Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:13])=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].C1(=O)O[CH2:17][CH2:16][O:15]1>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4]1[C:5]([O:13][CH2:17][CH2:16][OH:15])=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2]
Reactant: O=C1OCCO1
Reactant: CCOc1cc(C=O)c(F)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCOc1cc(C=O)c(F)cc1OCCO
Temperature: 25 °C
Yield: 90.8 %

Procedure:
The 5-ethoxy-2-fluoro-4-hydroxy-benzaldehyde (9.15 g) described in example 1.3 was dissolved in toluene (80 ml). Ethylene carbonate (5.25 g) and tetrabutylammonium iodide (1.83 g) were added and the mixture was heated to reflux for 22 h. The mixture was cooled to room temperature and filtered over a plug of silica gel. The product was eluted with hexane/ethyl acetate. The solvent was evaporated and the solid was washed with hot hexane to give 10.3 g of 5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-benzaldehyde as a slightly orange solid. MS: 228 ([M]+).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O.[CH3:25]C(C)([O-])C.[K+].CI>CN(C)C=O>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[N:6]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:25]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N(C)c2ccccc2N)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
Ethyl 2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.0 g) was dissolved in N,N-dimethylformamide (120 ml) and the mixture was stirred at 0° C., during which potassium tert-butoxide (3.0 g) was added portionwise. Methyl iodide (12.4 g) was added dropwise under ice-cooling and the mixture was stirred at 0° C. for 5 min and heated to room temperature. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (hexane:ethyl acetate=4:1) to give crude crystals (2.8 g) of ethyl 2-(N-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate. Without purification, the crystals were treated in the same manner as in Starting Material Synthesis Example 21 using ethanol (50 ml), 18% hydrochloric acid (50 ml) and tin(II) chloride-dihydrate (12.6 g) to give ethyl 2-(2-amino-N-methylanilino)benzo[b]thiophene-3-carboxylate (3.2 g).
Reaction SMILES: C([N:4]1[CH2:33][CH2:32][C:7]2[C:8]3[C:13](=[O:14])[N:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[CH2:19][CH2:18]4)[CH:11]=[N:10][C:9]=3[S:31][C:6]=2[CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]3[C:7]4[CH2:32][CH2:33][NH:4][CH2:5][C:6]=4[S:31][C:9]=3[N:10]=[CH:11]2)[CH2:18][CH2:19]1
Reactant: COc1ccccc1N1CCN(CCn2cnc3sc4c(c3c2=O)CCN(C(C)=O)C4)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1N1CCN(CCn2cnc3sc4c(c3c2=O)CCNC4)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
4.0 g (8.6 mmol) of 3,4,5,6,7,8-hexahydro-7-acetyl-3-[2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl]pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one were dissolved in 80 ml of 10% strength hydrochloric acid and stirred at a bath temperature of 100° C. for 2 h. The mixture was then poured into ice-water, made alkaline with concentrated sodium hydroxide solution and extracted twice with methylene chloride. The combined organic phases were dried and concentrated. 3.7 g of crude product were isolated and were recrystallized from 50 ml of isopropanol. 2.4 g (66%) of product with melting point 168-170° C. were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=O)[CH:3]1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([O:15]CC)=[O:14].S(=O)(=O)(O)[OH:19].[Cl-].[Na+]>>[C:13]([CH2:12][S:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2](=[O:1])[CH2:6][CH:5]([OH:19])[CH:4]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)CSCCCC1C(=O)C=CC1O
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CSCCCC1=CC(O)CC1=O

Procedure:
The solution, containing crude 3-hydroxy-2[3-(carbethoxymethylthio)propyl]cyclopent-4-en-1-one, is cooled and treated during 10 minutes with 75 ml of sulfuric acid (d=1.84) with stirring. The stirred solution is refluxed for 16 hours, cooled, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to chromatography on silica gel with chloroform progressively enriched in ether, ether, and ether progressively enriched in acetone to afford the subject compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9].[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:20][CH2:19]2)=[CH:30][CH:29]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: O=C(O)c1ccc(CN2CCN(CCO)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCN(CCO)CC3)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.4 %

