Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(4-fluoro-3-hydroxy-benzylcarbamoyl)-3-methyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.370 g, 0.73 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature 2 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)#[N:22]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccc(C#N)cc3)c3ccccc3nc21
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-cyanobenzylamine (1.2 g, 9 mmol) was heated on a steam bath for 3 hours, then was allowed to sit at room temperature overnight. The reaction mixture was poured into water and an oil separated. The oil was extracted with hot 10% ethanol/ethyl acetate, washed with water, and the organic layer was dried and evaporated. The residue was crystallized from ether/ethyl acetate and then was purified by recrystallization from ethyl acetate/hexane, followed by column chromatography on silca gel eluting with ethyl acetate and finally crystallization of the residue thus obtained from ethyl acetate/hexane to afford 280 mg of 1-ethyl-N-(4-cyanophenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as yellow crystals, m.p. 233°-234° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH2:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][NH:21][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CNC[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.50 g, 1.9 mmol) and methylamine (10 mL, 8 M solution in ethanol, mmol; used as solvent) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:31])([F:30])I>CN(C)C=O.O>[Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[CH:10][C:5]2[NH:6][C:7]([S:9][C:28]([F:31])([F:30])[F:27])=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)I
Reactant: S=c1[nH]c2cc(Cl)c(Oc3cccc(Cl)c3Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Sc1nc2cc(Cl)c(Oc3cccc(Cl)c3Cl)cc2[nH]1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Compound number 49 (i.e., 6-chloro-5-(2,3-dichlorophenoxy)-2-trifluoromethylthiobenzimidazole) was prepared as follows. A solution of 5-chloro-6-(2,3-dichlorophenoxy)-2,3-dihydro-1H-1,3-benzodiazole-2-thione (200 mg, 0.58 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) and potassium carbonate (120 mg, 0.87 mmol, 1.50 equiv) was placed into a 50-mL 3-necked round-bottom flask. The mixture was sustained by aeration with trifluoro(iodo)methane. The resulting solution was stirred for 2 h at 130° C. in an oil bath. The resulting solution was diluted with 50 ml of water. The resulting solution was extracted with 2×80 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA/PE (1:15). This resulted in 81.0 mg (34%) of 6-chloro-5-(2,3-dichlorophenoxy)-2-trifluoromethylthiobenzimidazole as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][CH:6]=1.[C-:17]#[N:18].[Na+].CS(C)=O>O>[C:17]([CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][CH:6]=1)#[N:18]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)C(CCCBr)=CCC2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(CCCC#N)=CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of 4-(3-bromopropyl)-6-methoxy-1,2-dihydronaphthalene (10 g, 35.6 mmol), sodium cyanide (1.92 g, 39.1 mmol) and dimethyl sulfoxide (20 ml) was stirred for 1 hour at room temperature. The mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to afford the titled compound (7.5 g, yield 93%, oil).
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[C:6]([O:11][CH:12]3[CH2:15][N:14](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[ClH:1].[CH2:2]1[C:10]2[C:5](=[C:6]([O:11][CH:12]3[CH2:13][NH:14][CH2:15]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: c1ccc(C(c2ccccc2)N2CC(Oc3cccc4c3CCC4)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1cc2c(c(OC3CNC3)c1)CCC2
Reaction time: 16 h
Yield: 73.5 %

