Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:14](Cl)[O:15][CH2:16][CH2:17][O:18][CH3:19]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[O:10][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:5]=[O:6]
Reactant: COCCOCCl
Reactant: O=Cc1cc(I)c(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1c(I)cc(C=O)cc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a stirred solution of 3,5-diiodo-4-hydroxybenzaldehyde (10.0 g, 26.7 mmol) in THF (267 mL) at 0° C. was added NaH (1.39 g, 34.7 mmol). After 0.5 h at this temperature, MEMCl (4.88 mL, 42.7 mmol) was added dropwise. The reaction mixture was stirred for another 15 min. at 0° C. and then at room temperature for 18 h. The resulting mixture was quenched with 0.1 N NaOH and extracted with Et2O (1000 mL). The organic layer was washed with 0.1 N NaOH (3×100 mL) and brine (100 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (5 to 15% EtOAc/petroleum ether gradient) to afford the product (8.60 g, 69%) as a solid; 1H NMR (CDCl3) δ 3.44 (s, 3H), 3.67 (t, J=5.5 Hz, 2H), 4.16 (t, J=5.5 Hz, 2H), 5.34 (s, 2H), 8.29 (s, 2H), 9.82 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N+:34]([O-:37])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:20][CH2:21][N:22]([C:31]4[CH:36]=[CH:35][N+:34]([O-:37])=[CH:33][CH:32]=4)[CH2:23][CH2:24]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(c2cc[n+]([O-])cc2)CC1
Temperature: 130 °C
Yield: 18 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (see stage 2 illustrative compound H-214) (200 mg, 0.486 mmol, 1 eq), 4-chloropyridine N-oxide (63 mg, 0.486 mmol, 1 eq) and DIPEA (0.210 ml, 1.215 mmol, 2.5 eq) in ethanol (10 ml) was heated for 72 h at 130° C. in a pressure vessel. The reaction mixture was concentrated under reduced pressure and the crude product was then prepurified by column chromatography (Alox, 1% methanol/dichloromethane). It was then further purified by means of preparative TLC. The desired product was in the form of a white solid. Yield: 18% (90 mg, 0.178 mmol) The indicated yield is based on 2 combined batches of size 200 mg
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:11]1[N:16]=[C:15]([C:17]2[C:18]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[C:19]3[CH2:24][CH2:23][CH2:22][N:20]3[N:21]=2)[CH:14]=[CH:13][CH:12]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:11]1[N:16]=[C:15]([C:17]2[C:18]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[C:19]3[CH2:24][CH2:23][CH2:22][N:20]3[N:21]=2)[CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: c1ccc(Cc2cccc(-c3nn4c(c3-c3ccnc5ccccc35)CCC4)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Zinc(II) chloride (0.34 mL, 1.0 M solution, 0.34 mmol) is added, at room temperature with stirring, to a solution of benzyl magnesium chloride (0.15 mL, 2.0 M solution, 0.31 mmol) in tetrahydrofuran (1 mL). After 15 min, Pd(PPh3)2Cl2 (5.4 mg, 0.0076 mmol) is added followed by a solution of 4-[2-(6-bromo-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (60 mg 0.153 mmol) in tetrahydrofuran (1 mL). The reaction mixture is stirred for 18 h at room temperature and quenched with saturated aqueous ammonium chloride (1 mL). The reaction mixture is concentrated in vacuo, filtered, and the residue chromatographed on SiO2 (20-50% acetone/hexanes) to yield the title compound, 33.4 mg (54%), as a white solid.
Reaction SMILES: [H-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](Cl)=[N+:20]([O-:25])[C:19]=1[C:26]([O:28][CH3:29])=[O:27]>C(OCC)(=O)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:16][C:11]2[CH:10]=[C:9]([Cl:8])[CH:14]=[C:13]([Cl:15])[CH:12]=2)=[N+:20]([O-:25])[C:19]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1c(Cl)ccc(Cl)[n+]1[O-]
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cl)ccc(Oc2cc(Cl)cc(Cl)c2)[n+]1[O-]
Yield: 76.5 %

Procedure:
To a dry 3-neck round bottom flask was added 60% NaH (0.432 g, 10.81 mmol), dry THF (30 mL) and 3,5-dichlorophenol (1.76 g, 10.81 mmol). The mixture was stirred until evolution of H2 (g) ceased. Methyl 3,6-dichloropyridine-2-carboxylate N-oxide (2.0 g, 9.00 mmol) was added in one portion and stirred at RT for 3 hr, diluted with ethyl acetate and 100 mL of water. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined extracts were dried (MgSO4) and concentrated to give 2.40 g of white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=2[OH:1])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccc1O

