Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][S:3]1(=[O:8])=[O:7].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>CN(C)C=O>[O:7]=[S:3]1(=[O:8])[N:2]([CH3:1])[CH2:6][CH2:5][N:4]1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCNS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.5 %

Procedure:
To a solution of 2-methyl-1,2,5-thiadiazolidine-1,1-dioxide (2.02 g, 14.8 mmol) in anhydrous dimethylformamide (30 ml) was added sodium hydride (60% dispersion in oil; 0.59 g) and the mixture was stirred at room temperature under nitrogen for 40 minutes. A solution of 1-fluoro-4-nitrobenzene (2.09 g, 14.8 mmol) in anhydrous dimethylformamide (15 ml) was added to the above solution and the mixture was refluxed for 1 hour. Water (200 ml) was added and products were extracted with ethyl acetate (2×150 ml), dried (MgSO4) and concentrated to an orange solid. Crystallisation from ethyl acetate (150 ml) afforded 2.61 g (68.7%) of the title compound as a pale orange solid; mp 155°-163° C.; δH (250 MHz, DMSO-d6) 8.29 (2H, d, J=9.3 Hz, Ar--H), 7.34 (2H, d, J=9.3 Hz, Ar--H), 4.00 (2H, t, J=6.4 Hz, --CH2 --), 3.57 (2H, t, J=6.4 Hz, --CH2 --), 2.78 (3H, s, --CH3); m/z (EI) 257 (M+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1.I[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[NH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:16][CH2:17][CH3:18])[C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: CCCI
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccc(N)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a suspension of NaH (493 g, 12.3 mmol) in DMF (10 ml) was added a solution of 4-aminophthalimide (2.00 g, 12.3 mmol) in DMF (10 ml) at 0° C. After stirring at room temperature for 1 h, iodopropane (1.20 ml, 12.3 mmol) was added to this mixture at 0° C. and stirred at room temperature for 28 h. The mixture was poured into water and extracted with AcOEt:toluene=2:1 (150 ml×3). The extract was washed with water, brine, dried (Na2SO4), and concentrated to give yellow solid, which was purified by column chromatography (silica gel: 130 g, CH2Cl2 only to CH2Cl2/MeOH=75/1) to give 1.14 g (45%) of yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]([F:23])=[C:17](Cl)[N:16]=1.CCN(CC)CC>C(#N)C>[Cl:14][C:15]1[N:16]=[C:17]([NH:1][CH:2]([C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:18]([F:23])=[CH:19][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CCOC(=O)CC(N)C(C)(C)CC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(Nc1nc(Cl)c(C#N)cc1F)C(C)(C)CC

Procedure:
A solution of ethyl 3-amino-4,4-dimethyl-hexanoate, 27a, (0.24 g, 1.28 mmol), 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.29 g, 1.53 mmol) and Et3N (0.43 mL, 3.07 mmol) in acetonitrile (4.8 mL) was stirred at 70° C. overnight. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (10-40% EtOAc/Hexanes gradient) to provide 205 mg of ethyl 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.75 minutes (M+H) 342.04.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[F:31])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]=1[F:27]>>[F:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[F:31])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:21][C:20]=1[F:27]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:14]([O-])=O)[C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:14])[C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17]
Reactant: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2cc(N)c(N)cc2n1C
Yield: 95.7 %