Procedure:
To a suspension of 3 g of 3-[(2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidine hydrochloride in 250 ml ethanol were added 600 mg of palladium hydroxyde on carbon powder and the mixture was hydrogenated in a Parr apparatus at 60 psi during 16 hours. After removal of the catalyst and evaporation of the solvent in vacuo the residue was washed several times with diethyl ether and decanted to remove the diphenylmethane formed. The remaining solid was crystallized from ethanoudiethyl ether, yielding 1.27 g of 3-[(2,3-dihydro-1H-inden-4-yl)oxy]-azetidine hydrochloride, m.p. 65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>ClC1C=CC=CC=1>[OH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)Cc2ccc(O)cc2)c(O)c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A suspension of 3-methoxyphenol (44.69 kg, 360 mol) and 4-hydroxyphenylacetic acid (68.5 kg, 450 mol) in 144 L of chlorobenzene was purged with nitrogen gas. Boron trifluoride diethyl etherate (177 L, 1440 mol) was added at 20 to 25° C. The suspension was heated to 80° C. and stirred for 4 to 5 h then cooled to 5 to 10° C. and stirred overnight.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O.O>O1CCCC1>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: O=Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1ccccn1)OCC
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
A solution of tetraethyl methylenediphosphonate (3.7 g, 13 mmol) in tetrahydrofuran (5 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 750 mg, 18 mmol) and tetrahydrofuran (15 ml) at 0° C., and the mixture was stirred at the same temperature for 20 minutes. Successively, a solution of 2-pyridinecarbaldehyde (1.3 g, 12 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (20:1, v/v) were collected and concentrated to give the titled compound (2.7 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C)C=O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[C:3]([C:12](=[O:23])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:2]([O:1][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:7]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(CCC(=O)c2c(O)cc(OC)cc2OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OC)cc(OC)c1C(=O)CCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Then, 30 ml of dimethylformamide was added to 5.0 g of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone and 420 mg of sodium hydride, and the mixture was stirred at 0° C. for 1 hour. Then, 2.6 g of methyl α-bromoacetate was added to the mixture, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour to effect a reaction. After the reaction, the reaction mixture was extracted with ethyl acetate and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel chromatography [230-400 mesh silica gel; eluting solvent=n-hexane/ethyl acetate (2/1)] and recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 5.3 g (yield=87.1%) of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a colorless plate.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([CH3:13])[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:14])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:15]OC(OC)N(C)C.CC(C)([O-])C.[K+].C1COCC1.Cl>CC1CCCO1>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7](=[C:6]([F:14])[CH:5]=2)[C:8](=[O:9])[NH:10][CH:15]=[CH:13]3)[CH2:2][CH2:3]1
Reactant: Cc1cc(C2CC2)cc(F)c1C(N)=O
Reactant: COC(OC)N(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: O=c1[nH]ccc2cc(C3CC3)cc(F)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-cyclopropyl-2-fluoro-6-methylbenzamide (37.2 g, 0.19 mol) in 2-methyltetrahydrofuran (MeTHF; 223 ml) was added 1,1-dimethoxy-N,N-dimethylmethanamine (29.8 g, 0.25 mol). The mixture was heated to 60° C. for 2 hours, then around 100 mL of MeTHF was distilled out under vacuum in order to remove Methanol. The reaction mixture was heated to 55° C. again, and potassium tert-butoxide, 1 M solution in THF (289 ml, 0.29 mol) was added dropwise. After 1 hr stirring at 60° C., the reaction mixture was allowed to cool down to room temperature and poured into HCl, 1 M solution (289 ml, 0.29 mol), and then THF/MeTHF was distilled out at 60° C. for crystallization. During the distillation, IPA (223 ml) was added slowly. After most of THF/MeTHF was removed, the solution was cooled down to ambient temperature. The desired product was crystallized out from IPA/water, collected by filtration and washed with water and cold IPA. The filter cake was dried under vacuum at 50° C. to afford 30.1 g of the title compound (77% isolated yield) as a white solid. MS (ESI) 204 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH2:10])=[N:12][NH:11][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: N#Cc1cc(Br)cnc1Cl
Solvent: CCO
Product: Nc1n[nH]c2ncc(Br)cc12

Procedure:
Compound 3 (307 mg, 1.4 mmol) was dissolved in EtOH (10 mL) in a microwave tube, to which 5 equivalent of NH2NH2 was added, and the reaction mixture was put on Microwave irradiation for 10 min at 170° C. Evaporated the solvent to obtain the title compound 4 in quantative yield.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([O:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([O:29][CH2:30][CH2:31][O:32][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1)[CH3:28]
Reactant: CCOCCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CCOCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 2-ethoxyethanol (76 μl; 0.781 mmol), example 51 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:8]([C:12]#[N:13])=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[Br:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:14][C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[CH2:11][CH2:10][C:9]=2[C:8]=1[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccc2c1CCC(=O)N2
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccc2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-oxo-1,2,3,4-tetrahydroquinoline-5-carbonitrile (145-1; 1.5 g, 0.0087 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.8 g, 0.01046 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. It was concentrated and diluted with ice cold water (100 mL) with constant stirring; the solid residue obtained was filtered and dried to obtain the title compound. MS (M+1): 251.2.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.ClCCl>O>[CH3:14][O:13][CH2:12][CH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=1
Reactant: COCCc1nc(Cl)c2nc[nH]c2n1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: COCCc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 75 %

Procedure:
6-Chloro-2-(2-methoxy-ethyl)-9H-purine (0.5 g, 2.4 mmol, synthesized by following the procedure reported by Crespo and al. (Journal of Medicinal Chemistry, 1998, Vol. 41, No. 21, p. 4024) was heated in morpholine (1 mL, 5 eq) at 150° C. for 15 minutes. Reaction mixture was cooled to room temperature and distributed between dichloromethane and water. Organic layer was washed 2 times with water, then with brine, dried over MgSO4 and 2-(2-methoxy-ethyl)-6-morpholin-4-yl-9H-purine (0.46 g, 75%) was isolated by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (108.6 mg, 0.27 mmol) was dissolved in absolute CH2Cl2 (14 ml) under N2 in a 50 ml Schlenk flask. Succinic anhydride (33 mg, 0.33 mmol) and a spatula-tip of 4-(dimethylamino)pyridine (DMAP) were added to the solution. The mixture was stirred at room temperature overnight. The mixture was then evaporated almost to dryness in vacuo and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 8:2:0.1, l=17 cm, V=5 ml). The fractions with the product were evaporated in vacuo and the residue was taken up in CH2Cl2 again. The mixture was filtered with a glass filter crucible G4 and Celite and the filtrate was evaporated in vacuo. The yield gave a yellowish solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O-:26])=[O:25])=[C:18]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:17]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][C:3]([CH3:4])([CH3:14])[CH3:1])=[O:25])=[C:18]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:17]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)COc1cc(N)ccc1OCC(=O)[O-]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1OCC(=O)OC(C)(C)C
Yield: 169.2 %

