Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[S:1][CH:2]=[CH:3][C:4]1=2)=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: c1cc2c(s1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2sccc21
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a solution of 15.0 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 150 ml of dichloromethane cooled to 0° C. is added 27.2 ml of triethylamine. After stirring 5 minutes, a solution of 28.0 g of 2-chloro-4-nitrobenzoyl chloride in 140 ml of dichloromethane is added slowly. The solution is stirred at room temperature overnight, diluted with 450 ml of dichloromethane and the solution washed with 200 ml each of water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried over Na2So4, filtered through a thin pad of hydrated magnesium silicate and the filtrate concentrated under vacuum. The residue is crystallized from ethyl acetate to give 24.3 g of off-white crystals, m.p. 131°-134° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=O)[C:12]=3[CH2:11][CH2:10][C:9]2=[O:20])=[CH:3][CH:2]=1.[S:27]=[C:28]1[NH:32][C:31](=[O:33])[CH2:30][S:29]1>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH:18]=[C:30]4[S:29][C:28](=[S:27])[NH:32][C:31]4=[O:33])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:20])=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cccc2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=S)SC1=Cc1cccc2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Yield: 116.6 %

Procedure:
1.50 g of 1-(biphenyl-4-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde and 0.761 g of 2-thioxo-1,3-thiazolidin-4-one were suspended in 20 ml of toluene. Two drops of piperidine and two drops of acetic acid were added to the suspension, followed by heating and refluxing for 4 hours. After allowing to cool, the solid thus precipitated was collected by filtration, and dried, giving 2.34 g (91% yield) of 1-(biphenyl-4-ylmethyl)-5-(4-oxo-2-thioxothiazolidine-5-ylidenemethyl)-3,4-dihydro-1H-quinolin-2-one as a yellow powder.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH2:29][CH2:28]2)=[O:7])[CH2:12][CH2:13]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCC(c3c[nH]c4ccccc34)CC2)CC1
Reaction time: 24 h
Yield: 33.6 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (599 mg, 1.7 mmole) was added to a solution of 3-piperidine-4-yl-1H-indole (340.5 mg, 1.7 mmole) in dioxane (12 ml). The reaction mixture was a clear solution above 40° C., and this solution was boiled for 24 hours under reflux. No precipitate was formed even at RT. The solvent was distilled off in vacuo. The residue contained, besides phenol, the two diastereoisomers of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (75 g). Methanol/EE (1:1; 800 ml) and methanol (500 ml) were used as eluent. The non-polar diastereoisomer (281 mg, m.p. 89°-93° C., 36%) and the polar diastereoisomer of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (262 mg, m.p. 104°-107° C., 34%) were thereby obtained in pure form.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH2:11][CH2:12][OH:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH2:11][CH2:12][O:13][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(NCCO)c1ccc(Br)s1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To a solution of 5-bromo-N-(2-hydroxyethyl)thiophene-2-sulfonamide (1.3 g, 4.54 mmol) in dry CH2Cl2 (40 mL) was added imidazole (0.371 g, 5.45 mmol, 1.2 eq). The reaction mixture was stirred at 0° C. for 5 min and tert-butylchlorodimethylsilane (0.82 g, 5.45 mmol, 1.2 eq) was added in one portion. The solution was stirred at 0° C. for another 1 h and allowed to warm to room temperature within 2 h. The reaction mixture was evaporated under reduced pressure and the resulting residue was dissolved in EtOAc. The EtOAc solution was washed with 1 N HCl, saturated NaHCO3, and brine, dried (Na2SO4) and filtered. The filtrate was concentrated by evaporation to afford 5-bromo-N-(2-(tert-butyldimethyl silyloxy)ethyl) thiophene-2-sulfonamide (600 mg, 55%). LC-MS (m/z)=400.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[NH:20][CH:19]=[C:18]2[C:26]1[N:34]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]([CH2:9][CH2:8][C:7]([O:11][CH3:12])=[O:10])[CH:19]=[C:18]2[C:26]1[N:34]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=1
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)c(OC)cc21
Reaction time: 16 h

Procedure:
