Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 63 %

Procedure:
Upon boiling a solution of 15.1 g 3-nitrobenzaldehyde and 26.0 g amidinoacetic acid ethyl ester in 250 ml ethanol for two hours, 2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 175° - 176° C (ethanol) is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-acetoxybenzoic acid (516 mg) and oxalyl chloride (0.5 ml) was stirred for 30 minutes. The mixture was concentrated under reduced pressure to give 4-acetoxybenzoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: CCc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(CNc1cccc(CC)c1)OCC
Yield: 34.6 %

Procedure:
To a 250-mL round bottom flask was added 3-ethylaniline (10.1 g, 83.2 mmol), bromoacetaldehyde diethyl acetal (10.8 g, 54.8 mmol) and sodium bicarbonate (7.04 g, 83.8 mmol) in absolute ethanol (40 mL). The resulting mixture was stirred at reflux for 5 d. The mixture was concentrated, diluted with ether (30 mL) and washed with water (2×60 mL). The organic solution was dried (MgSO4) and concentrated at reduced pressure. The residue was purified by flash chromatography (SiO2, 5% then 15% EtOAc/hexanes) to give the title compound (4.5 g, 75%) as a white solid. 1H NMR (DMSO-d6) δ 6.98 (m, 1H), 6.42 (m, 2H), 5.34 (m, 1H), 4.53 (m, 1H), 3.59–3.35 (m, 4H), 3.19 (m, 2H), 2.41 (m, 2H), 1.17 (m, 9H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].Cl[C:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1>C(O)C>[NH2:2][CH2:3][CH2:4][S:5][C:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cn2c(Cl)cccc2n1
Reactant: NCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2c(SCCN)cccc2n1
Yield: 53.1 %

Procedure:
To a suspension of cysteamine hydrochloride (2.95 g, 26 mmoles) in ethanol (100 ml) was added 60% sodium hydride (oily; 2.08 g, 26 mmoles) with stirring under ice-cooling and the mixture was stirred for 5 minutes. 5-chloro-2-methylimidazo[1,2-a]pyridine (3.33 g, 20 mmoles) was added to the mixture, followed by heating at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue which was washed with 1N-NaOH and dried over anhydrous potassium carbonate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate/ethanol/triethylamine=6:2:1) to obtain 2.2 g of the desired product (53.6%, brown oily product).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].O=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>O>[CH2:4]([C@H:3]1[C:11](=[O:12])[NH:13][CH:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[NH:2]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)COC(=O)CCC=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)COC(=O)CCC1NC(=O)[C@H](Cc2ccccc2)N1
Yield: 19.7 %

Procedure:
To a solution of L-phenylalaninamide hydrochloride (20 g, 0.1 mol) in water (200 ml), adjusted to pH 8.2 with 10% sodium hydroxide (about 35 ml), was added isobutyl 4-oxobutanoate (16 g, 0.1 mol). The solution was refluxed for 24 hours. After cooling, the solution was extracted with dichloromethane (4×200 ml). The organic phase was dried and evaporated to dryness under vacuum. The residue was chromatographed over silica gel (dichloromethanemethanol 9:1) to afford 6 g (20%) of the title compound, as an oil, which was characterized as the hydrochloride, m.p. 152°-155° C. (with decomposition) (after crystallization from ethanol-diethyl ether). NMR (DMSO-d6, CDCl3): deltaH =9.25 (b.s., 1H, CONH); 7.6-7.1 (c.a., 5H, PhH), 4.90 (t, J=6.1 Hz, 1H, NHCHNH); 4.17 (t, J=6.1 Hz, 1H, CHCH2Ph); 3.84 (d, J=6.9 Hz, 2H, COOCH2CH); 3.35 (c.a., 2H, CH2Ph); 2.50-1.60 (c.a., 5H, CH2CH2COO, CH2CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=304 (M+), 213 (M--C7H 7 +, 84 (C3H4N20)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:17][C:7]1([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: Cc1cnc(C2(O)CCC3(CC2)OCCO3)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(C2(O)CCC(=O)CC2)s1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 8-(5-Methyl-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.0 g, 4.14 mmol) in 20 mL of THF/3 N HCl (1:1) was stirred for 1 h at 50° C. After cooling to room temperature, the mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.82 g of 4-hydroxy-4-(5-methyl-1,3-thiazol-2-yl)cyclohexanone in 99% yield. MS (EI) (M+H)+=212.2.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1([N+:37]([O-:39])=[O:38])[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[CH:16][CH:15]1[OH:36].O>CN(C=O)C>[Br:13][C:14]1([N+:37]([O-:39])=[O:38])[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[CH:16][CH:15]1[O:36][CH2:2][C:3]([OH:5])=[O:4]
Reactant: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(O)C=C3)c2c1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(OCC(=O)O)C=C3)c2c1C
Reaction time: 15 h
Yield: 68.1 %

