Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[S:16][C:17]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:15]2[S:16][C:17]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.099 g, 0.533 mmol), 2-chloro-6-fluoro-1,3-benzothiazole (0.100 g, 0.533 mmol) and diisopropylethylamine (0.185 ml, 1.066 mmol) in DMSO (0.5 mL) contained in a microwave vial was capped and heated to 120° C. for 2 hrs. The mixture was diluted with water and extracted with EtOAc. EtOAc extract was concentrated to give crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate. To the crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate was added hydrogen chloride, 4N in 1,4-dioxane (10 ml, 40.0 mmol) and the resulting solution stirred at room temperature for 2 h and concentrated to afford crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride. The crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride was added to mixture of methyl (2-chloropyridin-3-yl)(methyl)carbamate, INTERMEDIATE 40, (0.107 g, 0.533 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl)]2-(2-aminoethyl)Ph)Pd(II) (0.021 g, 0.027 mmol), and sodium tert-butoxide (0.261 ml, 2.132 mmol) in dioxane (10 mL). The mixture was stirred at 100° C. for 2 h and concentrated. The residue was diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO on silica gel column eluting with 0-80% EtOAc/hexanes to give the title compound 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.092 g, 0.249 mmol, 46.7% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 8.07 (dd, J=5.18, 1.27 Hz, 1 H), 7.49 (dd, J=8.90, 4.79 Hz, 1 H), 7.32 (dd, J=8.12, 2.64 Hz, 1 H), 7.17 (dd, J=7.73, 1.27 Hz, 1 H), 6.97-7.07 (m, 2 H), 5.90 (br. s., 1 H), 5.33-5.50 (m, 1 H), 4.48-4.74 (m, 1 H), 3.48-3.67 (m, 2 H), 3.43 (s, 3 H), 2.34-2.63 (m, 2 H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:26]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:26])[C:3](=[O:2])[N:13]([C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)N[C@@H](C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n([C@@H](C)c2ccccc2)c1C
Temperature: 25 °C
Yield: 42 %

Procedure:
MeOH (150 mL) was added to a flask containing (5)-4-[1-(1-phenyl-ethylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (4.81 g, 15.9 mmol). NaOMe solution (3.6 mL, 15.9 mmol, 4.375 M in MeOH) and N-bromosuccinimide (3.4 g, 19 mmol) were added, and the resulting mixture was refluxed for 6 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl (100 mL) was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 2.34 g of the title compound as a yellow solid. MS: (+) m/z 372.20, 374.16 (M+Na, 79/81Br).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:25][C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)[C:9]=2[C:10]([O:15][CH3:16])=[N:11][CH:12]=1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (30.3 mg) obtained in Step A of Example 286 in DMF (2 mL) was added N-chlorosuccinimide (13.0 mg) at 0° C., and the mixture was stirred overnight at 80° C. To the reaction mixture was added N-chlorosuccinimide (6.0 mg), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added N-chlorosuccinimide (6.0 mg), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound (19.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CC(C)=O>[CH2:20]([N:22]([CH2:23][CH3:24])[C:10](=[O:19])[C:11]1[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=1[C:13]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[F:1])=[O:14])[CH3:21]
Reactant: CCNCC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Solvent: CC(C)=O
Product: CCN(CC)C(=O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
In 50 ml of acetone is dissolved 2.8 g of N-(2-fluoro-4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide. To the solution is added 0.8 g of diethylamine under stirring at room temperature. After further stirring for 30 minutes, the solution is concentrated to dryness under reduced pressure, followed by adding 50 ml of n-hexane to cool. The resultant crystals are recovered by filtration and recrystallized from n-hexane, to yield 2.0 g of the subject compound. Melting point: 105° C.-106° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[S:13][C:6]=12.NC1C=CC(OC2C=CN=C3C=C(C(N4CCCC4)=O)SC=23)=C(F)C=1>>[CH3:23][N:21]([CH2:20][C:16]1[CH:15]=[C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:24]=[CH:25][C:26]([NH2:28])=[CH:27][C:2]=3[F:1])[CH:11]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: CN(C)Cc1cccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Product: CN(C)Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Yield: 44 %

