ml (4.39 mmol) of a 1N tetrabutylammonium fluoride solution in THF.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][C@@H:11]([OH:13])[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][C@H:11]1[CH2:10][CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1)(=[O:26])=[O:25]
Reactant: O[C@H]1CCO[C@@H](c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCO[C@@H](c2ccccc2)C1
Yield: 62.6 %

Procedure:
A solution of cis-2-phenyltetrahydro-2H-pyran-4-ol (1 g) in DCM (20 mL) was cooled in an ice-salt water bath and treated with DIEA (2.2 g) and methanesulfonyl chloride (0.7 g) for 2 hours. The mixture was diluted with DCM (50 mL) and washed with water and brine. The organic layer was dried and concentrated. Preparative TLC provided 0.9 g of cis-2-phenyl-tetrahydro-2H-pyran-4-yl methanesulfonate.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH2:23][C:24](=[O:28])[NH:25]3)=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O>C(O)C.N1CCCCC1>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23](=[CH:34][C:30]4[NH:29][CH:33]=[CH:32][CH:31]=4)[C:24](=[O:28])[NH:25]3)=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)ccc2C1=Cc1ccc[nH]1

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 1.1 mmol) in DMF (1 ml) is added N-(3-amino-phenyl)-benzamide (0.26 g, 1.2 mmol), N,N-diisopropylethylamine (0.44 g, 3.4 mmol) and HATU (0.47 g, 1.24 mmol). The reaction is stirred for 20 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (3-benzoylamino-phenyl)-amide as off-white solid. This amide (15 mg, 0.04 mmol) is then heated with 1H-pyrrole-2-carbaldehyde (6.0 mg, 0.06 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine at 80° C. for 20 hours. The mixture is concentrated and the desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 6.41 (s, 1H), 6.93 (s, 1H), 7.31 (t, 1H, J=7.8 Hz), 7.44 (s, 1H), 7.48-7.51 (m, 3H), 7.54 (t, 2H, J=7.2 Hz), 7.59 (d, 1H, J=6.6 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 8.33 (s, 1H), 10.27 (s, 1H), 10.31 (s, 1H), 11.13 (s, 1H), 13.38 (s, 1H); LC-MS: 449.1 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.Cl.Cl.[NH2:25][C@H:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:25][C@H:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)=[O:16]
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N[C@@H]2CN3CCC2CC3)c(OC)c1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
4.0 ml of DMF, N,N′-Diisopropylethylamine (5.6 ml, 32.14 mmol), and 2,4-Dimethoxybenzoic acid (1.75 g, 9.64 mmol) was added to a flask charged with (S)-(−)-3-Aminoquinuclidine dihydrochloride (1.60 g, 8.03 mmol) and stirred ice-water bath under nitrogen atmosphere. To the mixture was added 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (3.05 g, 8.03 mmol) then mixture temperature was raised to ambient temperature slowly by removing the ice-water bath for 60 minutes. Reaction mixture was worked up by addition of 1N sodium hydroxide aqueous solution and extracted twice with ethyl acetate, combined organic layer was washed with saturated brine solution, dried over sodium sulfate, filtered, and concentrated to crude clear oil. Purification via preparative HPLC to obtain pure product of (S)-2,4-dimethoxy-N-(quinuclidin-3-yl)benzamide, (1.95 g, 84% yield) 1H NMR (400 MHz, Methanol-D4) δ (ppm): 7.42 (m, 1H), 7.11 (s, 2H), 4.45 (m, 1H), 3.95 (s, 3H), 3.83 (m, 1H), 3.80 (s, 3H), 3.39-3.27 (m, 5H), 2.37 (m, 1H), 2.19 (m, 1H), 2.11 (m, 2H), 2.01 (m, 1H). C16H22N2O3 =290.16 LCMS (M+H): m/z 291
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[NH2:26]/[C:27](/[CH3:36])=[CH:28]\[C:29]([O:31][CH:32]1[CH2:35][CH2:34][CH2:33]1)=[O:30]>C(O)C>[C:15]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:28]([C:29]([O:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:30])=[C:27]([CH3:36])[NH:26][C:23]=1[CH3:24])(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)c1ccccc1
Reactant: C/C(N)=C/C(=O)OC1CCC1
Solvent: CCO
Product: CC1=C(C(=O)OC2CCC2)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)c2ccccc2)=C(C)N1

