Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][CH:9]=[C:8]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:18].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][CH:9]=[C:8]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][NH:22][CH2:21]1)=[O:18]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)ccc1-c1cccs1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)ccc1-c1cccs1
Reaction time: 1 h
Yield: 36.6 %

Procedure:
tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-(thiophen-2-yl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (65 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate (5 ml) was added and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residual aqueous layer was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the object product (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1.[OH2:20]>CCOC(C)=O.[Cl-].[Na+].O.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:20])[N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Cc1cc(Cl)nc2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2c1C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of ruthenium trichloride (0.141 g, 0.681 mmol) and NaI04 (8.32 g, 38.9 mmol) in H2O (30 mL) at 0° C., a solution of tert-butyl 2-chloro-4-methyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.75 g, 9.73 mmol) in EtOAc (30 mL) was added. After stirring for 5 min., the reaction mixture was warmed up to rt and stirred. After stirring for 21.5 h, the mixture was diluted with EtOAc and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography on 80 g of silica gel (with 25 g pre-column of silica gel; eluent: heptane/EtOAc=100:0 to 70:30) to give tert-butyl 2-chloro-4-methyl-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.10 g) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (s, 1H), 3.98 (t, J=6.32 Hz, 2 H), 3.13 (t, J=6.32 Hz, 2 H), 2.70 (s, 3 H), 1.58 (s, 9 H).
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[N+:20]([C:23]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=1[NH2:25])([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>O1CCCC1.OS([O-])(=O)=O.[Na+].ClCCl>[NH2:25][C:24]1[CH:26]=[CH:27][C:28]([S:30]([NH:7][O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:32])=[O:31])=[CH:29][C:23]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Agent: NN
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
A solution of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (10.00 g, 43.30 mmol) in anhydrous tetrahydrofuran (100 mL) at ambient temperature under an Argon atmosphere was treated with anhydrous hydrazine (1.49 mL, 47.63 mmol). After stirring vigorously for 2.5 hours, the resulting slurry was filtered and washed with approximately 20 mL of anhydrous tetrahydrofuran. The filtrate was combined with o-nitroaniline-p-sulfonyl chloride (11.26 g, 47.63 mmol) and N,N-diisopropylethylamine (9.05 mL, 51.96 mmol) and stirred under an Argon atmosphere for 16 hrs. at ambient temperature. The reaction mixture was diluted with 1N NaHSO4 and dichloromethane and transferred to a separatory funnel. The organic phase was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with 5% aqueous potassium carbonate, dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 1:1 ethyl acetate : hexane. Fractions containing the product were combined, evaporated in vacuo to a residue and triturated with hexane. The slurry was filtered and the product was dried under high vacuum to provide 4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide (8.89 g, 68%) as a yellow solid. H1-NMR (chloroform-D3): 1.57 (m, 4H), 1.74 (m, 4H), 4.61 (m, 1H), 6.52 (b, 2H), 6.73 (s, 1H), 6.90 (d, 1H), 7.79 (m, 1H), 8.70 (d, 1H). MS(ESI): 324(M+Na).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[SH:26][C:27]1[S:28][CH:29]=[N:30][N:31]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([S:26][C:27]4[S:28][CH:29]=[N:30][N:31]=4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: Sc1nncs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Sc4nncs4)nc32)c(=O)[nH]c1=O
Temperature: 55 °C
Reaction time: 16 h

Procedure:
To a mixture of the product from example 44 step (viii) (0.20 g) and 2-mercapto-1,3,4-thiadiazole (0.120 g) in dry dimethylformamide (2 ml) was added 60% sodium hydride (0.041 g). The mixture was stirred for 16 h then heated at 55° C. for 24 h. The reaction mixture was diluted with water and neutralised by the addition of acetic acid. The aqueous was extracted with dichloromethane and the combined organic extracts were dried (MgSO4). The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with dichloromethane/5% ethanol.
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)(=[O:10])=[O:9])(=O)=O.[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:6][CH2:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(S(=O)(=O)CCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 70 °C
Yield: 20.9 %

Procedure:
A mixture of 102 (1.0 g, 3.2 mmol), 4-benzylpiperidine (103) (0.62 g, 3.5 mmol), and potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (10 ml) was heated at 70° C. overnight. It was allowed to cool to room temperature and partitioned between EtOAc (150 mL) and water (150 mL). The organic layer was washed with water (100 ml), brine (100 ml), dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (8:1 to 4:1 to 2:1 hexanes/EtOAc) to give 104 (0.26 g, 21%).
Reaction SMILES: [C:1]1([N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[OH-].[Na+]>O.C(O)(=O)C.[Zn]>[C:1]1([N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)N(N=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N(N)c1ccccc1