Procedure:
Starting from the compound 149 and following the same procedure as described above for the synthesis of compound 23 (scheme 6), title compound 150 was obtained in 44% yield MS (m/z): 394.0 (M+H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[C:16]([OH:17])=[C:15]([F:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl.O>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:15]([F:18])[C:16]=1[O:17][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: CCCCOc1ccc(Br)c(O)c1F
Reactant: COCCOCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(Br)c(OCOCCOC)c1F
Reaction time: 8 h
Yield: 99.8 %

Procedure:
60.4 ml (0.355 mol) of ethyldiisopropylamine were added with ice-cooling to 77.4 g (0.294 mol) of 6-bromo-3-butoxy-2-fluorophenol dissolved in 500 ml of dichloromethane, 40.3 ml (0.355 mol) of 2-methoxyethoxymethyl chloride were added dropwise, and the mixture was left to stirr overnight at room temperature. The batch was hydrolysed using water, extracted with dichloromethane and evaporated, and the crude product was filtered through silica gel with n-heptane/MTB ether (3:1), giving 103 g (99%) of 1-bromo-4-butoxy-3-fluoro-2-(2-methoxyethoxymethoxy)benzene as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:3]=1.N1C=CC=C(B(O)O)C=1.[CH3:29][C:30]1[O:31][CH:32]=[CH:33][N:34]=1.CC([O-])=O.[K+]>CO.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(N(C)C)=O>[CH3:19][O:18][C:15]1[N:14]=[CH:13][C:12]([C:4]2[CH:3]=[C:2]([C:32]3[O:31][C:30]([CH3:29])=[N:34][CH:33]=3)[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=2)=[CH:17][CH:16]=1
Reactant: Cc1ncco1
Reactant: COc1ccc(-c2cc(Cl)n3nc(N)nc3c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: OB(O)c1cccnc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cc(-c3cnc(C)o3)n3nc(N)nc3c2)cn1

Procedure:
A mixture of 5-Chloro-7-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced similar to Example 1A but substituting 6-methoxy-pyridine-3-boronic acid for 3-pyridine boronic acid (300 mg, 1.09 mmol), 2-methyl-oxazole (450 mg, 5.4 mmol), [Pd(PPh3)4] (130 mg, 0.11 mmol), KOAc (534 mg, 5.45 mmol) and DMA (4 mL) was microwaved at 200° C. for 15 min. The cooled mixture was taken up in MeOH/CHCl3, filtered through Celite, and then the filtrate was pre-adsorbed on SiO2. Column chromatography (3% MeOH/CHCl3) gave a solid which was triturated with a 1:1 mixture of DCM/hexane. Filtration gave 7-(6-methoxy-pyridin-3-yl)-5-(2-methyl-oxazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine.
Reaction SMILES: [O:1]=[C:2]1[N:13]2[CH2:14][CH2:15][N:4]([CH2:5][CH2:6][NH:7][CH2:8][CH2:9][N:10]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:12]2)[CH2:3]1.Cl.[OH-:21].[Na+]>>[N:10]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:4]([CH2:3][C:2]([OH:21])=[O:1])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: O=C(O)CN1CCNCCN2CCN(CC1)C(=O)C2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCNCC1
Yield: 86.5 %

Procedure:
20 g (0.074 mol) of 12-oxo-1,4,7,10-tetraazabicyclo[8.2.2]tetradecane-4-acetic acid, prepared as described in example 5, are dissolved in 88.8 g of 10% NaOH. The solution is refluxed overnight, then cooled and acidified to pH 12 by addition of conc. HCl. The resulting solution is percolated on a column containing 600 ml of anionic exchanger resin IRA420 (Rohm & Haas), which is washed repeatedly with water, then eluted with 1N HCl. The fractions containing the product are combined and concentrated at reduced pressure to a volume of about 500 mL. The solution is percolated on a column containing 2 L of polyvinylpyridine resin (PVP), eluting with water, the fractions containing the desalted product are collected, combined and concentrated to dryness under vacuum. The crude solid is recrystallized from methanol/acetone=8/2, finally dried in a static drier at 50° C. under vacuum. 18.5 g (0.064 mol) of 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid are obtained.
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:64]([O:66][C:67](=[O:71])[CH2:68][CH2:69][NH2:70])[CH3:65]>CN(C=O)C>[CH2:64]([O:66][C:67](=[O:71])[CH2:68][CH2:69][NH:70][C:23](=[O:24])[CH:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C@@H:11]1[CH2:26][CH2:27][CH2:28][N:10]1[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:29])=[CH:2][CH:3]=1)(=[O:8])=[O:9])[CH3:65]
Reactant: CCOC(=O)CCN
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)C(Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine (˜2 eq.) in DMF was added BOP (˜2.1 eq.) and NMM (˜4 eq.), and the reaction was stirred at room temperature for about 45 minutes. β-alanine ethyl ester (˜2 eq.) was added and the reaction stirred for about 16 hours at room temperature. The reaction mixture was extracted with water and diethyl ether. The combined organic solution was then washed with 0.2 N HCl, sat. NaHCO3 and sat. NaCl solutions. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% EtOAc/Hexane, Rf=0.18) to yield the title compound as a colorless oil, which was determined to be a mixture of diastereomers by NMR.
Reaction SMILES: FC1C=C(F)C=CC=1C[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:23])[CH:7]=1.BrN1C(=O)CCC1=O>C(#N)C>[OH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:23])[CH:7]=1
Reactant: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 165.3 %