Procedure:
340 mg (1.02 mmol) of 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-1-phenylbutane-1,3-dione are dissolved with 156 mg (1.8 mmol) of cyclobutyl 3-aminocrotonate in 5 ml of ethanol and heated under reflux under argon for 24 h. The reaction solution is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 206 mg (43% of theory) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].C1C(=O)N([Br:22])C(=O)C1>C1COCC1>[Br:22][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[C:4]([O:13][CH3:14])[CH:5]=1
Reactant: COc1ccc2ccccc2c1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1cc(Br)c2ccccc2c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To the solution of 1,2-dimethoxynaphthalene (3.83 g, 20.3 mmol) in THF (100 mL) was added dropwise at 0° C. a solution of NBS (3.62 g, 20.3 mmol) in THF (50 mL). After stirring at 0° C. for 0.5 h, the solvent was removed in vacuo and CCl4 was added. The mixture was filtered and the filtrate was concentrated. Column chromatography yielded the title compound as a yellow oil (3.72 g, 68%). 1H NMR (CDCl3) δ 8.1 (m, 2H), 7.60 (s, 1H), 7.49 (m, 2H), 3.99 (s, 3H) 3.98 (s, 3H); MS m/z 267 (M−H).
Reaction SMILES: C[O:2]C1C=C(OC2C=CC(O)=CC=2)C2CC(C3C=CC(OC)=CC=3)CCC=2C=1.Cl.ClCCN1CCCCC1.CO[C:41]1[CH:42]=[C:43]([O:59][C:60]2[CH:74]=[CH:73][C:63]([O:64][CH2:65][CH2:66][N:67]3[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]3)=[CH:62][CH:61]=2)[C:44]2[CH2:45][CH:46]([C:51]3[CH:56]=[CH:55][C:54]([O:57]C)=[CH:53][CH:52]=3)[CH2:47][CH2:48][C:49]=2[CH:50]=1>>[OH:57][C:54]1[CH:53]=[CH:52][C:51]([CH:46]2[CH2:47][CH2:48][C:49]3[C:50]([OH:2])=[CH:41][CH:42]=[C:43]([O:59][C:60]4[CH:61]=[CH:62][C:63]([O:64][CH2:65][CH2:66][N:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)=[CH:73][CH:74]=4)[C:44]=3[CH2:45]2)=[CH:56][CH:55]=1
Reactant: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCCN5CCCCC5)cc4)c3C2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(O)cc4)c3C2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc(C2CCc3c(O)ccc(Oc4ccc(OCCN5CCCCC5)cc4)c3C2)cc1

Procedure:
Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenoxy}ethyl}piperidine (180 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (104 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[O:12][N:11]=2)=[CH:6][CH:5]=1.N1C=CC=CC=1.F[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:32]([C:31]4[CH:35]=[CH:36][CH:28]=[CH:29][CH:30]=4)=[O:33])[CH2:16]3)[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2noc(C3CCCNC3)n2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-c2noc(C3CCCN(C(=O)c4ccccc4)C3)n2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
To a mixture of 3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (0.320 g, 1.08 mmol) in THF (2.3 ml, 0.5M) was added Pyridine (0.3 ml, 3.78 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (0.172 g-0.87 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/MeOH: 99/1) to afford 0.26 mg (66%) of {3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-phenyl-methanone as a white powder.
Reaction SMILES: O1CCOCC1.[C:7](O)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[N:17]1([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:7]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:18][CH2:19]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Yield: 23 %