Procedure:
Pure 1,2-dimethyl 5,6-dinitro benzimidazole (0.7 grams) and 0.2 grams Pd/C in 20 ml ethanol and 20 ml glacial acetic acid were hydrogenated for 4 hours. Filtering and evaporating resulted in 0.5 grams, 95% yield of a white solid having a melting point of 212° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:26][C:27]1[CH:32]=[N:31][C:30]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)=[C:29]2[NH:38][CH:39]=[C:40]([C:41](=[O:45])C(O)=O)[C:28]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1>[F:26][C:27]1[CH:32]=[N:31][C:30]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)=[C:29]2[NH:38][CH:39]=[C:40]([C:41](=[O:45])[C:18]([N:15]3[CH2:14][CH2:13][CH:12]([C:11]4[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[N:9][N:10]=4)[CH2:17][CH2:16]3)=[O:20])[C:28]=12
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnnn2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: O=C(C(=O)N1CCC(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
Part C: To a solution of tert-butyl 4-(1-phenyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.165 g, 0.50 mmol) in 1,4-dioxane (10 mL) at 25° C. was added 4.00 N HCl in 1,4-dioxane (10 mL), and the mixture was stirred at 25° C. for 16 h. The mixture then was concentrated under vacuum. The resulting solids were dissolved in DMF (10 mL). To this solution was added sequentially 2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.137 g, 0.50 mmol), N-methylmorpholine (0.165 mL, 1.50 mmol), and TBTU (0.176 g, 0.55 mmol), and the mixture was stirred at 25° C. for 24 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in hot methanol, and the solution then was allowed to cool slowly to room temperature. The precipitate was recovered by filtration, washed with methanol, and dried under vacuum to provide 1-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperidin-1-yl)ethane-1,2-dione (0.142 g) as an off-white solid; mp: 257-258° C.; HRMS: 487.1740 (M+H)+ [calc'd: 487.1755]; 1H NMR (500 MHz, DMSO-D6) δ 13.06 (br s, 1H), 9.02 (s, 1H), 8.32 (d, 1H, J=1.8 Hz), 8.30 (s, 1H), 8.12 (s, 1H), 7.58 (s, 5H), 4.37 (m, 1H), 3.67 (m, 1H), 3.32 (m, 1H), 3.25 (m, 1H), 3.03 (m, 1H), 2.01 (m, 1H), 1.88 (m, 1H), 1.83-1.70 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.Cl[CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[N:13]([CH3:18])[C:14]([CH2:16][CH3:17])=[N:15][C:11]=2[CH:10]=1>C(#N)C>[CH2:16]([C:14]1[N:13]([CH3:18])[C:12]2[CH:19]=[CH:20][C:9]([CH2:8][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:10][C:11]=2[N:15]=1)[CH3:17]
Reactant: CCc1nc2cc(CCl)ccc2n1C
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CC#N
Product: CCc1nc2cc(Cn3ccnc3)ccc2n1C
Yield: 54 %

Procedure:
A mixture of 6.8 parts of 1H-imidazole, 4.9 parts of 5-(chloromethyl)-2-ethyl-1-methyl-1H-benzimidazole monohydrochloride and 80 parts of acetonitrile was stirred and refluxed for 3 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethyl acetate. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.6 parts (54%) of 2-ethyl-5-(1H-imidazol-1-yl-methyl)-1-methyl-1H-benzimidazole; mp. 127.3° C. (compound 1).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][C:6]1[N:11]=[C:10](N)[CH:9]=[CH:8][CH:7]=1>>[CH3:5][C:6]1[N:11]=[C:10]([NH:1][C:2]([NH2:4])=[O:3])[CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=O
Reactant: Cc1cccc(N)n1
Product: Cc1cccc(NC(N)=O)n1
Temperature: 145 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a 25-mL round-bottom flask purged and maintained with an inert atmosphere of argon, was added urea (1.48 g, 24.64 mmol, 1.00 equiv) and 6-methylpyridin-2-amine (3 g, 27.74 mmol, 1.00 equiv). The resulting mixture was stirred for 2 h at 145° C. After cooling, the crude product (4 g) was purified using CombiFlash: Column, C18 silica gel; utilizing a mobile phase of CH3CN: H2O=0:100 to CH3CN: H2O=50:50 over 40 min. This resulted in the isolation of 1.2 g (32%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ ppm 9.07 (s, 1H), 7.56-7.52 (m, 1H), 7.18-7.14 (m, 1H), 6.80-6.75 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Product: CC(=O)OC(C)(C)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Exampe 68) and 2-acetoxyisobutyryl chloride. m.p.: 228-229° C. (recrystallized from ethyl acetate) IR(KBr)ν: 3500, 3250, 1740, 1710, 1620, 1600, 1570, 1540, 1480, 1350, 1230, 1180, 1150, 740 cm−1.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([NH:18][CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:18]([CH2:19][CH2:20][OH:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2s1
Reactant: OCCNCc1ccccc1
Solvent: CCOC(C)=O
Product: OCCN(Cc1ccccc1)c1nc2ccccc2s1