Procedure:
A mixture of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (70 mg, 0.46 mmol), 4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzoic acid (122 mg, 0.46 mmol), o-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and triethylamine (70 mg, 0.69 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 15 hours. Then the mixture was filtered and the solid was washed with water (10 mL), methanol (10 mL) and dichloromethane (10 mL) in turns to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzamide as white solid (30 mg, 16.4%). LRMS (M+H+) m/z: calcd 398.23. found 398. HPLC purity (214 nm): 89%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]=[O:19])[C:12]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=[C:25]2[CH:24]=[CH:23]1.CO.[OH-].[K+]>O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([C:24]2[C:25]3[C:26](=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=3)[NH:22][CH:23]=2)[OH:19])[C:12]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2[nH]cc(C(O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Into a reaction vessel, (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (25, 10.00 g, 34.3 mmol), 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (13, 4.91 g, 34.3 mmol), 50.00 mL of anhydrous methanol, and potassium hydroxide (2.77 g, 49.4 mmol) were added under nitrogen and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 500 mL of water and extracted with 3×500 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting residue was purified using silica gel column chromatography to provide the desired compounds (26, 4.62 g, 31%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al](C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:22]([C:30](OCC)=[O:31])[N:21]=[C:20]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>ClCCl.CCCCCCC>[CH:1]1([NH:7][C:30]([C:22]2[N:21]=[C:20]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])[N:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[C:23]=2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Reactant: NC1CCCCC1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Part C: Cyclohexylamine (0.91 ml, 8 mmol) is dissolved in dichloromethane (20 ml) and (CH3)3Al (4 ml of a 2 M solution in heptane, 8 mmol) is added. The resulting mixture is stirred for 10 minutes at room temperature and ethyl 1-(4-chlorophenyl)2-(2,4-dichlorophenyl)-5-(pyrolidin-1-ylmethyl)-1H-imidazole4-carboxylate (1.8 gram, 3.8 mmol) is added. The resulting mixture is stirred at room temperature for 16 hours, poured into an aqueous NaHCO3 solution, stirred for 30 minutes and filtered over hyflo. The filtrated is twice extracted with dichloromethane. The organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (dichloromethane/methanol=98/2 (v/v)) gives N-cyclohexyl-1-(4-chlorophenyl )-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide, compound 1 (1.06 gram, 53% yield). Melting point: 155-157° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:32][C:33]([F:37])([F:36])[CH2:34][SH:35]>O>[F:32][C:33]([F:37])([F:36])[CH2:34][S:35][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: FC(F)(F)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 85.3 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g of potassium carbonate and 2 ml of DMF, 0.15 g of 2,2,2-trifluoroethanethiol was added. The reaction mixture was stirred at room temperature for 1.2 hours. Water was added to reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.32 g of 2-[3-(2,2,2-trifluoroethylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 46”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[NH:17][CH2:18][CH2:19][CH2:20]O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:25])=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[NH:17][CH2:18][CH2:19][CH2:20][Cl:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1cccc(F)c1
Product: OC1(c2cccc(F)c2)C(NCCCCl)=Nc2ccccc21

Procedure:
Reaction of 3-(m-fluorophenyl-2-(3-hydroxypropylamino)-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 3-(m-fluorophenyl)-2-(3-chloropropylamino)-3H-indol-3-ol.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:27])[N:14]([CH2:15][CH2:16][O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28].CO>>[CH3:27][C:13]1[N:14]([CH2:15][CH2:16][O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:28])[C:11]=2[N:12]=1
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CCOC/C=C/c1ccccc1
Reactant: N
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOC/C=C/c1ccccc1
Temperature: 150 °C

Procedure:
4-Chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline (2.12 g, 5.61 mmol), was combined with an ammonia/methanol solution (7%, 70 mL) in a bomb and heated to 150° C. for 16.5 hours and cooled to ambient temperature. Analysis indicated that the reaction was incomplete. The solution was concentrated under reduced pressure to ˜10 mL, diluted with ammonia/methanol (7%, 50 mL) and reacted in a bomb at 150° C. for 8.5 hours to complete the reaction. The solution was partitioned between dichloromethane and saturated aqueous sodium bicarbonate and the organic layer removed. The aqueous layer was saturated with sodium chloride and extracted with dichloromethane (3×). The organic fractions were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting brown solid was recrystalized from methanol to provide 0.963 g of 2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 111.8-112.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.S([O-])([O-])=[O:16].[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][N+:3]=1[O-:16]
Reactant: O=S([O-])[O-]
Reactant: Cc1ccc(Oc2ccccc2)cn1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Oc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1,3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1(C)C=CC=CC=1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: OCCO
Reactant: O=Cc1ccsc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: c1cc(C2OCCO2)cs1
Yield: 86.7 %

Procedure:
20.3 g (181 mmol) of 3-thiophenealdehyde, 50 ml of ethylene glycol and 2.00 g (7.96 mmol) of PPTS were dissolved in 230 ml of toluene, and dehydration was carried out using Dean-stark. After completion of the reaction, the mixture was extracted with ethyl acetate. The extract was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to silica gel (ethyl acetate:hexane=1:10), to give 12.1 g (77.3 mmol, 86.7%) of the title compound as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:41])([CH3:42])[CH2:36]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCCBr)CCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Yield: 24.1 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (149 mg, 0.425 mmol) and potassium carbonate (294 mg, 2.126 mmol) in DMF (2 ml) was stirred and heated at 60° C. under nitrogen for one hour. 4-(3-Bromopropyl)-2,2-dimethyltetrahydro-2H-pyran (125 mg, 0.532 mmol) in dry DMF (1 ml) was added and the mixture heated at 60° C. under nitrogen for a further 2.5 hours. The reaction mixture was cooled to room temperature, quenched into water (10 ml) and extracted with DCM:EtOAc (1:1, 2×20 ml). The organic extracts were combined, dried by passage through a hydrophobic frit and concentrated under vacuum. The residue was purified by mass directed autopreparation. Product containing fractions were combined and evaporated to give the title compound (40 mg).
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.FCC1NC(=[O:17])CC1>>[NH2:7][CH:3]([CH:2]([F:9])[F:1])[CH2:4][CH2:5][C:6]([OH:17])=[O:8]
Reactant: O=C1CCC(C(F)F)N1
Reactant: O=C1CCC(CF)N1
Product: NC(CCC(=O)O)C(F)F

