Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl.C(O)C.O.O.[Sn](Cl)Cl>>[CH2:13]([CH:9]1[NH:8][C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:15][C:10]1=[O:11])[CH3:14]
Reactant: CCC(Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCC1Nc2ccc(F)cc2NC1=O
Temperature: 78 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
The heterogeneous mixture of 2-(4-fluoro-2-nitrophenylamino)butanoic acid (181.7 g, 750.0 mmol), 3 N aq. HCl (750.0 ml, 2250 mmol), and ethanol (1923 ml, 750.0 mmol) in 5-L three neck round bottom flask was added Tin(II) chloride dihydrate (507.7 g, 2250 mmol) and the organe mixture was heated at 78° C. with stirring using an overhead stirrer for 4 h ([Note 1]: The orange heterogeneous mixture became an orange homogeneous mixture and the orange color changed to a red color over ˜2 hour). After 4 h, the mixture was cooled to rt and concentrated under reduced pressure to remove ethanol, and left at rt for 48 h. The resulting yellow precipitate was collected by filtration and washed with water (500 mL). The yellow solid was suspended in ice water (1 L) and the mixture was adjusted ˜pH 13 with KOH (−250 g). The heterogeneous mixture was extracted with DCM (1 L×3). The combined organic layers were washed with water (1 L×1) and brine (1 L×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.92 g, 41.8% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 6.68 (dd, J=8.6, 5.5 Hz, 1H), 6.47-6.61 (m, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.62 (ddd, J=6.7, 5.0, 2.0 Hz, 1H), 1.50-1.72 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), Mass Spectrum (ESI) m/e=195.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13](Br)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2].[O:18]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13]([C:28]3[CH:29]=[CH:30][C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:26][CH:27]=3)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C2C=C(Br)SC2C1=O
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)CN1C(=O)C2C=C(c3ccc(Oc4ccccc4)cc3)SC2C1=O

Procedure:
The title compound was prepared from (2-bromo-4,6-dioxo-3a,4,6,6a-tetrahydro-thieno[2,3-c]pyrrol-5-yl)-acetic acid ethyl ester, example 1-d, and 4-phenoxy-phenyl boronic acid under conditions analogous to experimental example 3-a. NMR (CDCl3, 200 MHz): δ=7.58-7.54 (d, J=8.97 Hz, 2H), 7.41-7.34 (m, 3H), 7.20-7.0 (m, 4H), 4.35 (s, 2H), 4.27-4.17 (q, J=7.0, 2H), 1.32-1.25 (t, J=7.0 Hz, 3H).
Reaction SMILES: C[CH:2]([C:9]1[N:10]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([O:19][CH2:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=1)=[CH:13][CH:12]=2)[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].C1COCC1.[Li+].[OH-].Cl>CO>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)=[CH:13][CH:12]=3)[C:17]([CH3:18])=[C:9]2[CH2:2][C:3]([CH3:7])([CH3:8])[C:4]([OH:6])=[O:5])=[CH:33][CH:34]=1
Reactant: Cc1c(C(C)C(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4c3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4c3)cc12

Procedure:
A solution of the ester from Step 1 (278 mg), 3 mL THF, 3 mL MeOH, and 2.7 mL 1N LiOH was stirred at 80° C. for 4 hours under nitrogen. The solution was cooled, poured onto 1N HCl, extracted 2× EtOAc, washed 2× brine, dried (MgSO4), and evaporated. Purification of the residue by chromatography (silica gel; hexane/EtOAc 2:1) gave the title compound as a solid, m.p. 151.5°-152.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C@@H:20]([OH:22])[CH3:21])[CH:15]=1.CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9]([O:22][C@H:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH3:21])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@H](O)c1cccnc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A 534 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride in methylene chloride was added to a solution of 74 mg (0.606 mmol) of (S)-1-(3-pyridyl)ethanol and 0.080 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The mixture was stirred at 0° C. for 3.5 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 50% and 90% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.078 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15]O)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>ClCCl.O>[C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15][Br:50])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl{6-[(2,2-dimethylpropanoyl)amino]-4-(2-hydroxyethyl)pyridin-3-yl}acetate (2.30 g, 6.84 mmol) with imidazole (0.558 g, 8.20 mmol) in dichloromethane (50 mL) was treated with triphenylphosphine (1.79 g, 6.84 mmol) and carbon tetrabromide (2.72 g, 8.20 mmol). The reaction mixture was allowed to stir at room temperature for 2 h, then was diluted with water and the layers separated. The organic layer was washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4), filtered and concentrated. The residue was filtered through a short silica plug (20% EtOAc:hexanes eluent) to afford tert-butyl{4-(2-bromoethyl)-6-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}acetate which was used immediately in the next step. LC/MS (M+1)+=398.9;
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14](=[O:17])([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:5][C@@H:6]2[CH2:12][CH2:14][O:17][CH2:7]2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CN[C@@H]1CCOC1
Reaction time: 8 h