Procedure:
Methyl bromoacetate (0.150 mL, 1.58 mmol) was added to a stirred suspension of potassium carbonate (0.223 g, 1.61 mmol), 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.400 g, 0.789 mmol) in DMF (2.8 mL). After 15 h, the reaction mixture was added to water and extracted with ethyl acetate. Silica gel was added to the ethyl acetate and the solvent was removed. The adsorbate was flashed (9:1 petroleum ether: ethyl actetate) to provide the title compound as a yellow solid (0.305 g, 67%). This solid (0.050 g, 0.086 mmol) was dissolved in 1:1 THF:methanol (2 mL) and treated with aqueous potassium hydroxide (1.0 N, 0.30 mL, 0.30 mmol). After 25 min the reaction mixture was diluted with water, acidified with 10% aqeous HCl and extracted with ether. The ether phase was dried (sodium sulfate), concentrated and recrystallized from petroleum ether:ether to provide the title compound as a white solid (0.025 g, 51%): mp 228-229° C.: NMR (DMSO-d6); δ 8.23 (d, J=9 Hz, 1H), 8.14 (d, J=2 Hz, 1H), 8.04 (d, J=2 Hz, 1H), 7.69 (ddd, J=8, 7, 1, 1H), 7.54 (ddd, J=8, 7, 1 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 4.87 (d, J=6 Hz, 1H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H), 1.62 (s, 3H); MS (+FAB): 2 bromine isotope pattern 563 (40%), 565 (100%), 567 (50%); Anal. Calc. for C22H15Br2NO5S: C, 46.75, H, 2.68, N, 2.48. Found: C, 45.18, H, 2.66, N, 2.38.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[N:25]=2)[CH2:8]1)(C)(C)C.C(Cl)Cl.Cl.C([O-])(O)=O.[Na+]>CO>[OH:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[N:25]=2)[CH2:8]1
Reactant: CC(Nc1nccc(N2CC(O[Si](C)(C)C(C)(C)C)Cn3c2nc(-c2ccccc2)cc3=O)n1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(Nc1nccc(N2CC(O)Cn3c2nc(-c2ccccc2)cc3=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 7-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-9-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (20 mg) in MeOH (3 mL)-DCM (1 mL) was treated with HCl (conc. 1.5 mL). After the mixture was stirred at room temperature for 16 h, it was neutralized with NaHCO3 (aq) and then extracted with DCM (3×). The organic layer was dried (Na2SO4) and concentrated to a solid that was purified on silica (1-3% 2N NH3—MeOH in DCM) to provide the product as a white solid. 1HNMR (400 MHz, DMSO-d6): 8.12 (d, J 5.6,1 H), 7.94 (m, 2H), 7.70 (m, 1H, NH), 7.44 (m, 3H), 7.32 (t, J 7.2, 2H), 19 (m, 1H), 708 (d, J 5.6,1H), 5.50 (ds, 1H, OH), 5.01 (m, 1H, ), 4.39 (b, 1H), 4.22 (bt, 1.5 H), 3.89 (d, J 4.8,1H), 3.68 (m, 0.5H), 3.3 (b, 1H), 1.45 (d, J 7.2, 3H). M+1: 441.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1c(F)cncc1F)c1c(Cl)cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc(Cl)c1C(Cl)=Nc1c(F)cncc1F
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide (5.25 g, 16.7 mmol) in thionyl chloride (40 mL) was heated under reflux for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was azeotroped with toluene (×3) to afford the title compound as a yellow/brown solid (5.5 g, quantitative). LCMS (Method D): RT=3.77 min, m/z: 332 [M+H+].
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=1)=[O:5].[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Cu]I>[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=2)=[O:5])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Reactant: Oc1ccccc1N1CCCCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Oc2ccccc2N2CCCCC2)c1
Temperature: 150 °C

Procedure:
A suspension of 2-bromo-N-(3-(aminosulfonyl)phenyl)benzamide (0.10 g, 0.28 mmol), 2-(piperidin-1-yl)phenol (74 mg, 0.28 mmol), K3PO4 (0.12 g, 0.56 mmol), and CuI (53 mg, 0.28 mmol) in DMF (1 mL) and water (20 μL) was sealed in a glass tube and heated in a microwave oven at 150° C. for 15 min. The reaction was filtered and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(2-(piperidin-1-yl)phenoxy)-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 452.0 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:21]=[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=2)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11]1
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Oc1ccc2c(c1)C(=O)CCN2C(=O)CC
Yield: 110.3 %

Procedure:
A solution of propionyl chloride (1.018 g) in chloroform (5 ml) was added dropwise to a solution of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.09 g), N,N-dimethylaniline (1.513 g), and 4-dimethylaminopyridine (0.061 g) in chloroform (20 ml) with stirring and ice cooling over a period of 10 minutes After being stirred overnight at ambient temperature, the mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% hydrochloric acid, water, aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and evaporated in vacuo to give an oil of 4-oxo-1-propionyl-6-propionyloxy-1,2,3,4-tetrahydroquinoline (1.51 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([C:21]3[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
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: CN(C)C=O
Product: CC(C)C(C)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 120 °C
Yield: 10.8 %