Procedure:
Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. (2-Hydroxy-5-(trifluoromethyl)benzoic acid: refer to Chem. Pharm. Bull., 1996, 44, 734.)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:9]1(N)[C:14]([F:15])=[C:13](F)[C:12](F)=[C:11]([NH2:18])[C:10]=1F.Cl.Cl>>[F:15][C:14]1[CH:9]=[CH:10][C:11]2[NH:18][C:3]3[CH2:8][CH2:7][N:6]([CH2:2][CH2:1][C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)[CH2:5][C:4]=3[C:12]=2[CH:13]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: C=Cc1ccncc1
Agent: Cl
Product: Fc1ccc2[nH]c3c(c2c1)CN(CCc1ccncc1)CC3

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception 4-vinylpyridine was used instead of 2-vinylpyridine. The product was converted to the dihydrochloride salt; mp. 233°-235° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:35][CH:36]=[C:37]([CH2:39][O:40]C3CCCCO3)[N:38]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[O:35][CH:36]=[C:37]([CH2:39][OH:40])[N:38]=4)[CH:29]=3)[CH2:26][C:25](=[O:48])[NH:18][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J2) (170 mg) and (RS)-3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl}-propionic acid tert-butyl ester (Example K11) (270 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (110 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](S(C)=O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=2)[NH2:36])[CH2:29][CH2:28]1>>[O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:36][C:35]4[CH:37]=[CH:38][CH:39]=[C:33]([N:30]5[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]5)[CH:34]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)n2n1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cccc(N6CCCS6(=O)=O)c5)n4n3)c2)CC1
Yield: 20.8 %

Procedure:
Analogous to Example 1491c, 7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfinyl)pyrrolo[2,1-f][1,2,4]triazine (90.0 mg, 0.239 mmol) and 3-(4-Methylpiperazin-1-yl)aniline (91.4 mg, 0.478 mmol) were reacted to afford 7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-N-[3-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine (25 mg, 18%). LCMS (HPLC): 0.84 min, m/z=504 (M+H); 1H-NMR (DMSO-d6): 9.29 (s, 1H), 8.99 (s, 1H), 7.86 (d, 1H, J=7.8 Hz), 7.75 (s, 1H), 7.49 (m, 1H), 7.32 (m, 2H), 7.18 (d, 1H, J=8.0 Hz), 7.11 (m, 2H), 6.96 (d, 1H, J=4.7 Hz), 6.56 (d, 1H, J=7.8 Hz), 3.73 (t, 2H, J=6.4 Hz), 3.52 (t, 2H, J=7.4 Hz), 2.99 (m, 4H), 2.37 (m, 6H), 2.20 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)([CH3:19])(=[O:18])=[O:17].O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCCO1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCCO1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A solution of (tetrahydropyran-2-yl)methanol (6 g, 51.65 moles) in methylene chloride (80 ml) at 0° C. was added with triethylamine (8.27 ml, 59.4 moles) then with mesyl chloride (4.4 ml, 56.8 moles) in methylene chloride (5 ml). The temperature was left to rise to room value and after 30 minutes the mixture was poured into water and extracted in methylene chloride. The organic phases were anhydrified and dried to give 10 g of the title product (quantitative yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+:13]=[N-:14])[C@@H:9]([NH2:15])[C@H:8]([O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:7]=1)=[O:5])[CH3:2].[CH3:22][CH2:23][O:24]C(C)=O.C([O-])(O)=O.[Na+].C(OC(=O)C)(=O)C>CCCCCC.COC(C)(C)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+:13]=[N-:14])[C@@H:9]([NH:15][C:23](=[O:24])[CH3:22])[C@H:8]([O:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 118.5 mg of 28 and 1.0 mL of EtOAc in a 5.0 mL round-bottom flask equipped with a magnetic stirrer and an inert gas supply was added 1.0 mL of aqueous 1 M NaHCO3. To the stirred mixture was added 45.4 μL of acetic anhydride and the mixture was stirred for 1 h at RT. The organic phase was separated and dried (Na2SO4, 1 g), filtered and the filter cake was washed with 2.0 mL EtOAc. The combined filtrates were evaporated at 40° C./240 to 10 mbar to afford 139 mg crude product as beige solid. The solid was suspended in 1.40 mL of n-hexane and 0.70 mL tert-butyl methyl ether, stirred for one h at RT, cooled to 0-5° C. and stirred for 2 h at 0-5° C. The suspension was filtered and the filter cake was washed with total 0.70 mL of a pre-cooled (0-5° C.) mixture of n-hexane and tert-butyl methyl ether (2/1). The filter cake was dried at 45° C./9 mbar to afford 94 mg of 30 as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.N1CCCCC1.Cl[CH2:25][CH:26]1[O:28][CH2:27]1>>[O:28]1[CH:26]([CH2:25][O:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:8][O:9][C:4]=3[CH:3]=2)[CH2:27]1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: c1ccc(C2COc3cc(OCC4CO4)ccc3C2)cc1