Procedure:
To a stirred suspension of zinc dust (5.14 g, 0.079 mol) in water (15 ml) was added dropwise a solution of the compound of Example 560B (3.5 g, 0.02 mol) in acetic acid (9 ml) and the resultant mixture was stirred for 1 hr at r.t. Dichloromethane (20 ml) was added, the mixture was adjusted to pH 8–9 with 15% NaOH, The zinc dust was removed by filtration, and the crude reaction mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4). Yield 1.97 g (60%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([CH3:9])[O:3]1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC1C=C(Br)C=CC=1)C1C=CC=CC=1.[Mg].Cl>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([C:6]2([OH:8])[CH2:5][CH:4]([CH3:9])[O:3][CH:2]([CH3:1])[CH2:7]2)[CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1CC(=O)CC(C)O1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Agent: Brc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,6-dimethyltetrahydropyran-4-one (2.2 g) in tetrahydrofuran (5 ml) was added to a solution of 3-benzyloxyphenylmagnesium bromide [prepared by heating a mixture of 3-benzyloxybromobenzene (5 g), magnesium (0.5 g) and tetrahydrofuran (20 ml)] in tetrahydrofuran and the mixture was stirred at ambient temperature for 3 hours. The mixture was cooled to 5° C., ice (5 ml) and 2N hydrochloric acid solution (25 ml) were added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of toluene and ethyl acetate as eluent. There were thus obtained two isomers of 4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:11]=2[CH:12]=1.[CH3:15][C:16]1[N:17]([C@H:22]2[CH2:26][C@@:25]([CH:30]([CH3:32])[CH3:31])([C:27](O)=[O:28])[CH:24]=[CH:23]2)[C:18]([CH3:21])=[CH:19][CH:20]=1.CS(Cl)(=O)=O>>[CH3:15][C:16]1[N:17]([C@H:22]2[CH2:26][C@:25]([C:27]([N:9]3[CH2:8][CH2:7][C:6]4[N:5]=[CH:4][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:12][C:11]=4[CH2:10]3)=[O:28])([CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23]2)[C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)O)(C(C)C)C1
Agent: CS(=O)(=O)Cl
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)(C(C)C)C1

Procedure:
N-((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)-N-[(cis-3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1, is synthesized by sequentially coupling three building block compounds 4, 5 and 6 (Schemes 3, 4 and 5, below). An amidation reaction between 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine, 5, and (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)1-isopropylcyclopent-2-ene-1-carboxylic acid, 4, is carried out in the presence of methanesulfonyl chloride to afford 6-{[(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-en-1-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine. Deprotection of the pyrrole group was carried out at this stage using hydroxylamine as a through process to provide an amine salt. The amine salt and (3R)-3-methoxytetrahydro-4H-pyran-4-one, 6, are coupled through reductive amination, in the presence of a tributylamine buffer, and with NaBH(OAc)3 to afford (3S,4S)-N-((1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-1-yl)-3-methoxytetrahydro-2H-pyran-4-amine, 2. The cyclopentene moiety of compound 2 was then hydrogenated to form free base compound 1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]12[O:3][C:4]([CH3:8])([CH:14]3[C:10](=[O:9])[N:11]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:27])[F:26])[CH:17]=4)[C:12](=[O:15])[CH:13]31)[C:5]([CH3:7])=[N:6]2
Reactant: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Reactant: Cc1nc(C)c(C)o1
Solvent: Cc1ccccc1
Product: CC1=NC2(C)OC1(C)C1C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C12
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
2,4,5-Trimethyl oxazole (0.48 mL, 4.14 mmol) was dissolved in toluene (2.0 mL) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile (1.00 g, 3.76 mmol) was added. The reaction mixture was stirred at 75° C. under nitrogen for 2.5 hrs. The solution was cooled to room temperature and the resulting precipitate was filtered and rinsed with toluene to give 0.51 g (35%) of compound 211 as a light grey solid. NMR analysis revelaed that compound 211 was one isomer (exo/endo) however the identity of the isomer could not be determined by NMR analysis. HPLC: 100% at 2.85 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10–90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 378.42 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]#[N:17])[C:12]([F:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>C(O)CCC>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([NH:20][OH:21])=[NH:17])[C:12]([F:18])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CNc1nc(OCc2ccccc2)ncc1F
Reactant: NO
Agent: Cl
Solvent: CCCCO
Product: N=C(NO)Nc1nc(OCc2ccccc2)ncc1F
Temperature: 110 °C
Yield: 15 %