0.34 g of potassium carbonate and 0.243 ml of methyl acrylate are added, dropwise, to a solution of 1 g of 2-(5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 20 ml of anhydrous dimethylformamide, under an inert argon atmosphere at a temperature in the region of 20° C. The reaction medium is agitated at the same temperature for 16 hours. 20 ml of water and 20 ml of ethyl acetate are added. After separation by settling out, the organic phase is dried over sodium sulfate, filtered, and then concentrated under reduced pressure. After purification by flash chromatography (silica, dichloromethane as eluent, argon), the fractions containing the product are concentrated under reduced pressure. 1 g of methyl 3-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}propionate is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Yield: 32 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with phenyl isocyanate (660 mg, 5.51 mmol). Recrystallization from acetonitrile provided 670 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-phenylurea as light orange needles, m.p. ˜40° C. Analysis: Calculated for C23H26N6O2.1.0 C2H3N: % C, 65.34; % H, 6.36; % N, 21.34. Found: % C, 65.13; % H, 6.26; % N, 21.35.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]#[C:24][Si](C)(C)C)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:9]=1)=[O:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:23]([C:21]1[CH:20]=[CH:19][N:18]2[C:14]([C:10]3[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:30])([F:29])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=3)=[CH:15][N:16]=[C:17]2[CH:22]=1)#[CH:24]
Reactant: C[Si](C)(C)C#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of 1-(2,2,2-Trifluoro-ethyl)-3-[3-(7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-urea (25 mg, 0.06 mmol) in THF (5 ml) at 0° C. was added a 1M tetrabutylammonium fluoride solution (0.09 ml) and the reaction mixture stirred for 1 h at 0° C. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase HPLC to afford the product as an off-white solid (4.2 mg). MS: [M+H]+ 359
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Brc1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2nccs2)cc1Cl
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To a suspension of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (D69) (3 g), 2-bromo-1,3-thiazole (1.659 g) and Cs2CO3 (3.95 g) in 1,2-dimethoxyethane (DME) (40 mL)/water (10 mL) stirred under nitrogen at room temperature was added PdCl2(dppf)-CH2Cl2 adduct (661 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 2 h. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (150 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D70) (1.5 g). MS (ES): C12H12ClNOS requires 253. found 254.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[C:25]([CH3:32])=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[C:25]([CH3:32])[C:26]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1nn(-c2ccc(F)cc2)c2c1NCCC2
Product: Cc1nn(-c2ccc(F)cc2)c2c1N(C(=O)Cn1nc(C(F)(F)F)c(Cl)c1C)CCC2
Yield: 41 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid and 1-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 75 mg (41%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.47 (m, 0.8H), 7.40 (m, 1.2H), 7.14 (m, 2H), 5.11 (s, 1.2H), 5.01 (s, 0.8H), 3.81 (m, 2H), 2.85 (m, 2H), 2.29-2.40 (m, 6H), 2.07 (m, 2H); MS: (ES) m/z calculated for C20H19ClF4N5O [M+H]+ 456.1, found 456.1.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[C:6]=1[CH3:22].[SH:23][C:24]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1.[OH-].[Na+]>C(O)C>[NH:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[S:23][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[C:6]=1[CH3:22]
Reactant: Cc1c(OCCCl)ccnc1CSc1nc2ccccc2[nH]1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCCSc2nc3ccccc3[nH]2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 68.9 %

Procedure:
A mixture comprising 1.34 g (0.004 mol) of 2-[{4-(2-chloroethoxy)-3-methylpyridine-2-yl}methylthio]-1H-benzimidazol, 0.53 g (0.0035 mol) of 2-mercapto-1H-benzimidazole, 0.17 g (0.004 mol) of 95% sodium hydroxide and 30 ml of ethanol was stirred at 80° C. for 8 hours. After the completion of the reaction, the reaction mixture was filtered to remove inorganic matter. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 1.08 g of the title compound as a white crystal.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=O)[CH:10]=[CH:9][N:8]2[C:20]=1[CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>COCCOC>[C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13](=[S:37])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[CH:9][N:8]2[C:20]=1[CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(CC)C(=O)c1ccn2c(CC3CCOCC3)c(C(C)(C)C)nc2c1
Solvent: COCCOC
Product: CCN(CC)C(=S)c1ccn2c(CC3CCOCC3)c(C(C)(C)C)nc2c1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Compound 2 (60.0 mg, 0.160 mmol) obtained in Example 2 was dissolved in DME (1.0 mL). To this was added Lawesson's reagent (71.0 mg, 0.170 mmol), and then the mixture was stirred under ref lux for 1 hour. The solvent was evaporated off in vacuo and the residue was purified by column chromatography (hexane/ethyl acetate=50/50). The resulting crude crystals were reslurried with hexane to give the title compound (40.0 mg, 0.100 mmol, yield 65%).
