Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:28][CH3:29])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of 4-fluoro-N2-pyridin-3-ylbenzene-1,2-diamine (0.594 g, 2.9 mmol) in DCM (18 mL) at 0° C. were added (S)-2-tertbutoxycarbonylaminobutyric acid (650 mg, 3.2 mmol), HOAt (440 mg, 3.2 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (610 mg, 3.2 mmol) and the reaction mixture stirred at 0° C. for 2 h. The crude mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-60% EtOAc in cyclohexane) to afford {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]propyl}carbamic acid tert-butyl ester (839 mg, 75%). LCMS (Method J): RT 0.69 min [M+H]+ 389.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[O:25]C(C)=O>O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:10](=[O:25])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)C(=O)C1
Reaction time: 0.5 h

Procedure:
4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (13 g) in AcOEt (300 ml) was added at RT under an argon atmosphere to a vigorously stirred solution of RuCl3×H2O (1.71 g) and NaIO4 (44.078 g) in water (300 ml). This mixture was vigorously stirred 30 minutes at RT. Then water and AcOEt were added and the layers were separated. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated to give the crude product as brown oil (8.78 g) which was used in next reaction step without further purification. MS (ESI): 352.17 (M+Na)+ and 230.13 [(M-C5H8O2)H+]
Reaction SMILES: C([CH2:3][C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1)([CH3:8])[C:5]([OH:7])=[O:6])C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>CO>[S:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:16]1[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:4]([CH3:3])([CH3:8])[C:5]([OH:7])=[O:6])=[CH:15][CH:14]=1
Reactant: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Reactant: Nc1ccccc1S
Solvent: CO
Product: CC(C)(Oc1ccc(-c2nc3ccccc3s2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
In a methanol solvent, a solution including Compound 97c (1.0 eq.) and 2-aminothiophenol (1.0 eq.) was stirred at room temperature. After methanol was removed, the precipitate was filtered, and washed with cold methanol to obtain a solid target product.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:10][C:9]=2[F:23])[C:3]1=[O:24].[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33](Cl)(=[O:35])=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:18]=[CH:17][N:16]=[C:15]4[CH2:19][N:20]([CH3:21])[CH3:22])=[CH:10][C:9]=3[F:23])[C:3]2=[O:24])(=[O:35])=[O:34])=[CH:28][CH:27]=1
Reactant: CN(C)Cc1nccn1-c1ccc(N2CCCN(N)C2=O)c(F)c1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Solvent: ClCCl
Product: CN(C)Cc1nccn1-c1ccc(N2CCCN(NS(=O)(=O)C=Cc3ccc(Cl)s3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.6 mg (0.046 mmol) of the diHCl salt of 1-amino-3-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluorophenyl)-tetrahydropyrimidin-2(1H)-one prepared as above, were dissolved in 3 mL of anhydrous CH2Cl2. To this solution placed under N2 atmosphere were added 50 μL of TEA followed by 11.2 mg (0.046 mmol) of 2-(5-chlorothiophen-2-yl)ethenesulfonyl chloride. The mixture was stirred at room temperature overnight. An additional 3 mL of CH2Cl2 were added, and the mixture was washed twice with 2 mL of saturated NaHCO3 solution. The organic phase was dried and concentrated to yield 17.2 mg of a brown oil. A pur compound was obtained after purification by preparative HPLC. 1H NMR (500 MHz, MeOD) δ 7.53 (t, 1H), 7.49 (s, 1H) 7.41 (d, J=10.4 Hz, 1H), 7.29 (s, 1H), 7.27 (d, J=8.2 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.86 (d, J=3.8 Hz, 1H), 5.1 (m, 1H), 4.45 (q, 2H), 3.5 (m, 2H), 3.14 (m, 1H), 2.86 (s, 6H), 2.0 (m, 2H), ppm. LC-MS (ESI) 556.8 [M+NH4]+, tR=4.645 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 ml/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H25ClFN6O3S2 [M+H]+ 539.1102, found 539.1105.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])(=O)[CH3:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][C:1](=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)C1CC(C)(C)CCC1=O
Solvent: ClC(Cl)Cl
Product: CC(Cl)=C1CC(C)(C)CCC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
At 0° C., a solution of 2-acetyl-4,4-dimethyl-cyclohexanone (5.00 g, 29.7 mmol) in chloroform (15 mL) is treated with oxalyl chloride (7.54 g, 59.4 mmol). The mixture is heated to 60° C. and stirred for 15 min before it is poured onto water. The organic phase is separated, washed with sat. aq. NaHCO3 solution and brine, dried over MgSO4 and evaporated to dryness to give crude 2-(1-chloro-ethylidene)-4,4-dimethyl-cyclohexanone (3.2 g, containing regio-isomer) as a brown oil, LC-MS: tR=1.00 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Yield: 96.6 %