Procedure:
To a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride were added 1.2 g of benzoic acid and 3.0 g of 5-(1-piperazinylcarbonyl)oxindol hydrochloride. To this mixture, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide dissolved in 5 ml of methylene chloride was added dropwise at 10° to 20° C. under ice-cooling externally with stirring. Then, the mixture was stirred for 3.5 hours at the same temperature. Crystals which precipitated were filtered off, and the filtrate was concentrated to dryness under reduced pressure. The resultant residue was dissolved in 100 ml of methylene chloride, and the organic layer was washed, in turn, with 5% aqueous hydrochloric acid solution, 5% aqueous sodium hydrogen carbonate solution, and water, and dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was distilled off and the residue was recrystallized from methanol to give 0.79 g of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([CH:11]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([F:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])=[CH:29][CH:28]=3)[CH:13]2[C:24]([OH:26])=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][CH:12]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([F:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])=[CH:31][CH:32]=3)[CH:13]2[C:24]([OH:26])=[O:25])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C=C(c3ccc(CCCOc4c(F)ccc(F)c4Cl)cc3)C(C(=O)O)[C@@H](C1)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(c3ccc(CCCOc4c(F)ccc(F)c4Cl)cc3)C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 250 mL round-bottom flask equipped with a magnetic stirrer is suspended compound B1 (1.17 g, 1.80 mmol) and Pd/C (10% w/w, 1.20 g) in MeOH (100 mL). The resulting suspension is deoxygenated and then flushed with H2 gas for 15 min. Finally, the reaction mixture is vigorously stirred at rt under a static H2 atmosphere maintained with a balloon. After 2 h, quantitative consumption of compound B1 can be discerned. The reaction vessel is then vigorously purged with N2 and the suspension is filtered through a bed of Celite and SiO2. After washing the insolubles with copious quantities of CH2Cl2 and EtOAc, the filtrate is concentrated in vacuo to the title compound as a mixture of four diastereomers (1.116 g, 95% crude yield, ES−=648.9). This material is used further without purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])C[CH2:15][CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].ClC1N(C)C(=O)C2C(=C(I)C=CC=2)N=1.Cl.CC1(N)CC1>>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:15][CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19]
Reactant: Cn1c(NC2(C)CCC2)nc2c(I)cccc2c1=O
Agent: CC1(N)CC1
Agent: Cl
Agent: Cn1c(Cl)nc2c(I)cccc2c1=O
Product: Cn1c(NC2(C)CC2)nc2c(I)cccc2c1=O
Yield: 80 %

Procedure:
This compound (0.71 g, 80% yield) as a yellow crystalline solid was prepared according to the procedure described for intermediate 711, using 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700) (0.80 g, mmol), 1-methylcyclopropanamine hydrochloride (ChemBridge, San Diego, Calif.; 0.471 g, 4.38 mmol), and TEA (2.1 mL, 15.10 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, dd, J=7.5, 1.3 Hz), 7.93 (1H, dd, J=7.9, 1.3 Hz), 7.49 (1H, s), 6.89 (1H, t, J=7.7 Hz), 3.32 (3H, m), 1.58 (3H, s), 0.84 (2H, m), 0.74 (2H, m). m/z (ESI, +ve) 355.9 (M+H)+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][S:6][CH2:5][S:4]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1>[C:17]1([CH3:18])[CH:19]=[CH:20][C:14]([S:11]([O:1][CH2:2][C:3]2([CH2:9][O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH2:8][CH2:7][S:6][CH2:5][S:4]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: OCC1(CO)CCSCS1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCSCS2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4,4-bis(hydroxymethyl)-[1,3]dithiane (405 mg, 2.25 mmol) and TsCl (1.29 g, 6.75 mmol) in anhydrous pyridine (4 mL) was stirred at rt for 48 h. Solvent was removed in vacuo and co-evaporated with toluene (3×3 mL). CH2Cl2 (40 mL) and sat aq NaHCO3 (40 mL) were added, the phases separated and the organic phase dried (Na2SO4), filtered and concentrated under reduced pressure. The residue obtained was flash chromatographed (35-55% EtOAc in light petroleum) to provide 4,4-bis(p-toluenesulphonyloxymethyl)-[1,3]dithiane (525) as a white solid material.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([NH:14][NH2:15])=O)=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:21][CH:22]=1>C(O)CCC>[CH3:28][N:26]1[CH:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:14]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][N:3]=[CH:4]5)=[N:19][N:18]=3)[N:15]=2)[CH:24]=[N:25]1
Reactant: NNC(=O)Cc1ccc2ncncc2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CCCCO
Product: Cn1cc(-c2ccc3nnc(Cc4ccc5ncncc5c4)n3n2)cn1
Temperature: 25 °C
Yield: 5.7 %