Procedure:
To a stirred solution of Example 8D (0.03 g, 0.153 mmol) and potassium carbonate (0.2 g, 1.53 mmol) in acetonitrile (2 mL), at room temperature under nitrogen was added R(+)-3-aminotetrahydrofuran toluene-4-sulfonate (0.08 g, 0.32 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 248 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2 (2H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m), 5.43-5.9 (4H, m).
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CCCCCC)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CCCCCC)c1
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A mixture of 11.64 g of 3-(2-hexyl-4-tetradecylphenoxy)-1,2-propanediol, 12.32 g of trityl chloride and 40 ml of pyridine was stirred for 24 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, water, dried and the solvents evaporated under reduced pressure. The residue was coevaporated with toluene, giving 14.6 g of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20](O)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCSc2cc(C(=O)O)c(Cl)cc21
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)NC1CCSc2cc(C(=O)Nc3ccncc3)c(Cl)cc21
Yield: 104.1 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using 4-(tert-butoxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid (200 mg), 4-aminopyridine (54.7 mg) and 2-chloro-1-methylpyridinium iodide (178 mg), the objective 4-(tert-butoxycarbonylamino)-6-chloro-N-(4-pyridyl)thiochromane-7-carboxamide (254 mg) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:6]([CH2:8][CH2:9]Cl)[N:7]=1.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:24]=[N:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C>CO>[CH3:1][S:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:22]4[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=4[N:25]=[N:24]3)[CH2:31][CH2:30]2)=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:4]=1
Reactant: CSc1nc(CCCl)c(-c2ccc(F)cc2)[nH]1
Reactant: Fc1ccc2c(c1)nnn2C1CCNCC1
Agent: CSc1nc(-c2ccc(F)cc2)c(CCCl)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CSc1nc(-c2ccc(F)cc2)c(CCN2CCC(n3nnc4cc(F)ccc43)CC2)[nH]1
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 0.141 g of 2-methylthio-4-(2-chloroethyl)-5-(4-fluorophenyl)imidazole, 2-methylthio-5-(2-chloroethyl)-4-(4-fluorophenyl)imidazole, 0.095 g of 4-(5-fluoro-1H-benzotriazol-1-yl)piperidine, 0.19 ml of diisopropylethylamine and 0.6 ml of methanol was stirred with heating under reflux for 17 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Chromatorex NHDM1020, eluent: hexane-ethyl acetate=1:3). The purified product was recrystallized from ethanol-hexane to obtain 0.104 g of 2-methylthio-4-(4-fluorophenyl)-5-[2-[4-(5-fluoro-1H-benzotriazol-1-yl)piperidin-1-yl]ethyl]imidazole {2-methylthio-5-(4-fluorophenyl)-4-[2-[4-(5-fluoro-1H-benzotriazol-1-yl)piperidin-1-yl]ethyl]imidazole}.
Reaction SMILES: Br[C@@:2]1([O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@H:14]([O:15][CH:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:4]1[O:5][C:6](=[O:8])[CH3:7])O.CC1C=C(C)C=C(C)N=1.[Br:55][CH2:56][CH2:57][OH:58]>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:6]([O:5][C@@H:4]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:14]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:2]1[O:58][CH2:57][CH2:56][Br:55])(=[O:8])[CH3:7]
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: OCCBr
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 23 h
Yield: 76.2 %