Procedure:
17 g 7-hydroxy-3-phenyl-3,4-dihydro-2H-1-benzopyrane, 0.1 cm3 piperidine and 100 cm3 1-chloro-2,3-epoxypropane were stirred for 6 hours at a temperature of 90° C. The solution was evaporated under reduced pressure, the residue was dissolved in 150 cm3 benzene and the obtained solution was extracted twice with 25--25 cm3 saturated sodium carbonate solution. The benzene phase was separated from the precipitated resin, clarificated with charcoal, filtered and evaporated. Crystallizing the residue from methanol, 15 g pure crystalline 1,2-epoxy-3-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane was obtained (m.p. 117°-119° C.).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH:26]([CH3:28])[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CC1CCO
Temperature: 25 °C
Reaction time: 9 h
Yield: 87.9 %

Procedure:
To a solution of the crude TBDPS-protected alcohol 11a (464 mg, 0.742 mmol) in dry THF (6 mL) at 0° C. was added TBAF (1.0M/THF, 0.93 mL, 0.927 mmol), and the reaction mixture was allowed to warm to rt while stirring under N2. Since TLC showed incomplete reaction after 5 h, 0.75 eq. TBAF (0.56 mL) was added. After 9 h, the reaction mixture was quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 177 mg (88%) of the title compound as a colorless oil which solidified upon high vacuum to give a white powder. mp 49.8-50.2° C.; [α]D22 −30.8 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 4.50 (appbd, 1 H, J=4.5 Hz), 3.66 (bs, 2 H), 2.94 (m, 1 H), 2.36 (bs, 1H), 1.82 (bs, 1 H), 1.71 (m, 1 H), 1.45 (s, 9 H), 1.39 (t, 2 H, J=7.2 Hz), 1.01 (bs, 2 H), 0.90 (dd, 6 H, J=10.2, 6.6 Hz), 0.50 (m, 1 H), 0.43-0.27 (m, 2 H); HRMS (ESI) m/z calcd for C15H29NO3Na 294.2045, found 294.2064.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.O>ClCCl>[Br:1][CH2:2][CH2:3][C:4]([NH:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: CCCCCCCCN
Reactant: O=C(Cl)CCBr
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCNC(=O)CCBr
Reaction time: 1 h
Yield: 54.3 %

Procedure:
3-Bromopropionyl chloride (25.7 g) was dissolved in dichloromethane (150 ml), cooled to -10° and a solution of octylamine (20.7 g) in dichloromethane (50 ml) was added over 10 minutes at -10° to 0°. Pyridine (12.7 g) in dichloromethane (50 ml) was added to the white suspension at -10° to 0° giving an orange solution. After stirring for 1 hour at 0°, water (100 ml) was added, the phases separated and the aqueous phase extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with dilute sodium hydroxide and water, dried over MgSO4, filtered through a bed of silica gel and evaporated to give 3-bromo-N-octylpropanamide as a colourless solid (21.49 g, 54%) (mp 48°-55°).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([O:30][CH3:31])=[O:29])[CH2:17][CH2:16]1)=O)(C)(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:31][O:30][C:28](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([N:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)=[O:32]
Reactant: COC(=O)c1ccccc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1C(=O)N1CCNCC1
Reaction time: 2 h