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 2) (15.85 g, 41.130 mmol) suspended in acetonitrile (165 mL) was cooled in an ice-bath. N-bromosuccinimide (7.687 g, 43.186 mmol) was added and the ice-bath was removed. The reaction mixture was stirred for 1.5 hours at room temperature. Reaction was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded an off white solid (17.63 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.17 (dt, J=1.41, 7.85 Hz, 1H), 7.90 (t, J=1.81 Hz, 1H), 7.67-7.41 (m, 3H), 7.05-6.88 (m, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 3.95 (s, 1H), 2.01 (s, 3H). ES-HRMS m/z 464.0286 (M+H C21H16BrF2NO4 requires 464.0304).
Reaction SMILES: [F:1][C:2]1([CH2:18][OH:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1([CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(F)(CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of benzyl 4-fluoro-4-(hydroxymethyl)-piperidine-1-carboxylate (1.0 g, 3.7 mmol) in CH2Cl2 (10 mL) at RT was added methanesulfonyl chloride (0.29 mL, 3.7 mmol) and triethylamine (1.04 mL, 7.5 mmol). The reaction mixture was stirred at rt for 5 min, and partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2 hexanes:EtOAc) to give benzyl 4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate. M.S. (M+1): 346
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=[N:21][CH:22]=3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Reactant: OB(O)c1cncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc3ccccc23)c2cccnc2n1
Yield: 77.8 %

Procedure:
426 mg 4-chloro naphthyridine from example 1, 682 mg 4-isoquinoline boronic acid pinacole ester, 945 mg sodium carbonate were dissolved with 30 ml dioxan and 3 ml water, flushed with nitrogen, and 172 mg tetrakistriphenylphosphine palladium(0) were added. After 105 min reflux workup as in example 20 yielded a brownish oil, which was crystallized with ether to give 436 mg of product with correct LC-MS: M+H+ 386 and Rt˜2.22 min.
Reaction SMILES: C(O)(=O)C.[C:5]([N:9]([CH3:35])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[CH:13]=1)=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([O:28][CH3:29])[CH:20]=3)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.[Zn]>[C:5]([N:9]([CH3:35])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[CH:13]=1)=[CH:23][C:22]([NH2:25])=[C:21]([O:28][CH3:29])[CH:20]=3)=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: COc1cc2c(cc1[N+](=O)[O-])-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(cc1N)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid (0.39 ml) was added portionwise to a solution of the product of example 94 (300 mg) in THF (10 ml) at 0° C., followed by the portionwise addition of zinc (893 mg). After stirring for 2 h at room temperature, the reaction mixture was filtered over decalite. The filtrate was concentrated in vacuo and dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Residue was purified by preparative HPLC (0→100% acetonitrile; system 1).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH3:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:19]([C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:36][C:34]1[CH:35]=[C:27]2[C:28](=[CH:32][CH:33]=1)[C:29](=[O:30])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH3:18])=[C:19]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxybutylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(C(C)C)CC)(C)C.C([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[CH2:50][C:51](=[O:53])[NH2:52])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[C:57]([C:59]1[CH:86]=[CH:85][C:62]([CH2:63][C@@:64]2([CH3:84])[N:68]3[C:69]([C:72]([OH:74])=O)=[CH:70][N:71]=[C:67]3[N:66]([C:75]3[CH:80]=[C:79]([Cl:81])[CH:78]=[C:77]([Cl:82])[CH:76]=3)[C:65]2=[O:83])=[CH:61][CH:60]=1)#[N:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.C(Cl)Cl>[C:57]([C:59]1[CH:86]=[CH:85][C:62]([CH2:63][C@@:64]2([CH3:84])[N:68]3[C:69]([C:72]([NH:48][C@H:49]([CH2:50][C:51]([NH2:52])=[O:53])[C:54]([OH:56])=[O:55])=[O:74])=[CH:70][N:71]=[C:67]3[N:66]([C:75]3[CH:80]=[C:79]([Cl:81])[CH:78]=[C:77]([Cl:82])[CH:76]=3)[C:65]2=[O:83])=[CH:61][CH:60]=1)#[N:58]
Reactant: NC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@H](CC(N)=O)C(=O)O)n21
Reaction time: 14 h
Yield: 73.2 %