Procedure:
2-Chlorobenzothiazole (13 g) and 2-(benzylamino)ethanol (29 g) were heated together in a sealed vessel at 120° C. for 20 h. After cooling, the reaction mixture was dissolved in ethyl acetate (200 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3×100 ml), water (3×100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and evaporated to give the title compound (m.p. 95-96° C.; dichloromethane/hexane).
Reaction SMILES: Cl.C([O:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:30][CH2:31][OH:32])[C:15]([S:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[Cl:29][C:24]1[CH:23]=[C:22]([S:21][C:15]2[N:14]([CH2:30][CH2:31][OH:32])[C:13]([CH2:12][CH2:11][CH2:10][OH:9])=[N:17][C:16]=2[CH:18]([CH3:20])[CH3:19])[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CCCO)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 26.6 %

Procedure:
To 14 ml of concentrated hydrochloric acid, 1.4 g (2.9 mmol) of the alcohol (136e) was added and the mixture was heated at 110° C. For 7 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-ethyl acetate) to provide 300 mg (yield 26%) of 3-(5-(3,5-dichlorophenylthio)-1-(2-hydroxyethyl)-4-isopropyl-1H-imidazol-2-yl)-propan-1-ol (137d) as oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:28])(=[O:27])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[OH:30][C@@H:31]([CH2:44][NH2:45])[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH:45][CH2:44][C@H:31]([OH:30])[CH2:32][O:33][C:34]4[C:42]5[NH:41][C:40](=[O:43])[NH:39][C:38]=5[CH:37]=[CH:36][CH:35]=4)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)(=[O:28])=[O:27])=[CH:8][CH:7]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from {4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acid methyl ester (which was obtained in Example 232) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 278 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.85 (m, 5H), 3.30-3.50 (m, 2H), 3.69 (s, 3H), 3.80-4.05 (m, 3H), 4.87 (s, 2H), 6.56 (d, J=7.8 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.65-6.90 (m, 5H), 7.02 (d, J=9.0 Hz, 2H), 7.59 (d, J=9.0 Hz, 2H), 10.60 (s, 1H), 10.75 (brs, 1H); MS (ES) m/z: 626.1 (MH+); HRMS Calcd. for C30H36N5O8S(MH+): 626.2285. Found: 626.2298.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCCCCCCl
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCOc1cccc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 15.0 g (0.088 mole) of 3-hydroxybiphenyl, 13.3 g (0.097 mole) of 6-chlorohexan-1-ol, and 13.8 g (0.01 mole) of potassium carbonate in 250 ml of dry dimethylformamide is stirred and heated to reflux for 3 hours. The mixture is cooled to room temperature, diluted with water, and extracted with ether, the ether extracts dried and evaported under reduced pressure to give a light yellow oil. The crude product is vacuum distilled to give a fraction boiling between 150 and 190° C. (0.05 mmHg), and solidifying to a soft solid, corresponding to the pure desired product.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2([C:24]([F:27])([F:26])[F:25])[O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(O[N:50]1[C:55](=[O:56])[CH2:54][CH2:53][C:51]1=[O:52])=[N+](C)C)C>C1COCC1>[O:52]=[C:51]1[CH2:53][CH2:54][C:55](=[O:56])[N:50]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:6]([C:5]#[C:4][CH:1]3[CH2:3][CH2:2]3)([C:24]([F:27])([F:26])[F:25])[C:7]=2[CH:16]=1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
A solution of 35 mg (0.091 mmol) of the acid 11 in 2 mL of anhydrous THF was cooled to 0° C., and 30 μL (0.15 mmol) of N,N-diisopropylethylamine was added followed by 40 mg (1.28 mmol) of O-(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate. The reaction mixture was allowed to warm up to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP preparative HPLC using acetonitrile and water as a mobile phase containing 0.1% of trifluoroacetic acid to give 30 mg (00.62 mmol, 68%) of 12 as a white powder [LC-MS; M+H 481.0].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-5-(methanesulfonyl)benzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)benzamide. MS (Q1) 420.95 (M)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>>[CH3:13][C:10]1[S:9][C:7]2=[N:8][C:3]([CH2:2][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:5]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[C:6]2[C:11]=1[CH3:12]
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc2c(c1)OCO2
Reactant: c1nc[nH]n1
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc2c(c1)OCO2