Procedure:
A mixture of 3-amino-7-bromo-5-(3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G (332 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (347 mg), tetrakis(triphenylphosphine)palladium(0) (128 mg), aqueous sodium carbonate solution (2 M, 1.11 ml) and N,N-dimethylformamide (6.0 mL) was heated with microwave irradiation at 120° C. for 1 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). To the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (36.0 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C@H:4]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:5][O:6][C:7]1[C:8]([C:23]([CH3:25])=[CH2:24])=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[CH:23]([C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:3][CH:2]([CH3:1])[CH3:34])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3)([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: C=C(C)c1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](COc1cc2c(cc1C(C)C)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Yield: 1146 %

Procedure:
A mixture of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-9-(prop-1-en-2-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.1 g, 0.215 mmol) and palladium on carbon (0.07 g, 0.066 mmol) in MeOH (3 mL) and ethyl acetate (3 mL) was stirred at RT under a balloon of hydrogen gas for 24 h. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-isopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.04 g, 2.464 mmol, 1% yield) as a brown oil, which was carried on without further purification. LC/MS (ESI) m/e 468.4, [(M+H)+, calcd for C27H38N3O4, 468.3]; LC/MS retention time (method D): tR=1.00 min.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([OH:39])[C:10]1([OH:43])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.CC(C)=O>[CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([O:39][CH2:5][CH2:6][CH3:7])[C:10]1([O:43][C:1](=[O:8])[CH2:2][CH2:3][CH3:4])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Solvent: CC(C)=O
Solvent: CCO
Product: CCCOC1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1(CCC)OC(=O)CCC
Yield: 123.1 %

Procedure:
The allyl ether 21 (182 mg, 0.26 mmol) was dissolved in a mixture of 7 mL ethanol and 1 mL acetone and 18 mg Wilkinson catalyst (19 μmol) was added. The mixture was stirred in a hydrogen atmosphere for 3 days, before the solvents were removed under reduced pressure. The residue was chromatographed by preparative HPLC (95% MeOH, 40 mL/min, tRet=35.00 min) to give 26 as a colorless solid(108 mg, 0.16 mmol; 59.2% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:34])[C:24]=4[NH:25][C:26]([O:28][C@H:29]([CH3:33])[CH:30]([CH3:32])[CH3:31])=[O:27])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:33][C@@H:29]([O:28][C:26]([NH:25][C:24]1[N:23]([CH3:34])[N:22]=[N:21][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:15][CH:16]=1)=[O:27])[CH:30]([CH3:31])[CH3:32]
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)C(C)C)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)[C@@H](C)OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)nnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
1-{4′-[5-((R)-1,2-Dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (97 mg) was dissolved in 2 mL of THF and 2 mL of ethanol. To this clear solution was added 1N NaOH solution 2 mL. The clear solution was stirred at room temperature overnight. Solvents were evaporated and the residue was dissolved in water (12 mL). The solution was filtered. The filtrate was treated with hydrochloric acid (1N, 2.5 mL). The white precipitate was filtered and dried in air to provide 1-{4′-[5-((R)-1,2-dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid as a pale yellow solid (84 mg, 89.3% yield). LC/MS calcd for C25H28N4O4 (m/e) 448.0, obsd 449.2 (M+H); 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.52 (br, 1H), 0.88 (br, 5H), 1.04-1.25 (m, 5H), 1.35-1.43 (m, 2H), 1.62-1.85 (br, 1H), 3.80 (s, 3H), 4.55 (br, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 9.34 and 9.67 (br s, 1H), 12.30 (br s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:22][C@@H:23]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (CAN 2743-40-0) as starting materials. MS (EI): m/e=413.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: OB(O)c1cncnc1
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: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cncnc2)CC1
Yield: 93 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), pyrimidin-5-yl boronic acid (12 mg, 0.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and a 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (26 mg, 95%), LC-MS (ESI, 3.5 min) Rt 1.19 min, m/z 318 (100%, [M+H]+); m/z (ESI) C15H17ClN5O requires 318.1116 found [M+H]+ 318.1114.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[K+].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CS(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1ccnc1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A solution of 2-chloro-5-nitroanisole (1.0 g, 5.33 mmol), KOH (0.438 g, 7.81 mmol) and imidazole (1.45 g, 21.3 mmol) in DMSO (5 mL) was heated to 80° C. for three hours. The reaction mixture was poured into ice water. The precipitate was collected and washed with water to afford the title compound (0.75 g, 64%). 1H NMR (CDCl3): δ8.84 (1H, s), 8.07 (2H, m), 7.66 (1H, d), 7.55 (1H, s), 7.44 (1H, s), 4.09 (3H, s); LC-MS: m/z 220.07 (M+H)+