Procedure:
To a solution of 2-benzyloxy-5-fluoro-pyrimidin-4-yl-cyanamide (2.9 g, 0.012 mol) in n-butanol (30 mL) in a 100 mL sealed tube was added hydroxylamine hydrochloride (4.1 g, 0.059 mol) and the solution was heated at 110° C. for 2 h. The reaction was cooled and checked by TLC and was determined to be complete. The solvent was removed in vacuo and the resulting mixture was diluted with water and extracted with EtOAc (3×30 mL). The organic layers were dried over Na2SO4, filtered, and evaporated. The crude product was purified further with reverse phase chromatography to yield the title compound (500 mg, 15% yield) as an off white solid; mp 150-152 dec.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.44 (d, J=2.6 Hz, 1H), 7.41 (m, J=13.8, 6.3 Hz, 5H), 5.34 (s, 2H); MS (EI) m/z 278 (M)+.
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C1N2CCN(CC2)C1.C(N(CC)CC)C>C(OCC)(=O)C.C(#N)C>[S:18]([O:1][CH:2]([CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)C(=O)OCC(C)C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(OS(=O)(=O)c1ccc(C)cc1)C(=O)OCC(C)C
Reaction time: 4 h

Procedure:
To a solution of (S) isobutyl 2-hydroxybutyrate (2.72 Kg) and p-toluenesulfonylchloride (3.6 Kg) in ethyl acetate (14 L) at 20° C. was added a solution of DABCO (286 g) and triethylamine (4.7 L) in ethyl acetate (10 L) over 2 h. The reaction was aged at 20-25° C. for 4 h. The mixture was washed with three times with water (10 L, 2 L and 2 L) and the organics concentrated and solvent switched into toluene. The concentrated toluene solution of (S) 2-isobutyl tosylbutyrate was used as is in coupling reaction. Alternatively, acetonitrile can be used in place of ethyl acetate, in which case the reaction proceeds faster.
Reaction SMILES: [O:1]=C1N=C(C(O)=O)C=N1.[OH:10]N1C2C=CC=CC=2N=N1.O.[C:21]([NH:31][C@H:32]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([NH2:45])=[O:44])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)(=[O:30])[C:22]1[NH:29][C:27](=[O:28])[NH:26][C:24](=[O:25])C=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[OH2:1].[OH2:10].[OH2:25].[O:28]=[C:27]1[N:29]=[C:22]([C:21]([NH:31][C@H:32]([C:39]([N:41]2[CH2:48][CH2:47][CH2:46][C@H:42]2[C:43]([NH2:45])=[O:44])=[O:40])[CH2:33][C:34]2[N:38]=[CH:37][NH:36][CH:35]=2)=[O:30])[CH:24]=[N:26]1
Reactant: O=C1N=CC(C(=O)O)=N1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)C1=NC(=O)N=C1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
To 100 ml of dimethylformamide are added 5.1 g of 2-oxo-imidazole-4-carboxylic acid, 5.8 g of 1-hydroxybenzotriazole and L-histidyl-L-prolinamide dihydrobromide (prepared as described in Example 2 from 15.4 g of N-benzyl-oxycarbonyl-L-histidyl-L-prolinamide). After chilling to -5° C. while stirring 11.1 ml of triethylamine and thereafter the solution of 8.3 g of N,N'-dicyclohexylcarbodiimide in 30 ml of dimethylformamide are added. The stirred mixture is chilled for 30 minutes longer and then it is stored for 12 hours at room temperature. The precipitate formed is sucked off and the solution is evaporated under reduced pressure and at a temperature of about 35° C. The residue is mixed with 100 ml of water, stored for 12 hours at 0° C. filtered and then the filtrate is treated with a cationic exchanger and thereafter with 1n ammonia as described in Example 2. The ammoniacal filtrates are combined, evaporated under reduced pressure to a small volume and finally lyophylized. The residue is subjected to countercurrent distribution in the system n-butanol/water. The fractions containing the main product are combined, evaporated to dryness and the residue is dissolved in 50 ml of methanol and reprecipitated by addition of 500 ml of chloroform, which treatment then is repeated once. After drying in vacuum 4.7 g (27% of the theoretical yield) of 2-oxo-imidazole-4-carbonyl-L-histidyl-L-prolinamide trihydrate are obtained. This substance on heating above 180° C. begins to sinter and on heating to 212° C. it is molten.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[C:16]([F:15])[CH:17]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1c(Cl)nc2ccc(F)cc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(F)c2)nc2ccc(F)cc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-6-fluoro-3-methylquinoline (300 mg, 1.3 mmol), 5-fluoropyridin-3-ylboronic acid (160 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0) (151 mg, 0.13 mmol), sodium carbonate (242 mg, 2.28 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-6-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].N1C=CC=CC=1.Cl[C:17]1[C:22]2[CH:23]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:26]([C:24]2[S:25][C:21]3[CH:20]=[CH:19][N:18]=[C:17]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[C:22]=3[CH:23]=2)(=[O:28])=[O:27])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=S(=O)(Cl)c1cc2c(Cl)nccc2s1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cl
Product: O=S(=O)(Nc1ccc(Cl)c(Cl)c1)c1cc2c(N3CCNCC3)nccc2s1
Reaction time: 1 h
Yield: 2.6 %