Procedure:
In substantially the same manner as in Example 2, ethyl 6-chloromethyl-4-(3,4-methylenedioxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate was allowed to react with 1H-1,2,4-triazole to produce ethyl 2,3-dimethyl-4-(3,4-methylenedioxyphenyl)-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.109°-110° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:31][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(-c2ncc[nH]2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a solution of 1-{1-[4-(2-imidazolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.0 g) and potassium carbonate (0.35 g) in dimethylformamide (10 ml) is added methyl iodide (0.16 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Further, to the mixture are added methyl iodide (0.16 ml) and potassium carbonate (0.3 g), and the mixture is stirred at room temperature for 8 hours. The mixture is poured into icewater, extracted with ethyl acetate, washed with water and dried over sodium sulfate. After concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=25:1) and recrystallized from ethyl acetate to give 1-{1-[4-(1-methyl-2-imidazolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.15 g) as colorless scales, m.p. 177°-179° C.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1C=CN=C1>>[CH3:3][Si:2]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: OCc1ccccc1
Agent: Cn1ccnc1
Product: C[Si](C)(C)OCc1ccccc1
Temperature: 0 °C
Yield: 88 %

Procedure:
5.50 g (51.0 mmol) of chlorotrimethylsilane were added dropwise to a solution of 5.00 g (46.0 mmol) of benzyl alcohol and 4.20 g (51.0 mmol) of 1-methylimidazole while stirring at 0° C. The reaction mixture was stirred for a further 30 minutes at 0° C. and for 5 minutes at 80° C., resulting in the formation of a liquid two-phase mixture. The upper phase was separated off to give 7.30 g (theory: 8.29 g) of benzyl trimethylsilyl ether as a colorless oil having a purity of 99% (GC).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[C:7]([O:13]C(=O)C)=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[N:31]1([C:2]2[O:6][C:5]3[C:7]([OH:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=3[C:3]=2[C:17](=[O:30])[C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2c(-n3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (30 mg, 0.063 mmol) and imidazole (60 mg, 0.88 mmol) in a mixture of toluene:triethylamine (3 mL: 2 drops) was refluxed for 4 hours (tlc). Solvent was distilled under vacuum and the crude residue was purified by PTLC (eluent=ethyl-acetate: 1% triethylamine) to give the title compound as a yellow solid; (8 mg, 30%); 1H NMR (300 MHz, CDCl3) δ 8.24 (bs, 1H), 7.52 (b, 1H), 7.19 (b, 1H), 7.06 (s, 2H, benzoyl Hs), 6.99 (d, 1H, J=8.60 Hz), 6.93 (d, 1H, J=8.66 Hz), 3.96 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.76 (s, 6H, 2×OMe).
Reaction SMILES: CC(CSC[C@H]1[O:11][C@@H:10](N2C3NC=NC(=O)C=3N=C2)[C@H](O)[C@@H]1O)C.Cl.[CH3:25][O:26][C:27](=[O:32])[C@H:28]([CH2:30][OH:31])[NH2:29].C(Cl)(Cl)=O>>[CH3:25][O:26][C:27]([CH:28]1[CH2:30][O:31][C:10](=[O:11])[NH:29]1)=[O:32]
Reactant: CC(C)CSC[C@H]1O[C@@H](n2cnc3c(=O)nc[nH]c32)[C@H](O)[C@@H]1O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C(Cl)Cl
Product: COC(=O)C1COC(=O)N1

Procedure:
The preparation of 1-1 was carried out according to the literature procedure (see: Sibi, M. P. et al, J. Chem. Soc. Perkin Trans. 1 1994, 1675). Thus, 39.5 grams of serine methyl ester hydrochloride was reacted with phosgene (20% solution in toluene, 175 mL) to give 42 grams of desired product. 1H NMR (400 MHz, acetone-d6): δ 7.1 (br s, 1H, NH), 4.64–4.56 (m, 2H), 4.44 (dd, 1H), 3.77 (s, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[Cl:13][C:14]1[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24]Cl)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>O>[Cl:13][C:14]1[C:19]([C:20]2[O:21][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(CCl)NC(=O)c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(c2cccnc2Cl)=N1

Procedure:
2 l of toluene and 155 g (1.84 mole) of sodium bicarbonate are then added to the solution of 2-chloro 3-(1,1-dimethyl 2-chloro-ethyl)aminocarbonylpyridine thus formed and the mixture is refluxed with vigorous stirring until the starting material has completely disappeared (10 to 15 H). The water formed by the reaction of the hydrochloric acid liberated with the sodium bicarbonate is collected in a separator, and the sodium chloride formed is filtered off and washed with toluene. The filtrate is then concentrated under reduced pressure to give 2-chloro 3-(4,4-dimethyl 2-oxazolinyl)pyridine in the form of a yellow oil which can be purified by distillation under reduced pressure.