Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:8].CN(C)C=O.[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C1C=CN=CC=1)C.C1C=CC=CC=1>[C:24]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:10]1=[O:18])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1cccs1)C1C(=O)Nc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(C(=O)Cc2cccs2)c2ccccc21
Reaction time: 0.02 h
Yield: 4.4 %

Procedure:
A stirred mixture of 1.29 g (5.0 mmole) of 3-([2-thienyl]acetyl)-2-oxindole, 1.22 g (10.0 mmole) of 4-(N,N-dimethylamino)pyridine and 15 ml of N,N-dimethylformamide was cooled in an ice-bath, and then 562 mg (5.5 mmole) of acetic anhydride was added dropwise, with stirring, during 1 minute. Stirring was continued for 3.25 hours at ice-bath temperature, and then the reaction mixture was filtered. The filtrate was poured onto a mixture of 3N hydrochloric acid and water, which caused formation of a solid and a gum. The solid was recovered by filtration and the gum was recovered by decantation. The gum was triturated under isopropanol-water giving further solid material, which was also recovered by filtration. The two solids were combined and extracted with hot benzene, leaving a dark, gummy residue. The benzene solution was cooled and evaporated in vacuo, and the residue was recrystallized from toluene to give 66 mg of the title compound, m.p. 136°-137° C. The mother liquors from the recrystallization were evaporated in vacuo and the latter residue was recrystallized from hexane to give a second crop, 90 mg, of the title compound, m.p. 135°-136° C. The second crop was submitted to elemental analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[S:13]([OH:16])(=O)=[O:14].[CH3:17][NH:18][CH3:19]>CO.C(Cl)Cl.Cl>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]=1[S:13]([N:18]([CH3:19])[CH3:17])(=[O:16])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: CNC
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
In a dry flask under argon filled with 2,4-dimethyinitrobenzene (1.0 g, 6.61 mmol), chlorosulfonic acid (5 mL) was added dropwise. The resulting solution was stirred at 130° C. for 4 h, and then the mixture was poured slowly onto ice. A light brown precipitate formed and was isolated by filtration. The solid was dissolved in methanol (20 mL), and dimethylamine (3 mL) was added with stirring. After 15 min, the reaction mixture was diluted with methylene chloride and 1 M HCl. The layers were separated, and the organics were dried and concentrated. Purification of the residue by flash chromatography (15% ethyl acetate/hexanes) provided 2,4-dimethyl-5-nitro (N,N-dimethyl)benzenesulfonamide (626 mg, 37%) as a white solid. Anal. Calcd for C10H14N2O4S: C, 46.50; H, 5.46; N, 10.85. Found: C, 46.68; H, 5.25; N, 10.71.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[NH:7][C:8]2=[O:13])([O-:3])=[O:2].[OH-:15].[Na+].Cl>O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([C:8]([NH2:7])=[O:13])[C:5]=1[C:6]([OH:14])=[O:15])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
Commercially available 4-nitro-isoindole-1,3-dione (1) (25 g, 0.13 mol) was stirred in water (300 mL) at 0° C. Over a few minutes, an aqueous solution of sodium hydroxide (30% w/w, 35 g, 0.26 mol) was added. The mixture was stirred for 1.5 h at 0-5° C. The cold solution was acidified with concentrated HCl (22 mL, 0.26 mol) and the product precipitated as a white solid. After allowing to stand overnight in a refrigerator, the mixture was filtered to afford the title compound (26.3 g, 96%) as a white solid: 1H NMR (300 MHz, DMSO) δ 8.2 (s, 1H), 8.15 (d, 1H), 7.93 (d, 1H), 7.88-7.65 (m, 2H); ESIMS m/z 211 ([M+H]+), m/z 209 ([M−H]−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=[O:12].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 91.5 %

Procedure:
A dry reaction flask equipped with a reflux condenser, N2 inlet and a magnetic stirring bar was charged with 3-nitrophenol (76.45 g, 550 mmol), K2CO3 (76.45 g, 550 mmol) and dry acetone (500 mL) under N2 atmosphere. To this at room temperature was added ethyl bromoacetate (55.44 mL, 500 mmol) over a period of 15 min. The reaction mixture was refluxed for 16 h, cooled and poured over ice-water (4 Kg). The resulting aqueous solution was extracted with CH2Cl2 (3×500 mL), dried over anhydrous Na2SO4 and solvent was removed to obtain 103 g (92%) of the desired ethyl 4-nitrophenoxyacetate. 1H NMR (CDCl3): δ 8.20 (d, 2H, J=8.2 Hz), 6.95 (d, 2H, J=8.1 Hz), 4.72 (s, 2H), 4.25 (q, 2H), 1.23 (t, 3H); LCMS: ret. time: 27.07 min.; purity: 100%; MS: 267 (M+ acetonitrile).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C.C(OCC)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1.[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CC(Cc1c[nH]c2ccccc12)NC(=O)NCC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C