Procedure:
When in the procedure of Example 5 500 mg of 5-difluoromethyl-2-pyrrolidone is substituted for 5-fluoromethyl-2-pyrrolidone, 4-amino-4-difluoromethylbutyric acid is obtained.
Reaction SMILES: [Na+].[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Reactant: Nc1c(C(=O)[O-])cccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CCc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of 2-amino-3-nitro-benzoic acid sodium salt (205 mg, 1.0 mmol), 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (219 mg, 1.0 mmol) and HATU (400 mg, 1.05 mmol) in DMF (2 mL) was added DIEA (0.52 mL, 388 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 1 h and heated at 70° C. for 1 h, and then evaporated under reduced pressure. The residue was purified by chromatography (50:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (300 mg, 78%). 1H NMR (MeOH-d4) δ 2.44 (s, 3H), 2.50-2.85 (12H), 6.74 (dd, J=9 Hz and 9 Hz, 1H), 7.23 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 1H), 8.29 (d, J=9 Hz, 1H). ESI-MS m/z 384.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:1]([CH2:10][C:9]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1
Reactant: Nc1cc(Br)c2ccccc2n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc(N(Cc2ccccc2)Cc2ccccc2)nc2ccccc12
Reaction time: 0.5 h
Yield: 185.2 %

Procedure:
A solution of 2-amino-4-bromoquinoline (244 mg, 1.09 mmol) in THF (5 mL) at 0° C. was treated with NaH (96 mg, 60% dispersion in oil, 2.4 mmol), stirred for 30 min, treated with benzyl bromide (0.335 mL, 2.4 mmol), stirred at room temperature for 3 days, poured into water (30 mL), extracted with EtOAc (2×10 mL), dried (MgSO4), concentrated in vacuo, purified by chromatography [SiO2; heptane-EtOAc (10:1)] and the resulting solid recystallised (MeOH) to give the product (407 mg, 99%) as a white crystalline solid: IR νmax (Nujol)/cm−1 3059, 3020, 2955, 2925, 2854, 1609, 1592, 1542, 1498, 1455, 1426 and 1358; NMR δH (400 MHz, CDCl3) 4.89 (4H, s), 7.15 (1H, s), 7.20-7.68 (11H, m),7.56 (1H, t, J 7.0 Hz), 7.69 (1H, d, J 8.7 Hz) and 7.94 (1H, d, J 8.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:21]3[CH:22]=[CH:17][C:18]([N+:26]([O-:28])=[O:27])=[CH:19][C:20]=3[N+:23]([O-:25])=[O:24])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 1-chloro-2,4-dinitrobenzene were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 2 hours. Chromatography afforded the title compound (73%) as a dark red solid: mp, 177.0°-179.0° C.; 13C NMR (DMSO-d6) δ148.2, 135.6, 135.2, 130.1, 129.6, 128.2, 127.9, 124.3, 123.5, 119.6, 116.9. 116.3, 113.3, 112.5, 60.0, 45.2, 23.0; FAB HRMS calculated for C18H19N5O4.[H+ ]370.1517, found 370.1492.
Reaction SMILES: CN1CCOCC1.[C:8]([OH:11])(=[O:10])[CH3:9].Cl[CH:13]([O:15][C:16]([CH2:18][NH:19][CH2:20][C:21]([O:23][CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:49])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:47])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])=[CH:34][C:33]=2[CH3:48])[C:26]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:25]1=2)=[O:22])=[O:17])[CH3:14]>O>[C:8]([O:11][CH:13]([O:15][C:16]([CH2:18][NH:19][CH2:20][C:21]([O:23][CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:49])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:47])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])=[CH:34][C:33]=2[CH3:48])[C:26]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:25]1=2)=[O:22])=[O:17])[CH3:14])(=[O:10])[CH3:9]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CNCC(=O)OC(C)Cl)c3cc(Cl)ccc32)c(C)c1
Reactant: CC(=O)O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(=O)OC(C)OC(=O)CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.4 %

Procedure:
N-methylmorpholine (0.31 ml, 2.8 mmol) was added dropwise to an acetic acid (0.32 ml, 5.6 mmol) solution of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-chloroethoxycarbonyl)methylamino]acetate (0.35 g, 0.56 mmol) under cooling with ice, and the mixture was stirred at room temperature for two days. Water was added to the reaction mixture, and then the resulted precipitates were collected by filtration and air-dried. The dried product was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.26 g (72%) of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-acetoxy-ethoxycarbonyl)methylamino]acetate as amorphous.