Procedure:
A solution of the crude acetobromo sugar 49 (20.5 g; 29.3 mmol) in dry methylene chloride (100 ml) was added dropwise (ca 20 min) to a cold (-78°) solution of silver trifluoromethanesulfonate (nonpurified, commercial material; 10.3 g; 40 mmol), 2,4,6-tri-methylpyridine (3.6 g; 30 mmol) and 2-bromoethanol (17.5 g; 140 mmol) in methylene chloride (250 ml) under nitrogen. The reaction mixture was stirred in the dark for 23 h during which time it had reached room temperature. The yellowish-white precipitate, that had formed, was removed and the resulting colorless solution was washed consecutively with 1M hydrochloric acid, water, saturated sodium hydrogen carbonate solution and water. Drying (sodium sulfate), filtration and evaporation gave a residue which crystallized spontaneously. Recrystallization from ethyl acetate, followed by evaporation of the mother liquor and recrystallization from methanol, gave a total of 16.6 g (77%) of the title compound 15. Melting point and optical rotation are shown in Table 1 and the 13C- and 1H-NMR data are shown in Table 2 and 3 , respectively.
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].[CH:23]1([N:29]=[C:30]=[S:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]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][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[S:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: S=C=NC1CCCCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)NC1CCCCC1
Yield: 60 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with cyclohexyl isothiocyanate (794 mg, 5.62 mmol) to provide 1.35 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylthiourea as a tan powder, m.p. 199-200° C. Analysis: Calculated for C23H32N6OS: % C, 62.70; % H, 7.32; % N, 19.07. Found: % C, 62.37; % H, 7.20; % N, 18.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16](O)=[O:17])=[N:9][NH:8][C:7]2=[O:23].[CH2:24]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[C:15]([C:16]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH2:24][CH3:25])[CH2:28][CH2:29]3)=[O:17])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: O=C(O)c1cc(F)cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Reactant: CCOC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC1CCN(C(=O)c2cc(F)cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Reaction time: 1 h

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-fluorobenzoic acid (128), 4-ethoxypiperidine and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate were dissolved in DMF (10 mL), to this was added DIPEA and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam (130 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 2.00-1.38 (4H, m), 3.29-3.05 (1H, m), 3.57-3.34 (5H, m), 4.08-3.91 (1H, m), 4.68 (2H, s), 6.90 (1H, d), 6.97-6.94 (2H, m), 7.67 (1H, t), 7.80 (1H, d), 8.50 (1H, dd); NH missing; m/z (LC-MS, ESI+), RT=2.06 (M+H 444).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([NH2:24])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25]([CH:30]1[CH2:35][C:34](=[O:36])NC1=O)(OCC)=[O:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:19][CH2:20][CH:21]([N:24]1[C:25](=[O:26])[CH2:30][CH2:35][C:34]1=[O:36])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)C1CC(=O)NC1=O
Reactant: CCCCCCCCCCCCCCCCCCOCC(N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(CO)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 21 %

Procedure:
A mixture of 3.43 g (10 mmoles) of 3-octadecyloxy-2-aminopropanol synthesized according to the method of J. Hajdu et al. [J. Org. Chem., 48, 1197-1202 (1983)] and 1.73 g (10 mmoles) of carboethoxysuccinimide in 50 ml of dichloromethane was stirred, and 1.01 g of triethylamine was added to the mixture under ice-cooling. The resulting mixture was stirred at room temperature for 30 hours and concentrated to dryness. The residue was purified by silica gel chromatography to give 894 mg of the desired 2-succinimidopropane derivative.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]2[CH:9]([CH2:10][CH2:11][CH3:12])[O:8]2)=[O:6])[CH2:3][CH2:2]1.[N-:13]=[N+:14]=[N-:15].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[N:13]([CH:9]([CH2:10][CH2:11][CH3:12])[CH:7]([OH:8])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6])=[N+:14]=[N-:15]
Reactant: CCCC1OC1C(=O)NC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCC(N=[N+]=[N-])C(O)C(=O)NC1CC1
Temperature: 65 °C