Procedure:
The more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea (219 mg, 0.5 mmole) was dissolved in ethyl methyl ketone (40 ml). Chlorotrimethylsilane (95 μl, 0.75 mmole) was added dropwise with stirring at RT. After one hour's stirring at RT, no precipitate had formed. The reaction solution was reduced to 5 ml under a vacuum and combined with diethyl ether (15 ml). The mixture was then vigorously stirred at RT for 1 h. An almost colorless precipitate was formed. The solid was filtered out, washed with diethyl ether (3×3 ml) and dried under a vacuum. The hydrochloride of the more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea (219 mg, m.p. 170-174° C., 93%; Example 26) was obtained in this manner as a colorless solid.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[C:14]([CH3:22])[CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.C([N:25](CC)CC)C.[C:30]([O:33]CC)(=[O:32])C>C(#N)C.[Ag]N=C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:20])[F:21])=[C:14]([CH3:22])[CH:13]=3)[CH2:11][O:33][C:30](=[O:32])[NH:25]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: C=C(c1cccc(Br)c1)c1ccc(OC(F)F)c(C)c1
Reactant: CCOC(C)=O
Agent: O=C=N[Ag]
Agent: II
Solvent: CC#N
Product: Cc1cc(C2(c3cccc(Br)c3)COC(=O)N2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of iodine (5.5 g, 1.1 eq.) in ethyl acetate (60 ml) was added dropwise to a suspension of silver isocyanate (3.3 g, 1.2 eq) and 4-[1-(3-bromo-phenyl)-vinyl]-1-difluoromethoxy-2-methyl-benzene (CAS 1180015-79-9) (6.7 g, 1 eq.) in acetonitrile (80 ml) and ethyl acetate (20 ml). During the addition the suspension was cooled in an ice-bath. The resulting brown suspension was stirred for 1 hour at room temperature. After an TLC sample indicated complete conversion of the starting material, the reaction mixture was filtrated and concentrated in vacuo. The crude was dissolved in tert-butanol (100 ml) and triethylamine (2.76 ml, 1 eq.) was added. The mixture was stirred at 100° C. overnight. For the workup the mixture was allowed to cool to room temperature, then the solvent was removed at reduced pressure and the residue taken up in ethyl acetate. The solution was washed with water (3×20 ml), dried over sodium sulphate and concentrated at reduced pressure. The residue was purified by chromatography on silica gel using a 9:1-mixture of cyclohexane and ethyl acetate as the eluent. There were obtained 5.1 g (67% of theory) of the (RS)-4-(3-bromo-phenyl)-4-(4-difluoromethoxy-3-methyl-phenyl)-oxazolidin-2-one as a white solid. MS (ISP): m/z=398 [M+H]+.
Reaction SMILES: IC1C(C)=CC=CC=1C(O)=O.[NH2:12][CH2:13][C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:22].F[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[CH3:20][C@@H:19]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=2[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)=[O:22])[C@@H:14]1[CH2:13][NH:12][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1-c1ncccn1
Agent: Cc1cccc(C(=O)O)c1I
Product: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1-c1ncccn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A230 using 2-iodo-3-methylbenzoic acid to make ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](O)(C)[CH3:22]>>[CH3:21][C:22]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:13]2[N:14]=1
Reactant: CC(C)O
Reactant: Nc1c(-c2ccccc2)ccnc1Nc1ccccc1
Product: Cc1nc2c(-c3ccccc3)ccnc2n1-c1ccccc1
Yield: 74 %