Procedure:
3,4-Dichloroaniline (0.49 mmol), was dissolved in acetonitrile (1 mL) and pyridine (0.440 mL, 4.03 mmol) was added to a solution of 4-chlorothieno[3,2-c]pyridine-2-sulfonyl chloride (0.445 mmol) dissolved in acetonitrile (1 mL). The reaction was shaken for 1 h, controlled with HPLC and the solvent was removed. The crude product was used in the next step without further purification. To the reaction mixture from the previous step, dissolved in DMSO (1 mL), piperazine (15 equiv.) and K2CO3 (1 equiv.) was added. The reaction was stirred at 100° C. for 24 and than concentrated. The product was purified by LC-MS and gave 5.8 mg (2.6%) of the title product. 1H NMR (270 MHz, CH3OH-d4) δ ppm 8.07-8.05 (m, 2H) 7.73 (d, J=6.60 Hz, 1H) 7.46-7.41 (m, 2H) 7.16 (dd, J=8.71, 2.38 Hz, 1H) 3.94-3.90 (m, 4H) 3.92 (m, 4H) 3.53-3.50 (m, 4H); LC-MS 443 (M−H)+; Purity (HPLC) 95%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C1=CCN(c2ncccc2Cl)CC1

Procedure:
A solution of 1-(3-chloropyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (compound 24) (8 g, 34 mmol) and thionyl chloride (12 g, 100 mmol) in benzene was refluxed for two hours. The solvent was evaporated to give a crude product, which can be directly used for the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:27])=[CH:26][CH:25]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CCN(C)C)cc1
Yield: 60.6 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (150 mg, 0.64 mmol) was reacted with 4-[2-(dimethylamino)ethyl)aniline (110 mg, 0.64 mmol) to afford the desired product (143 mg, 60%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.86 (br s, 1H), 8.99 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.22-7.15 (m, 2H), 7.11-7.04 (m, 2H), 2.87 (t, J=8.1 Hz, 2H), 2.70-2.60 (m, 2H), 2.55 (s, 3H), 2.39 (s, 6H); ESI MS m/z 369 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([CH:18]=[O:19])[NH:5][C:4]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:2].C1CC=CCC=1>C(O)C.[Pd]>[C:23]([O:22][C:20]([C:4]1[NH:5][C:6]([CH:18]=[O:19])=[C:7]([C:8]([OH:10])=[O:9])[C:3]=1[CH2:1][CH3:2])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 4-benzyl 2-tert-butyl 3-ethyl-5-formyl-1H-pyrrole-2,4-dicarboxylate (1.316 g, 3.682 mmol) in ethanol (15.0 mL) was added 10% palladium on carbon (1.300 g, 3.68 mmol) and 1,4-cyclohexadiene (3.50 mL, 36.82 mmol). The reaction was stirred under N2 for 2 h prior to filtration through a pad of Celite. The filtrate was washed with 50 mL of ethyl acetate and the combined organics concentrated in vacuo. The resultant residue was purified by preparative reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CD3OD) δ 10.23 (s, 1H); 3.10 (q, J=7.3 Hz, 2H); 1.61 (s, 9H); 1.16 (t, J=7.3 Hz, 3H). HRMS (ES) exact mass calculated for C13H17NNaO5 (M+Na+): 290.1001. Found 290.1001.