Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:50])/[C:15](=[N:29]\[O:30][C:31]3([C:34]([O:36][CH:37]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:35])[CH2:33][CH2:32]3)/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:11](=[O:51])[NH:10]2)[N:4]=1.N1([C:57]([O:59][CH2:60][CH2:61][NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[O:58])C=CN=C1>C(Cl)Cl>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:29]/[O:30][C:31]2([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:33][CH2:32]2)/[C:14]([NH:13][C@@H:12]2[C:11](=[O:51])[NH:10][C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:57](=[O:58])[O:59][CH2:60][CH2:61][NH:62][C:63](=[O:64])[O:65][C:66]([CH3:67])([CH3:68])[CH3:69])[CH:7]=[N:6]2)=[O:50])[N:17]=1)=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CN)n2)cs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (90 mg, 0.13 mmol) in DCM (2 mL) at 0° C. was added a solution of 2-((tert-butoxycarbonyl)amino)ethyl 1H-imidazole-1-carboxylate (0.59 ml, 0.19 mmol) in DCM (0.6 mL). After stirring at rt for 12 h, another 3 equiv 2-((tert-butoxycarbonyl)amino)ethyl 1H-imidazole-1-carboxylate (1.18 ml, 0.38 mmol) was added. After stirring at rt for additional 60 h, the reaction mixture was partitioned between DCM (40 mL) and water (20 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-5%) to afford the title compound (64 mg, 56%). LCMS: Rt=1.09 min, m/z=903.5 (M+1) Method 2m_acidic.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH2:14]Cl)(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][S:9]2(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=1
Reactant: O=S(=O)(CCCCl)Nc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1c1ccc(Br)cc1F
Reaction time: 24 h
Yield: 122.3 %

Procedure:
N-(4-bromo-2-fluorophenyl)-3-chloropropane-1-sulfonamide (8.27 g, 0.025M) and potassium carbonate (5.10 g, 0.0375M) was dissolved in dimethylformamide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for a further 24 hrs after which time it was partitioned between diethylether (500 ml) and water (500 ml). The organics were washed with 1N HCl (300 ml) and then water (100 ml) The organics were then dried over magnesium sulfate, filtered and the solvent concentrated in vacuuo to afford the title compound as a brown oil (9.0 g). 1H NMR (CDCl3): δ 2.40-2.50 (m, 2H), 3.25-3.40 (m, 2H), 4.00 (m, 2H); 6.78 (m, 2H), 7.10 (d, J=2.56 Hz, 1H),).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:22][CH2:21][CH2:20][S:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C=CC=CC=1>C(Cl)Cl.O1CCCC1.O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:22][CH2:21][CH2:20][S:19][CH2:18]2)[C:13]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCCSC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCCSC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3(R)-(tetrahydro-thiopyran-3-yl)-propionic acid (52 mg, 0.143 mmol) in methylene chloride (1 mL) was treated with N,N-dimethylformamide (0.1 mL) and then cooled to 0° C. The reaction mixture was treated with a 2.0M solution of oxalyl chloride in methylene chloride (143 μL, 0.286 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (1 mL) and was treated dropwise with a solution of 2-aminopyrazine (27.2 mg, 0.286 mmol) in tetrahydrofuran (1 mL) and pyridine (57.8 μL, 0.715 mmol). The resulting reaction mixture was stirred at 25° C. for 30 min. The reaction mixture was then diluted with water (2 mL) and extracted with methylene chloride 3×5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 1/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-pyrazin-2-yl-3 (R)-(tetrahydro-thiopyran-3-yl)-propionamide (44 mg, 69.8%) as a colorless gum: EI-HRMS m/e calcd for C19H22ClN3O3S2 (M+H)+ 440.0864. found 440.0867.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1.[CH3:30][NH2:31].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.CO.CC(O)C>[CH3:27][O:26][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:28][CH3:29])[N:3]=[C:2]([NH:31][CH3:30])[N:11]=[C:10]2[C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2nc(Cl)nc(-c3cccc(NC(=O)OC(C)(C)C)c3)c2cc1OC
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(-c2cccc(NC(=O)OC(C)(C)C)c2)c2cc(OC)c(OC)cc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
In a SUS autoclave were placed 420 mg (1.00 mmol) of t-butyl [3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]carbamate, tetrahydrofuran (2.5 mL), and 2-propanol (1.25 mL), to this mixture was added a methanol solution (2.5 mL) of 40% methylamine, and the mixture was stirred at 90° C. for 8 hours. The reaction mixture was allowed to cool and then poured into a mixed solution of ethyl acetate (40 mL), tetrahydrofuran (40 mL), and 5% w/w sodium chloride solution (50 mL) to extract the organic layer. The organic layer was washed with 5% w/w sodium chloride solution (50 mL) and then concentrated under reduced pressure. To the concentration residue was added t-butyl methyl ether (2.1 mL), and the mixture was crystallized with a spatula and then stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration and dried to give 348 mg of a target product (yield: 83.8%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[O:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C:7]1=[O:12]>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:9]1[CH2:10][CH2:11][O:6][C:7](=[O:12])[CH2:8]1)[CH3:2]
Reactant: CCNCC
Reactant: O=C1C=CCCO1
Product: CCN(CC)C1CCOC(=O)C1
Reaction time: 20 h