Procedure:
Quinazolin-6-yl-acetic acid hydrazide (0.032 g, 0.158 mmol) and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (0.031 g, 0.158 mmol) were heated to 165° C. in butanol (2 mL) for five hours. The reaction was cooled to room temperature, evaporated in vacuo and purified via silica gel column chromatography eluting with 5% methanol in dichloromethane to give 0.00311 g (7%) of 6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinazoline. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.29 (s, 1H), 8.06 (d, 2H, J=9.6 Hz), 7.60 (d, 2H, J=9.6 Hz), 7.55 (m, 1H), 7.17 (d, 1H, J=8.0 Hz), 6.08 (s, 1H), 4.58 (m, 2H), 3.89 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for C18H14N8; found: 343.3 (M+H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([OH:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([O:30][CH2:10][O:11][CH3:12])[CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COCCl
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOc1cc(OCc2ccccc2)ccc1C=O

Procedure:
N,N-diisopropylethylamine (1.98 ml) and chloromethyl methyl ether (0.76 ml) were added to a solution of 4-benzyloxy-2-hydroxybenzaldehyde (2071 mg) in tetrahydrofuran (30 ml), and this reaction mixture was stirred and heated under reflux for 19 hours. N,N-diisopropylethylamine (2.7 ml) and chloromethyl methyl ether (1.04 ml) were further added, and the resulting mixture was stirred and heated under reflux for another 10 hours. After water was added, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, then filtered through silica gel and alumina. The filtrate was concentrated under reduced pressure to give the title compound (2470 mg). This compound was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[N:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 38 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (120 mg, 0.4 mmol), using 1-(6-chloro-3-pyridinyl)-1-ethanone instead of 4-fluoroacetophenone, was converted to the title compound (64 mg, 38%) which was obtained as a light yellow solid. MS: m/e=417.2 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-:20]#[N:21].[K+]>CN(C=O)C>[F:19][C:16]([F:17])([F:18])[C:13]1([CH2:12][C:20]#[N:21])[CH2:14][CH2:15]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCC1(C(F)(F)F)CC1
Temperature: 60 °C
Yield: 39.4 %

Procedure:
Treat a solution of (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (12 g, 40.8 mmol) in DMF (150 mL) with potassium cyanide (3.5 g, 53 mmol) and heat at 50-70° C. for 3 days. Add water, extract with EtOAc (3×), wash the combined organics with water, then brine, dry and concentrate under reduced pressure to give the title compound (2.4 g, 39%). 1H NMR (400 MHz, CDCl3): δ 2.81 (s, 2H), 1.24-1.18 (m, 2H), 0.95-0.92 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[NH:16][C:17]([NH2:19])=[S:18].FC(F)(F)C(O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]3[S:18][C:17]([NH2:19])=[N:16][N:12]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(N)=S
Reactant: N#Cc1ccc(N2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nnc(-c2ccc(N3CCCCC3)cc2)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
To a solution of 4-piperidin-1-yl-benzonitrile (3 g) and thiosemicarbazide (1.8 g) in toluene (30 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred at 60° C. for 6 hours. The reaction mixture was placed in water, the solution was adjusted to pH 9 with 1N sodium hydroxide and the precipitate was collected by filtration to give 5-(4-piperidin-1-yl-phenyl)-[1,3,4]thiadiazol-2-yl-amine (3.58 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:14]#[N:15])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1
Product: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
A mixture of 6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (200 mg) and POCl3 (10 mL) was heated to 90 C for 18 h. The reaction was concentrated, and the residue was dissolve in EtOAc, cooled to 0 C, and quenched by careful addition of saturated aqueous sodium bicarbonate. The mixture was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous solution was washed twice with EtOAc. The combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography (25 g silica, 3-30% EA/hex) gave a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH2:18])=O)=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]#[N:18])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
78 g (290 mmol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide were suspended in 380 ml of dioxan and 68 ml of pyridine and treated dropwise at 0° with 59 ml (424 mmol) of trifluoroacetic anhydride. After stirring at 50° for two hours the reaction mixture was poured into 2 l of ice-water and the crystals were filtered off under suction, rinsed with water and dried. There were obtained 60 g (82%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile of m.p. 232°-234°.