Procedure:
A solution of 2-amino-5-chloropyridine (0.064 g, 0.5 mmol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (0.156 g, 0.5 mmol) in acetonitrile (3 ml) is stirred at 100° C. for 18 hr. The mixture is concentrated and purified on silica (0 to 100% EtOAc in hexanes) to give the title compound (165 mg, 97% yield). LCMS m/z=342.3 [M+H]+, tR=2.86 min.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([C:22](O)=[O:23])=[CH:10]2)=[O:5].CN(C)CCCN=C=NCC.Cl.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][C:2]([CH3:1])([CH3:26])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([C:22]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[CH:44][CH:45]=1)=[O:23])=[CH:10]2)=[O:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
75 mg (0.21 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-phenyl-1H-indole-2-carboxylic acid from Example LIX, 61.55 mg (0.32 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 13.1 mg (0.11 mmol) of 4-dimethylaminopyridine are initially charged in 4 ml of dichloromethane. 44.6 mg (0.21 mmol) of tert-butyl 4-aminophenylcarbamate are added, and the mixture is stirred at RT for 3 hours. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH:6]=[C:7]([NH2:9])[NH2:8])[CH3:3].C(N(CC)CC)C.[C:18](#[N:21])[CH:19]=[CH2:20]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:10])[C:6]([CH2:20][CH2:19][C:18]#[N:21])=[C:7]([NH2:9])[NH2:8])[CH3:3]
Reactant: CCOC(=O)C=C(N)N
Reactant: C=CC#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCC#N)=C(N)N
Yield: 25 %

Procedure:
The resulting 3,3-diamino-acrylic acid ethyl ester hydrochloride (2.2 g, 13.2 mmol) was suspended in tetrahydrofuran (40 mL), triethylamine (2 mL, 14.3 mmol) and acrylonitrile (1.2 mL, 19.3 mmol) were added thereto, and the solution was refluxed for 6 hours. After the reaction was completed, the resulting triethylamine hydrochloride was filtered, and the filtrate was concentrated to obtain the title compound (0.6 g, 3.3 mmol, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>CC(=O)CC>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH2:6][NH:7][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17]
Reactant: O=S1(=O)CCCO1
Reactant: COc1cc(CN)cc(OC)c1OC
Solvent: CCC(C)=O
Product: COc1cc(CNCCCS(=O)(=O)O)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 3,4,5-trimethoxybenzylamine (2.2 mL, 12.7 mmol) in 2-butanone (20 mL) was added 1,3-propane sultone (1.66 g, 13.3 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 90% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec., the solid was collected by filtration, and dried in vacuo; affording compound AY, 2.61 g (64%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][S:21]([CH3:23])=[O:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].CO.I([O-])(=O)(=O)=[O:36].[Na+]>O>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][S:21]([CH3:23])(=[O:36])=[O:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CS(=O)CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 17 h
Yield: 12.7 %

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-ethoxyamino)-methyl]-benzamide (10 mg, 0.017 mmol) obtained in Example 10 in a mixed solvent of methanol (1.8 mL) and water (0.2 mL) was added sodium metaperiodate (6 mg, 0.026 mmol) at room temperature, and the mixture was stirred for 17 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-ethoxyamino)-methyl]-benzamide (1.3 mg, 13%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.CC(O)=O>CCO>[Cl:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[N:1]/[C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(/N=C/c2ccc(Cl)cc2)cn(C)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a stirred solution of 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) (5.2 g, 37.6 mmol) in EtOH (100 mL) were added 4-chlorobenzaldehyde (5.04 g, 35.8 mmol) and AcOH (0.410 mL, 7.17 mmol). The resulting mixture was heated up and stirred at 85° C. for 1 hr. The reaction was concentrated under reduced pressure and the resulting crude mixture was triturated in Et2O to afford the title product (7.6 g, 29.2 mmol) as beige solid. tR: 0.92 min (LC-MS 2).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].Br[CH:14]([C:16]1[N:21]2[N:22]=[CH:23][N:24]=[C:20]2[N:19]=[CH:18][CH:17]=1)[CH3:15]>COCCOC>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:14]([C:16]2[N:21]3[N:22]=[CH:23][N:24]=[C:20]3[N:19]=[CH:18][CH:17]=2)[CH3:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: CCSc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCSc1ccc(OC(C)c2ccnc3ncnn23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(ethylthio)phenol (1.54 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of diethylether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.28 g, (m.p. 65°-67° C.).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([SH:15])[CH:10]=1.CC(C)([O-])C.[K+].Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH:10]=1
Reactant: Clc1ccc(Br)nc1
Reactant: COC(=O)c1cccc(S)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Sc2ccc(Cl)cn2)c1
Yield: 79.7 %