Procedure:
At 20 to 30° C., 4.00 g of diethylamine was added to 5.10 g of 5,6-dihydro-2H-pyran-2-one. The resulting mixture was allowed to stand for 20 hours, followed by concentration under reduced pressure, whereby β-(diethylamino)-δ-valerolactone was obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)[CH2:13][CH2:14]CC>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCC(=O)Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCCCC(=O)CC(=O)OC
Yield: 95.5 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 138.7 g (1.15 mol) of valeryl chloride. The pH in this gave 151 g (GC purity 82.5%) of methyl valerylacetate (yield 79.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[H-].[Na+]>CN(C=O)C.C1COCC1>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][CH:2]([CH3:7])[C:3](=[O:12])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Reaction time: 4 h
Yield: 72 %

Procedure:
7.52 g of 2-amino-4-chloro-5-nitrophenol is added to a mixture of 1.6 g of sodium hydride in 60 ml of DMF and mixed with 1.1 equivalents of D,L-2-bromopropionic acid ethyl ester in 20 ml of THF at 5° C. It is stirred for 4 hours. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. 1.7 g of crude product, which is recrystallized from isopropyl ether, results. The yield is 72%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([CH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)([CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[O:31]1CCCC1.[C:36](Cl)(=[O:40])[C:37]([CH3:39])=[CH2:38]>O>[C:36]([OH:40])(=[O:14])[C:37]([CH3:39])=[CH2:38].[C:36]([OH:40])(=[O:31])[C:37]([CH3:39])=[CH2:38].[F:1][C:2]([F:22])([F:23])[C:3]([CH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)([CH:8]1[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1)[C:4]([F:5])([F:7])[F:6]
Reactant: C=C(C)C(=O)Cl
Reactant: C1CCOC1
Agent: OC1CCC(C(C2CCC(O)CC2)(C(F)(F)F)C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)O

Procedure:
Into a reaction vessel equipped with a stirrer, thermometer and dropping funnel were placed 0.3 mole (104.4 g) of 4,4'-(perfluoroisopropylidene)dicyclohexanol, 1 mole (101.2 g) of triethylamine and 700 ml of tetrahydrofuran. To the mixture was added dropwise 1 mole (104.5 g) of methacryloyl chloride while cooling the mixture with ice. The mixture was maintained at a temperature below 20° C. for 8 hours with stirring. The reaction mixture was poured into a large excess amount of water and the resulting precipitates were recovered and washed with methanol to obtain 69 g of 4,4'-(perfluoroisopropylidene)dicyclohexanol dimethacrylate in the form of white solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:52][O:53][C:54]1[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=1)[C:57](=[O:60])[CH2:58]Br.O>O1CCCC1>[CH3:52][O:53][C:54]1[CH:55]=[C:56]([C:57](=[O:60])[CH2:58][N:2]([CH3:1])[S:3]([C:6]2[S:7][C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[C:22]([C:45]6[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=6)=[N:23][N:24]([C:26]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:25]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:9][CH:10]=2)(=[O:5])=[O:4])[CH:61]=[CH:62][CH:63]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CN(C)S(=O)(=O)c2ccc(-c3ncnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5-c5ccc(F)cc5)cc34)s2)c1
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
50 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 5 mL tetrahydrofuran, then 0.07 mL of 1.0 M lithium bistrimethyl silyl amide was added thereto under ice-cooling, and the mixture was stirred for 0.5 hour. Under ice-cooling, a solution of 80 mg 3-methoxyphenacyl bromide in 2 mL tetrahydrofuran was added thereto and stirred for 1.5 hour. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 17 mg of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
2.0 g of 5-(4-acetoxybenzylidene)thiazolidine-2,4-dione [prepared as described in step (a) above] was dissolved in 80 ml of acetic acid and was hydrogenated by passing hydrogen at atmospheric pressure through the solution at 90° C. for 5 hours in the presence of 2.0 g of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was filtered off, and the filtrate was diluted with toluene. The acetic acid solvent was then removed by distillation as a toluene azeotrope. The crystals which separated out on adding toluene and hexane to the concentrate were collected by filtration and dried to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].N>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19. b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18 hours at 100° C. The reaction mixture was cooled to RT and excess of POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine and then dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH+, 171.34. c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) was charged to high pressure autoclave PV10832 (Parr 160 ml) with methylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions containing product were evaporated and the residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H, dd), 6.79-6.84 (1H, m); m/z: (ES+) MH+, 166.31.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH:20]1([CH:23]2[NH:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH:20]1([CH:23]2[NH:28][CH2:27][CH2:26][N:25]([C:2]3[CH:11]=[C:10]4[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]4[CH:12]4[CH2:14][CH2:13]4)=[CH:4][C:3]=3[F:19])[CH2:24]2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNC(C2CC2)CN1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C4CC4)C3)c(F)cc2c1=O
Temperature: 140 °C
Yield: 17.5 %