Procedure:
0.70 mol of N2,4-diphenylpyridine-2,3-diamine and 2.56 mol of ethoxy ethylene malononitrile was added in 10 ml of isopropanol, and refluxed for 6 hours. The solution was removed and was purified by using column chromatography to thereby produce a solid crystalline product at a yield of 74%.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:27]=[C:28]([N:32](C)[C:33](=O)OC(C)(C)C)[CH:29]=[CH:30][CH:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18]COCCOC)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(Cl)Cl.CO>FC(F)(F)C(O)=O>[F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COCCOCOCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N(C)C(=O)OC(C)(C)C)c3)n2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(Nc2nc(Nc3ccc(OCCO)cc3)ncc2F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
In a 25 mL, 3-neck RBF equipped with a calcium chloride guard tube, tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamate (0.4 g) in was charged in trifluoroacetic acid (6.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 8 hr. The reaction was monitored by TLC using DCM: methanol (9.6:0.4) as mobile phase. After completion of the reaction, the reaction mixture was quenched in water and neutralized with sodium bicarbonate. Product was extracted in DCM and the organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Crude material was purified by using Combiflash chromatography. Product was eluted with 1.7% methanol in DCM and concentrated to give 0.105 g of 2-(4-((5-fluoro-4-((3-(methylamino)phenyl)amino)pyrimidin-2-yl)amino)phenoxy)ethanol. M+1=457.8. 1H NMR: DMSO-d6 (400 MHz): 2.65 (d, 3H, J=5.2), 3.69 (t, 2H, J=4.8), 3.92 (t, 2H, J=4.8), 4.85 (t, 1H, J=5.6), 5.54 (d, 1H, J=4.8), 6.29 (s, 1H), 6.79 (d, 2H, J=8.8), 6.86 (s, 1H), 7.03 (s, 2H), 7.55 (d, 2H, J=9.2), 8.02 (s, 1H), 8.93 (s, 1H), 9.04 (s, 1H).
Reaction SMILES: C[SiH](C)[O:3][CH:4](C(C)(C)C(C)C)[C@H:5]1[N:10]2[C:11]3[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=O)[NH:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C1COCC1>[NH3:7].[F:21][C:18]([F:19])([F:20])[C:13]1[CH:14]=[CH:15][C:16]2[CH:17]=[C:9]3[CH2:8][NH:7][CH2:6][C@@H:5]([CH2:4][OH:3])[N:10]3[C:11]=2[CH:12]=1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3ccc(C(F)(F)F)cc3n21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N
Product: OC[C@@H]1CNCc2cc3ccc(C(F)(F)F)cc3n21
Temperature: 25 °C
Yield: 25 %
Yield: 144.7 %

Procedure:
To a solution of 0.240 g (S)-4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 3 ml THF was added 1.2 ml of a 1M solution of lithium aluminium hydride in THF. The mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and the 10 ml ethyl acetate and 10 ml water were added. The phases were separated and the organic phase was purified by chromatography on silica gel with 190:10:1 dichloromethane:methanol:25% aqueous ammonia eluant to yield 0.11 g of the title compound as white crystals (m.p.: 126-127° C.).
Reaction SMILES: O.[SH-].[Na+:3].C([S:11]([C:14]1[N:19]=[C:18]([N:20]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[S:21]([N:24]2[CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:17]=[C:16]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])[N:15]=1)(=O)=O)C1C=CC=CC=1>CS(C)=O>[N:24]1([S:21]([N:20]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:18]2[CH:17]=[C:16]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])[N:15]=[C:14]([S-:11])[N:19]=2)(=[O:22])=[O:23])[CH2:27][CH2:26][CH2:25]1.[Na+:3]
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc(S(=O)(=O)Cc2ccccc2)n1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc([S-])n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Sodium hydrosulfide hydrate (1.18 g) was added to a solution of the subtitle product of step iv) (8.0 g) in DMSO (67 ml) and the green solution stirred for 2 h. A farther aliquot of sodium hydrosulfide hydrate (0.79 g) was added and stirred for 1 h. This aliquot addition was repeated twice more before heating the solution at 50° C. for 30 min. The resulting reaction solution was used directly in the following step. The subtitle compound was also kept as a stock solution for further reaction with alkyl halides, described in Examples 41-42.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15](I)=[CH:14][C:13]=1[CH3:20]>>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=2)=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C)c(Br)c(C)c2)cn1

Procedure:
The title compound is prepared from 2-methyl-pyridine-5-boronic acid and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.93 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Reactant: CN(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CCNc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and (2-bromoethyl) dimethylamine (0.02 g, 0.1 mmol) in acetonitrile (1 mL) was treated with potassium carbonate (0.04 g, 0.3 mmol). The mixture was stirred overnight at 50° C. and filtered. The filtrate was concentrated and purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (DMSO-d6) δ 8.12-8.18 (m, 2H), 7.86-7.95 (m, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.12-7.20 (m, 3H), 6.64 (s, 1H), 6.27 (s, 1H), 3.23-3.26 (m, 3H), 2.57-2.65 (m, 1H), 2.31 (s, 6H), 1.24 (s, 1H), 0.85 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.N1CCCCC1>C1C=CC=CC=1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cccs1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2C1=Cc1cccs1
Yield: 55 %

Procedure:
A mixture of oxindole (16.5 g, 0.12 mole), thiophene-2-carboxaldehyde (19.1 g, 0.17 mole) and piperidine (1 ml) in 200 ml of benzene is heated at reflux temperature for 4 hours, during which time water is separated by means of a Dean-Stark trap. Solvent is removed in vacuo and the residue is crystallized twice from ethanol to give 15 g of the product: m.p. 208.5°-210°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[CH3:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[I-].[K+]>CC(C)=O>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][N:31]3[CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:5][CH:4]=2)=[CH:16][CH:15]=1)(=[O:13])[CH3:11]
Reactant: BrCc1ccc(CBr)cc1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(CN3CCC(C)CC3)cc2)cc1