Reaction SMILES: C(N(CC)CC)C.BrCC[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.Cl.[C:20]1([CH3:28])[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:28])=[CH:21][CH:22]=2)[NH2:27])=[CH:16][CH:15]=1
Reactant: Cc1ccc(NN)cc1
Reactant: COc1ccc(CCBr)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(N(N)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Triethylamine (5.2 mL 37.8 mmol) and (1-(2-Bromoethyl)-4-methoxybenzene (1.9 mL, 12.60 mmol) were added to a solution of p-tolylhydrazine hydrochloride (2 gm, 12.60 mmol) in ethanol (30 mL) and the resulting solution was stirred at RT for an 1 h after which it was heated at 90° C. for 2-3 h. The reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3, and extracted in ethyl acetate. The combined organic layers was dried over Na2SO4 and concentrated to obtain (1-(4-methoxyphenyl)-1-p-tolylhydrazine (2.8 g). (1-(4-methoxyphenyl)-1-p-tolylhydrazine (2.8 g, 10.9 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1.5 gm, 10.9 mmol) were taken in ethanolic HCl (30 mL), and stirred at RT for 15 min and the solvent was removed in vacuo. The residue was taken in ethanol (30 mL) and heated at 90° C. for 3. After completion of the reaction (the progress of the reaction was monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3. The product was extracted in ethyl acetate and the organic layers were separated, dried over Na2SO4 and concentrated. The resulting crude product was purified over neutral alumina (10% Me-OH in dichloromethane) to obtain the product as free base (500 mg). The NMR data for the compound is as follows: 1H NMR (DMSO)—7.40-7.35 (d, 1H), 7.25 (s, 1H), 6.90-6.85 (d, 1H), 6.85-6.80 (d, 2H), 6.80-6.75 (d, 2H), 4.25-4.10 (t, 2H), 3.85-3.75 (m, 1H), 3.65 (s, 3H), 3.00-2.80 (t, 2H), 2.65-2.55 (d, 2H), 2.30 (s, 3H), 2.20-2.00 (m, 1H), 1.95 (s, 3H), 1.45-1.40 (m, 2H), 1.40-1.35 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=O)[CH2:9][CH:10]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[C:11](=O)[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH:10]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:11][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)CC(C(=O)N2CCCCC2)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCN(CCC(CN2CCCCC2)c2ccc(N)cc2)CC1

Procedure:
1-[(4-Nitrophenyl)acetyl]piperidine was alkylated with methyl bromoacetate in the same manner as in Reference Example 47, hydrolyzed with 1 M sodium hydroxide aqueous solution in methanol, and then condensed with 1-methylpiperazine in the same manner as in Reference Example 5 to obtain 1-methyl-4-[3-(4-nitrophenyl)-4-oxo-4-piperidin-1-ylbutanoyl]piperazine (ESI: 389). This piperazine compound was subjected to the reduction of nitro group in the same manner as the catalytic hydrogenation shown in Reference Example 3 and then treated with lithium aluminum hydride to obtain 4-[3-(4-methylpiperazin-1-yl)-1-(piperidin-1-ylmethyl)propyl]aniline. ESI: 331.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[C:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:4](O)[C:3]=1[C:20](=[O:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[F:40])[C:34](Cl)=[O:35]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[F:30][C:31]1[CH:32]=[C:33]([C:34]2[O:35][C:4]3[C:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:6]([OH:13])[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:2]([OH:1])[C:3]=3[C:20](=[O:23])[C:21]=2[CH3:22])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(F)c(F)c3)c(C)c(=O)c2c1O