Procedure:
A mixture of 787 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.736 g of 3-cyclopropylpiperazine and 8 ml of pyridine was heated at 140° C. in a pressure bottle for 18 hours and then purified as described in Example 95, giving 182 mg of the desired product, mp 245° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22].[CH2:24](O)[CH3:25].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCO
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reaction time: 8 h
Yield: 85 %

Procedure:
6.9 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid, 70 ml of ethanol and 4 g of concentrated sulfuric acid are heated at boiling for 8 hours. The liquid is reduced in volume, poured into water and ice, extracted with ether, washed with sodium carbonate solution, the organic solution is dried and reduced in volume. Ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate is obtained with a yield of 85%; F 51.5°-52.5°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17][CH:18]1[CH2:22][CH2:21][C:20](=O)[C:19]1=[O:24].C(O)(=O)C>C(O)C>[CH3:17][CH:18]1[C:19](=[O:24])[C:20]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)=[CH:21][CH2:22]1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: CC1CCC(=O)C1=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C#CC=C2CCN(C3=CCC(C)C3=O)CC2)n1

Procedure:
A mixture of the Compound of Example 3 (500 mg, 2.36 mmol), 3-methyl-1,2-cyclopentanedione (350 mg, 3.11 mmol), acetic acid (0.18 mL, 3.11 mmol) in ethanol (10 mL) was refluxed for 8 h. The reaction mixture was evaporated, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 85:15, affording the title product as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1.ClCCl>O1CCCC1.CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=3)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.050 g, 0.16 mmol) was suspended in tetrahydrofuran (30 mL). N,N-diisopropylethylamine (28 μL, 0.16 mmol) was added to the suspension and then nicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour by which time a solution was obtained. Thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher Rf and only a trace of starting material. Aminomethyl resin (100 mg) was added and the reaction mixture was stirred for 5 minutes. The solvent was removed under vacuum. The residue was dissolved in dichloromethane and placed on a layer of silica gel. The silica gel was eluted first with dichloromethane and then with 9:1 dichloromethane:methanol. The cleanest fractions were combined and then concentrated under vacuum to provide N3-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]nicotinamide as a white powder. 1H NMR (300 MHz, CDCl3)™ 8.91 (m, 1H), 8.68 (d, J=4.5 Hz, 1H), 8.45 (d, J=4.3 Hz, 1H), 8.03 (m, 2H), 7.30-7.40 (m, 2H), 6.98 (s, 2H), 5.51 (s, 1H), 4.86 (apparent t, J=7.9 Hz, 2H), 3.66 (q, J=6.5 Hz, 2H), 2.92 (apparent t, J=7.7 Hz, 2H), 2.05 (m, 2H), 1.75-1.95 (m, 4H), 1.51 (m, 2H), 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C23H27N7O (M+) 417.2277, found 417.2276.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([S:87][CH2:88][C:89]3[N:90]=[C:91]([C:94]4[CH:99]=[CH:98][C:97]([Cl:100])=[CH:96][CH:95]=4)[S:92][CH:93]=3)[N:82]=[C:81]([N:101]3[CH2:104][CH2:103][CH2:102]3)[C:80]=2[C:105]#[N:106])=[CH:75][CH:74]=1)=[O:68])[CH3:66]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([S:87][CH2:88][C:89]3[N:90]=[C:91]([C:94]4[CH:95]=[CH:96][C:97]([Cl:100])=[CH:98][CH:99]=4)[S:92][CH:93]=3)[N:82]=[C:81]([N:101]3[CH2:102][CH2:103][CH2:104]3)[C:80]=2[C:105]#[N:106])=[CH:75][CH:74]=1)=[O:68])[CH3:66])=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
32.73 mg (0.094 mmol) of N2,N6-bis(tert-butoxycarbonyl)-L-lysine were initially charged in 1.5 ml of DMF. 19.8 mg (0.103 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 17.4 mg (0.129 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 55.5 mg (0.429 mmol) of N,N-diisopropylethylamine were added, and the mixture was then stirred at RT for 15 min, 64 mg (0.086 mmol) of 2-{4-(2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyanopyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate (Example 45) were then added and the mixture was stirred at RT overnight. The crude product was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 76 mg (92% of theory) of the target compound.