Procedure:
2-Chlorotrityl resin (0.536 g, 0.75 mmol/g) was placed in a dry glass fritted shaker flask. To the resin was added CH2Cl2 (10 mL), diisopropylethylamine (0.522 mL) and Fmoc-L-asparagine (0.265 g, 0.75 mmol) and the reaction was agitated on an orbital shaker for 14 h. The reaction solution was drained and the resin washed with CH2Cl2/MeOH/DIEA (17:2:1; 3×10 mL), CH2Cl2 (3×10 mL), DMF (3×10 mL), and CH2Cl2 (3×10 mL). The resin was swelled with DMF (2 mL) and the solvent drained. A solution of 50% piperidine in DMF (10 mL) was added to the resin and the reaction was agitated on an orbital shaker for 90 min. The reaction solution was drained and the resin washed with DMF (2×10 mL), CH2Cl2 (2×10 mL), DMF (2×10 mL), CH2Cl2 (2×10 mL), and DMA (1×2 mL). (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.132 g, 0.30 mmol) and HATU (0.285 g, 0.75 mmol) were dissolved in DMA (2 mL), and the resulting solution added to the resin. Diisopropylethylamine (0.130 mL, 0.75 mmol) was added and the reaction agitated on an orbital shaker for 48 h. The reaction solution was drained and washed as described above. The resin was treated with 10% TFA in CH2Cl2 and agitated on an orbital shaker for 90 min. The reaction solution was collected and the resin washed with CH2Cl2 (4×3 mL). The filtrates were combined with the supernatant and the volatiles removed in vacuo at 40° C. The residue was dissolved in CH2Cl2 (5 mL) and washed with water (2×5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, the solution decanted, and the solvent removed in vacuo to afford 0.122 g (73%) of (R)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-succinamic acid as an orange foam.
Reaction SMILES: [C:1]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30]>>[C:1]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:30][CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCc1ccccc1F
Reactant: CCCCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCCCC#Cc1ccc(CNCCc2ccccc2F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dodec-1-ynylbenzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 394.4. HPLC (Condition A), Rt: 5.00 min (HPLC purity: 93.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(Cl)(Cl)=O.N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C)c1C(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10 g of 2,6-dimethylbenzoic acid in 22 g thionyl chloride was stirred at reflux temperature for 2 hours. Removal of the excess thionyl chloride afforded the crude acid chloride as a yellow oil. This intermediate was added to a stirred solution of 4 mL of methanol in 10.8 mL pyridine at 65°-70° C. After completion of the addition, the resulting mixture was stirred at room temperature for 2 hours and then poured into 75 mL ice-water. The aqueous layer was extracted with four 50-mL portions of ether and the combined organic extracts were back-washed with saturated sodium bicarbonate solution, 5% aqueous hydrochloric acid, and water. Drying and evaporation of the solvent gave a pale yellow oil which was purified by bulb-to-bulb distillation (40°-50° C., 0.5 mm Hg) to afford 9.5 g of pure 2,6-dimethylbenzoic acid, methyl ester as a colorless liquid; IR (film) 1725 cm-1 ; NMR(CDCl3) δ 2.3 (s, 6H), 3.9 (s, 3H), 7.0-7.4 (m, 3H).