Procedure:
TFA (1.2 mL) was added to a stirred solution of 4-(2-Methoxycarbonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.58 mmol) in DCM (5 mL) at 0° C. The resulting mixture was stirred at the same temperature for 2 hours. DIPEA (1.5 mL) was added to the cold reaction mixture and the mixture was concentrated under reduced pressure to afford 2-(piperazine-1-carbonyl)-benzoic acid methyl ester.
Reaction SMILES: C[I:2].[CH2:3]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][CH2:24][OH:25])[N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:26]COCC>CN(C)C=O>[I-:2].[CH2:3]([NH:15][C:16]1[CH:21]=[CH:20][N+:19]([CH3:26])=[C:18]([NH:22][CH2:23][CH2:24][OH:25])[N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOCC
Reactant: CCCCCCCCCCCCNc1ccnc(NCCO)n1
Reactant: CI
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNc1cc[n+](C)c(NCCO)n1
Product: [I-]
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl iodide (0.8 ml, 0.012 m) is added to a stirred solution of 4-(n-dodecylamino)-2-(2-hydroxyethylamino)pyrimidine (3.2 g, 0.01 m) in anhydrous dimethylformamide (25 ml), and the stoppered solution allowed to stir overnight. Anhydrous ether (180 ml) is added slowly in small portions, and the resulting precipitate is allowed to age (stirring) for about one hour. The mixture is filtered, the mother liquors are displaced with small portions of ether, and the cake is washed well with ether and dried to yield 3.4 g (76%) of colorless 4-(n-dodecylamino)-2-(2-hydroxyethylamino)-1-methylpyrimidinium iodide, m.p. 118°-119° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:38]1([C@@H:48]([N:50]=[C:51]=[O:52])[CH3:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][C:51](=[O:52])[NH:50][CH:48]([C:38]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[CH:41]=[CH:40][CH:39]=4)[CH3:49])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: C[C@H](N=C=O)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2(OC(=O)NC(C)c3cccc4ccccc34)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To 15 mL dichloromethane was added 3-benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 1.00 g (1.98 mmol) and stirred to dissolve. To this was added (S)-1-(1-naphthyl)ethyl isocyanate 414 mg (2.1 mmol) and a catalytic amount of 4-dimethylaminopyridine 20 mg (0.164 mmol). The mixture was stirred at room temperature for 24 hours. The solution was washed with 50 mL water and 50 mL brine, and the organic phase was separated and dried over magnesium sulfate, then evaporated to dryness. The crude product was then purified by flash chromatography (150 g silica gel, 10% EtOAc/CH2Cl2). The product was isolated by evaporation of the appropriate fractions to give 840 mg (60%) as a white foam. The product was identified by 1H NMR, MS, [M+H]+ =704 Da. and microanalysis.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32]Cl)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1)#[N:21].C(N(C(C)C)CC)(C)C>C(#N)C>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[C:31]([CH2:32][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:16]=[CH:17][CH:18]=[C:3]([CH3:2])[CH:4]=4)([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11]3)=[CH:30][N:29]=[CH:28]2)=[CH:34][CH:35]=1)#[N:21]
Reactant: Cc1cccc(CC2(C(N)=O)CCNCC2)c1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CC2(C(N)=O)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 4-(3-methylbenzyl)isonipecotamide hydrochloride salt (134 mg, 0.5 mmol), 1-(4-cyanobenzyl)-5-chloromethyl-imidazole hydrochloride salt (134 mg, 0.5 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform saturated with ammonia gas. After collection and concentration of appropriate fractions, the residue was triturated with anhydrous diethyl ether. The white solid precipitated was filtered to provide the title compound.
Reaction SMILES: [NH:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3].[OH-].[Na+].[C:14](Cl)([Cl:16])=[O:15]>C(OCC)C.O>[Cl:16][C:14]([N:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3])=[O:15]
Reactant: O=C(Cl)Cl
Reactant: CC1CCC2CCCCC2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1CCC2CCCCC2N1C(=O)Cl

Procedure:
A mixture of 15 g decahydro-quinaldine dissolved in 200 ml of diethylether and 4 g of sodium hydroxide in 50 ml of water is reacted while stirring and cooling at -5° to 0° with 10 g of phosgene. An ethereal solution of 1-chlorocarbonyl-2-methyl-decahydro-quinoline is obtained. When an aqueous solution of 8.4 g of sodium ethylmercaptide is added to the ethereal solution at room temperature with stirring, 16 g of an almost colorless oil are obtained. The physical constants of this oil coincide with those of the compound of Example 1.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][NH:17]2)=[O:15])=[CH:5][CH:4]=1)#[N:2].[CH:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31].C1C=CC=CC=1>CCCCC>[CH2:22]([O:21][C@H:19]1[CH2:18][N:17]2[C@@H:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:14](=[O:15])[C@@H:16]2[CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(NC(=O)[C@@H]2C[C@@H](OCc3ccccc3)CN2)c2ccccc12
Reactant: CC(C)(C)C=O
Solvent: CCCCC
Solvent: c1ccccc1
Product: CC(C)(C)[C@H]1N(c2ccc(C#N)c3ccccc23)C(=O)[C@@H]2C[C@@H](OCc3ccccc3)CN21
Yield: 86.3 %

Procedure:
A suspension of 33B (151 mg, 0.38 mmol) and pivalaldehyde (100 μl, 0.90 mmol) in a mixture of dry benzene (0.5 ml) and dry pentane (5.0 ml) was refluxed for 25 hr with a Dean-Starke receiver (Ref: Org. Lett., 2 (18) 2781-2783, (2000)). The reaction mixture was evaporated to dryness and dried in vacuo. Purification using automated flash chromatography (35 g silica gel column, EtOAc/hexane gradient) gave the title compound as a light pink-colored solid (144.1 mg, 86.3%). m.p. 155-157° C. MS (ES): m/z 440 [M+1]+.