Procedure:
To a dimethylformamide (7.0 mL) solution of 3-mercapto-benzoic acid methyl ester (600 mg, 3.5 mmol) was added potassium t-butoxide (500 mg, 4.0 mmol). Upon stirring the reaction at room temperature for 15 min, 2-bromo-5-chloro-pyridine (700 mg, 3.5 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(5-chloro-pyridin-2-ylsulfanyl)-benzoic acid methyl ester (780 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.C1CCCCC1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1COCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)CC(=O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of NaH (60% suspension in mineral oil, 1.42 g, 36 mmol) in dry THF (50 mL) was added ethyl acetoacetate (4.3 g, 33 mmol) dropwise at 0° C. After 10 min stirring at this temperature, a 2.0 M solution of n-BuLi in cyclohexane (17.7 mL, 35 mmol) was added dropwise under N2. The stirring was continued at 0° C. for 10 min., 4-fluorobenzyl bromide (9.45 g, 50 mmol) was then added dropwise at 0° C. The resultant solution was allowed to warm to rt. After 20 min, the reaction as quenched with 2 N HCl/Et2O (20 mL/40 mL). Layers were separated, the aqueous layer was extracted with ether (3×50 mL). Combined ether solution was washed with H2O (50 mL), brine (50 mL), and dried with Na2SO4. After removal of the solvent under reduced pressure, the resultant oily material was purified by flush column chromatography on silica gel (hexane to 4:1 hexane/EtOAc). The corresponding intermediate 5-(4-Fluoro-phenyl)-3-oxo-pentanoic acid ethyl ester was obtained as a colorless liquid (7.16 g, 92%). 1H NMR (300 MHz, CDCl3) δ1.25 (t, 3H, J=7), 2.80-2.95 (m, 4H), 3.40 (s, 2H), 4.10-4.25 (m, 2H), 6.9-7.0 (m, 2H), 7.1-7.2 (m, 2H). ESMS calcd (C13H15FO3): 238.1; found: 239.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:16][NH:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:17]([CH3:18])[CH3:16])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 7 h
Yield: 61 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-fluoro-2-nitro-benzoic acid methyl ester (J. Fluorine Chem.; 63; 1-2; (1993); 25-30) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 7 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 8a was obtained in 61% yield (3.08 g, 13.7 mmol).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].FC(F)(F)C([O-])=O.[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:25]=1[CH:38]1[CH2:42][CH2:41][NH2+:40][CH2:39]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:5]([O:4][C:2]([N:40]1[CH2:41][CH2:42][CH:38]([C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:24]=2[O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:39]1)=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: c1ccc(COc2ccc(C3CC[NH2+]C3)c(OCc3ccccc3)c2)cc1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
In a 10 ml round-bottomed flask, 0.25 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is dissolved in 5 ml of tetrahydrofuran in the presence of 0.25 ml of N,N-diisopropylethylamine. 0.108 g of isobutyl chloroformate is added and the reaction mixture is stirred for 30 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 0.22 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutyl ester is obtained. Yield=66%.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCOCC>CN(C=O)C>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(NCCn2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quin-oline-1,10-dione (1.00 g, 2.7 mM, prepared in Example 4a. and p-anisidine(1.33 g, 10.8 mM) were stirred and heated to reflux in DMF (20 mL) for 1.5 hours to give a brown solution. The solution was cooled to room temperature and ether (80 mL) was added to give a dark suspension. The suspension was stirred for two hours and filtered. The collected solids were washed with ether (150 mL) to give the title compound as a tan powder(1.17 g, 60%), mp 239°-241° C.; MS(CI): 413.
Reaction SMILES: ClC1C=CC(C2C3CN([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])CC3ON=2)=CC=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[CH3:53][O:54][C:55]1[N:60]=[CH:59][C:58]([C:61]2[C@@H:65]3[CH2:66][NH:67][CH2:68][C@@H:64]3[O:63][N:62]=2)=[CH:57][CH:56]=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:67]3[CH2:68][CH:64]4[CH:65]([C:61]([C:58]5[CH:59]=[N:60][C:55]([O:54][CH3:53])=[CH:56][CH:57]=5)=[N:62][O:63]4)[CH2:66]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: COc1ccc(C2=NO[C@H]3CNC[C@@H]23)cn1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2=NOC3CN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5-c4ccc(F)cc4F)CC23)cn1

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using TFA salt 4c. Acid 102 was isolated as a tan solid.