Procedure:
α,α′-Dibromo-para-xylene (30 mmol), 4-hydroxyacetophenone (20 mmol), and potassium carbonate (50 mmol) were refluxed in 50 ml of acetone for 12 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel (eluent: methylene chloride/petroleum ether/methanol (60/38/2)). The product (2 mmol), 4-methylpiperidine (6 mmol), potassium carbonate (8 mmol), and catalytic amounts of potassium iodide were refluxed in acetone for 12 hours. The solvent was evaporated. The residue was washed with water and extracted with ethyl acetate. The solvent was removed under reduced pressure. The product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[I:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[IH:11].[CH2:12]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][C:2]1=[NH:10])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCI
Reactant: Nc1nc2ccccc2s1
Product: CCCCn1c(=N)sc2ccccc21
Product: I
Yield: 63.5 %

Procedure:
Benzothiazol-2-ylamine (1.0 g, 6.6 mmol) and 1-iodobutane (0.90 mL, 7.9 mmol) were processed as described in Example 46A. Recrystallization from ethyl acetate provided 1.4 g (63%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 0.92 (t, J=7.3 Hz, 3 H), 1.32-1.46 (m, 2 H), 1.60-1.73 (m, 2 H), 4.19-4.28 (m, 2 H), 7.40-7.47 (m, 1 H), 7.54-7.62 (m, 1 H), 7.73 (d, J=7.8 Hz, 1 H), 8.00 (dd, J=7.8, 1.0 Hz, 1 H), 10.00-10.13 (m, 1 H); MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C.C1C[O:33][CH2:32]C1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:32](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: C1CCOC1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCO)OC1CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A stirred suspension of N,N'-carbonyldiimidazole (3.24 g, 20 mmol) in The (40 mL) was warmed up to 50° C., and a solution of 1-benzyl-4-hydroxypiperidine (3.82 g, 20 mmol) in THF (17 mL) was added dropwise over 10 min. Stirring was continued for 2 hrs. at room temperature (RT), and a solution of 6-aminohexanol (3.50 g, 30 mmol) and triethylamine (3.04 g, 30 mmol) in THF (40 mL) was added dropwise over 10 min. When the reaction mixture turned cloudy, the rate of stirring was increased, and a clear solution was obtained within 20-30 min. The mixture was refluxed for 2 hrs., concentrated in vacuo, and the residue was partitioned between ether (70 mL) and water (35 mL). An alternative partitioning between ethyl acetate and water was equally effective. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give the title compound (6.68 g, yield 100%) as a light, yellowish oil. TLC (chloroform-5% methanol) showed a single spot at Rf 0.5; 1H NMR (300 MHz, CDCl3) δ1.37 (m, 4H, CH2), 1.47-1.61 (m, 4H, CH2), 1.67 (m, 2H, CH2, piperidine ring axial protons), 1.88 (m, 2H, CH2, piperidine ring equatorial protons), 2.22 (t, J=9 Hz, 2H, CH--N--CH, piperidine ring axial protons), 2.69 (m, 2H, CH--N--CH, piperidine ring eq. protons), 3.16 (q, J=6.5 Hz, 2H, CH2 --NH), 3.49 (s, 2H, CH2 --Ph), 3.62 (t, J=6.5 Hz, 2H, CH2 --O), 4.66 (m, 1H, CH--O), 4.73 (t, J=6 Hz, 1H, NH), 7.23-733 (m, 5H, Ar--H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17](O)=[O:18])=[C:14]([I:16])[N:15]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH3:29]>C1COCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([NH2:29])=[O:18])=[C:14]([I:16])[N:15]=2)[C:8]([CH3:20])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2nc(I)c(C(=O)O)o2)c(C)cn1
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(I)c(C(N)=O)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-1,3-oxazole-5-carboxylic acid (10.0 g, 26 mmol) in THF (200 mL) was added TEA (11.0 mL, 78.0 mmol). The reaction mixture was allowed to stir at rt for 1 h and then isobutyl carbonochloridate (10.0 mL, 74.0 mmol) was added. The reaction mixture was allowed to stir at rt for 5 hr and then saturated ammonia in THF (100 mL) was added. The reaction mixture was allowed to stir at rt for 30 min and was then diluted with water. The organic solvent was removed by evaporation and the slurry was filtered. The solid was collected, washed with water and dried to give 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-1,3-oxazole-5-carboxamide (8.7 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[CH3:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][NH:19][CH3:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: CN
Solvent: CCO
Product: CNCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
A solution containing 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (5.5 g, 20.4 mmol), obtained as explained in EP 106515, a 40% solution of methylamine in ethanol (60 mL) and ethanol is stirred at 100° C. for 16 h in a closed vessel. The product is isolated by flash chromatography as a white solid.