Temperature: 25 °C
Yield: 1.2 %

Procedure:
Under nitrogen atmosphere, 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]propan-1-one (300 mg, 0.943 mmol), anhydrous potassium carbonate powder (817 mg, 5.91 mmol), TBAB (tetrabutyl ammonium bromide, 477 mg, 1.47 mmol) and 3,4-difluorobenzoyl chloride (348 mg, 1.97 mmol) were dissolved in toluene (30 mL), and refluxed for 6 hours. After cooling, toluene was removed, and then water (20 mL) was added. The aqueous solution was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. A brown residue was obtained after removal of solvent. The residue was dissolved in a 5% potassium carbonate aqueous solution and heated to reflux for 2 hr. After cooling to ambient temperature, the mixture was acidified to pH 6 with 1N HCl solution, and extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was removed. The crude product was purified by silica gel column chromatography (eluent:ethyl acetate/petroleum ether, 1:50) to give the desired compound (5 mg, yield 1.2%). 1H NMR (400 MHz, CDCl3): δ=13.18 (s, 1H), 7.50-7.45 (m, 1H), 7.41-7.37 (m, 1H), 7.34-7.28 (m, 1H), 6.35 (s, 1H), 5.29-5.17 (m, 2H), 3.46 (d, 2H, J=7.2 Hz), 3.44 (d, 2H, J=7.2 Hz), 2.14 (s, 3H), 1.84 (s, 3H), 1.77 (s, 3H), 1.72 (s, 6H); LC-MS (ESI) m/z 441.7 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19]/[N:20]=[C:21](/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)\[CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:16][CH:15]=1.O.CO.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19]/[N:20]=[C:21](/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)\[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCC(=O)[O-])c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Yield: 84.9 %

Procedure:
E-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino)-4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyric acid (366 mg, yield 88%) as colorless crystals. m.p. 142-143° C.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:6]=1I.[C:15]([Si](C)(C)C)#C.Cl.[OH-].[K+]>C(N(CC)CC)C.C(O)(C)(C)C.[Cu]I>[Br:12][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][C:9]=1[F:11])[NH:4][CH:3]=[CH:15]2
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Nc1cc(F)c(Br)cc1I
Agent: [Cu]I
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Fc1cc2[nH]ccc2cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A mixture of 70 mg (0.1 mmol) Pd(PPh3)2C12 and 27 mg (0.142 mmol) CuI in triethylamine was refluxed under argon during 20 min, cooled to 0° C., treated with 7 g (0.019 mmol) (4-Bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester, stirred 10 min at room temperature, treated with 2.95 (0.021 mmol) ethinyltrimethylsilane, and stirred 1 h at room temperature. 2M aqueous HCl and ice were added and the mixture extracted three times with EtOAc. The combined organic layers were washed subsequently with H2O and saturated aqueous NaCl, dried with MgSO4 and the solvent was evaporated. The crude product obtained was dissolved in 50 ml tert-butanol, treated with 3.2 g (0.023 mol) KOH and the resulting mixture refluxed for 1.5 h. The solvent was evaporated and the residue distributed between icy water and Et2O. The organic layer was washed with water and dried with MgSO4. Evaporation of the solvent and column chromatography on silica gel with hexane/EtOAc 9:1 gave of 3.2 g (80%) 5-Bromo-6-fluoro-1H-indole, MS: 213 (M, 1Br).