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (200 mg, 1.07 mmol) and t-butyl [(4-amino-o-phenylene)dioxy]diacetate (415 mg, 1.17 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1-1/1) to give 473 mg of di-t-butyl [[4-[(5-cyano-2-benzofuranyl)carbonylamino]-o-phenylene]dioxy]diacetate as a colorless solid (84%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)[CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.Cl>ClCCl.CCOCC>[CH3:32][N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)[CH2:20][CH2:19]2)[CH:22]=1
Reactant: Cn1c(-c2cccc(N3CCN(CC4COCCN4C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(-c2cccc(N3CCN(CC4COCCN4)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 3-{4-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazin-1-ylmethyl}-morpholine-4-carboxylic acid tert-butyl ester (0.07 g, 0.15 mmol) in dichloromethane (1 mL) was added 2M HCl in Et2O (3 mL) and the resulting solution was stirred for 7 h at room temperature.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23]1[CH:36]=[CH:35][C:34]2[C:33](=[O:37])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:38])[C:25]=2[CH:24]=1>>[CH:24]1[C:25]2[C:26](=[O:38])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33](=[O:37])[C:34]=2[CH:35]=[CH:36][C:23]=1[CH2:22][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c(=O)[nH]c1=O
Yield: 36 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (178 mg, yield: 36.0%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]([CH3:16])([CH3:15])[CH2:8][C:7]=2[N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:15][C:9]1([CH3:16])[CH2:8][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(n1)CC(C)(C)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCc2ccc(C(=O)O)nc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
7,7-Dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid methyl ester (1.88 g, 8.57 mmol) was dissolved in THF (30 mL) and water (10 mL). Lithium hydroxide monohydrate (616 mg, 25.7 mmol) was added with stirring at room temperature and the reaction mixture was stirred at reflux temperature for 1 h. The mixture was cooled, acidified with 2 N HCl to pH=5 and extracted with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was stirred with ethyl acetate (5 mL) at 40° C.; n-heptane (10 mL) was added and stirring at room temperature continued for 30 min. The precipitate was filtered and dried to give 1.7 g (96%) of the title compound as white solid; MS (ISP): m/e 206.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]2=[CH:5][CH:4]=1.[Li]C(C)(C)C.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[C:15]([O:14][C:12]([N:11]1[C:6]2[C:7](=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:9]=[C:10]1[B:24]([OH:29])[OH:25])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(cc(B(O)O)n2C(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
To a solution of tert-butyl 5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (3 g, 12.08 mmol) in 40 mL of dry THF was added dropwise t-BuLi (1.16 g, 18.12 mmol) at −78° C. Then the solution was stirred at −78° C. for 1 hour. Then triisopropyl borate (4.55 g, 24.17 mmol) was added dropwise to the solution still at −78° C. The mixture was stirred at −78° C. for 2 hours and quenched the reaction with 1 M of HCl at low temperature to pH=3˜4. After it was extracted with EtOAc, the combined organic phase was washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using column (petroleum ether:ethyl acetate=3:1) to provide (1-(tert-butoxycarbonyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)boronic acid (1.3 g, yield: 37%). 1H-NMR (CDCl3, 400 MHz) δ 8.10 (d, J=9.2 Hz, 1H), 7.46 (s, 1H), 6.88˜6.84 (m, 2H), 6.70 (d, J=9.2 Hz, 1H), 3.98 (s, 3H), 1.71 (s, 9H). MS (M+H)+: 293.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7](Cl)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][NH2:23])[CH3:19]>C(OCC)(=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][NH:23][C:7](=[O:8])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:19]
Reactant: CCOC(CN)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(CNC(=O)OCc1ccccc1)OCC
Reaction time: 6 h
Yield: 98 %

Procedure:
An aqueous solution (400 ml) of sodium carbonate (31.8 g) and carbobenzoxy chloride (51.2 g) were added to a solution of 2,2-diethoxyethylamine (42.0 g) in ethyl acetate (300 ml) under ice-cooling, and the mixture was stirred for 6 hours. After separating the mixture into layers, the organic layer was washed successively with 0.5N hydrochloric acid, an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried and concentrated to give pale orange oily benzyl 2,2-diethoxyethylcarbamate (78.6 g).