Procedure:
A flask equipped with an overhead stirrer, thermometer and reflux condenser was placed under a nitrogen atmosphere then charged with compound 38 (20.0 g, 118 mmol), sodium azide (NaN3; 31.0 g, 473 mmol), magnesium sulfate (MgSO4; 14.0 g, 118 mmol) and methanol (MeOH; 200 mL). The mixture was heated to 65±5° C. for 2 hours then cooled to 25±S ° C. and filtered through a pad of Celite 545. The solvent was removed under reduced pressure resulting in a thick oil which was taken up in IPAc (250 mL) then washed with water (3×250 mL). The organic phase was dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide compound 40 as a white solid. 1H NMR (500 MHz, d6-DMSO) 7.87 (s, 1H), 5.97 (d, J=6.0, 1H), 4.02 (dt, J=6.0, 3.8 Hz, 1H), 2.70-2.65 (m, 1H), 1.60-1.20 (m, 4H), 0.88 (t, J=7.0 Hz, 3H), 0.63-0.58 (m, 2H), 0.51-0.46 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1C(OC(C)(C)C)=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:37]3[CH2:36][CH2:35][NH:34][C@@H:33]([CH3:32])[CH2:38]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](C)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-methylpiperazine-1-carboxylic acid, tert-butyl ester and purified by HPLC.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]3[CH3:22])[CH:7]=[CH:8][CH:9]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[CH3:49][C:50]1([CH3:64])[O:54][CH:53]([CH2:55]OS(C(F)(F)F)(=O)=O)[CH2:52][O:51]1>CN(C=O)C>[CH3:49][C:50]1([CH3:64])[O:54][CH:53]([CH2:55][N:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[C:18]3[C:13]([N:14]([CH3:22])[C:15](=[O:21])[N:16]([CH3:20])[C:17]3=[O:19])=[CH:12]2)[CH2:52][O:51]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O
Reactant: CC1(C)OCC(COS(=O)(=O)C(F)(F)F)O1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC3COC(C)(C)O3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil) (234 mg, 5.86 mmol) was added portionwise to a solution of 5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate Nf) (1000 mg, 3.66 mmol) and dibenzo-18-crown-6 (132 mg, 0.366 mmol) in DMF (28.1 mL) at 0° C. The solution was warmed to room temperature and stirred for 20 minutes, then re-cooled to 0° C. (2,2-Dimethyl-1,3-dioxolan-4-yl)methyltrifluoromethane sulfonate (Intermediate Sb) (1547 mg, 5.86 mmol) was added dropwise over 5 minutes. The mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with saturated NH4Cl(aq) (10 mL) and extracted with DCM (3×30 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum to afford the title compound as a red/brown amorphous solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:5]=1[C:6]([NH2:8])=[NH:7].C1O[C:18]2([CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)OC1>>[ClH:1].[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([N:21]2[CH2:22][CH2:23][C:18]3([N:7]=[C:6]([NH2:8])[C:5]4[C:4](=[C:12]([F:13])[CH:11]=[CH:10][C:9]=4[F:14])[NH:3]3)[CH2:19][CH2:20]2)=[O:33])=[CH:30][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reactant: N=C(N)c1c(F)ccc(F)c1N
Agent: Cl
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)N=C(N)c2c(F)ccc(F)c2N3)cc1

Procedure:
This was prepared with 2-amino-3,6-difluorobenzamidine dihydrochloride (Example G) and 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal by the method of Example 1 to give the title compound as a yellow solid, m.p >270° C., MS (+CI) 382 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:30])[C:13](=[O:29])[C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:17]([O:27][CH3:28])=[CH:16][CH:15]=3)=[O:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>CN(C)C=O>[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH:2][C:3]2([C:6]([NH:8][CH2:9][CH2:10][C:11]3[N:12]([CH3:30])[C:13](=[O:29])[C:14]4[C:19]([C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][C:17]([O:27][CH3:28])=[CH:16][CH:15]=4)=[O:7])[CH2:5][CH2:4]2)=[O:45])=[CH:42][CH:41]=1
Reactant: COc1ccc2c(=O)n(C)c(CCNC(=O)C3(N)CC3)c(-c3ccccc3)c2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2(C(=O)NCCc3c(-c4ccccc4)c4cc(OC)ccc4c(=O)n3C)CC2)cc1
Reaction time: 72 h

Procedure:
To a solution of 1-amino-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide hydrochloride (30 mg, 0.117 mmol) in 3 mL of dimethylformamide was added triethylamine (0.049 mL, 0.35 mmol), followed by 4-(methoxy)benzoyl chloride (24 mg, 0.14 mmol). After 3 days, the mixture was concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. ESI+MS: 526.0 [M+H]+.