Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pd].[Pt](=O)=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][NH:12][CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1cncc(-c2ccc(CCO)cc2)c1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(c2ccc(CCO)cc2)C1
Reaction time: 6 h

Procedure:
A solution of 5.40 g (19.6 mmol) of the compound from Example 55A in concentrated acetic acid (124 ml) was admixed with 1.00 g of palladium/carbon (10% palladium) and 1.00 g of platinum(IV) oxide. This was followed by hydrogenation under a hydrogen atmosphere at standard pressure for 6 h, then addition of another 1.00 g of palladium/carbon (10% palladium) and 1.00 g of platinum(IV) oxide, and hydrogenation under a hydrogen atmosphere at standard pressure overnight. This was followed by hydrogenation in a Pan apparatus under a 3 bar hydrogen atmosphere for a further 2 h. The reaction solution was filtered through Celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue was codistilled repeatedly with toluene and then dried under high vacuum. Yield: 6.63 g (56% of theory, purity 44%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21](OC)=[O:22])=[CH:17][N:16]=2)=[CH:9][CH:8]=1.N.CO>O1CCCC1>[OH:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:10]2[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=2)=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccncc2)nc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(/C=C/c2ccncc2)nc1
Reaction time: 0.75 h
Yield: 73.8 %

Procedure:
To a suspension of lithium aluminum hydride (31.1 mg) in tetrahydrofuran (1 ml) was dropwise added a solution of methyl 2-[(E)-2-(4-pyridyl)vinyl]pyridine-5-carboxylate (385 mg) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 45 minutes at the same temperature. Aqueous ammonia was dropwise added thereto at 0° C. and then methanol (5 ml) was further added thereto, and the mixture was stirred for 2 hours. After filtration the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, and the solution was washed with water and brine and dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was washed with diisopropyl ether to give 5-hydroxymethyl-2-[(E)-2-(4-pyridyl)vinyl]pyridine (251 mg).
Reaction SMILES: N#N.[F:3][C:4]([F:17])([F:16])[C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11](O)=[O:12])=[CH:7][CH:6]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]([F:17])([F:16])[C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([Cl:26])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of trans-4-(trifluoromethyl)cinnamic acid (20 mg, 0.10 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.02 mL, 0.23 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.6 %

Procedure:
To a stirred solution of methyl 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetate (710 mg, 1.79 mmol) in THF (10 ml) was added 0.25 N NaOH (10 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetic acid (643 mg, 94%) as colorless powder. 1H-NMR (DMSO-d6) δ3.56 (s, 2H), 7.05 (m, 1H), 7.21 (dd, J=8.6, 1.7 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.46 (d, J=8.1 hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 8.06 (d,d J=7.6 Hz, 1H), 8.86 (s, 1H), 8.89 (s, 1H), 12.40 (s, 1H); MS (ESI) m/z 382 (M++1), 384 (M++3).
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=2)[C:17]=1[NH2:18]>>[CH2:7]([C:8]1[NH:11][C:12]2[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=3)[C:17]=2[N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2cccc(C(=O)O)c2)c1=O
Reactant: O=C(O)Cc1ccccc1
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2cccc(C(=O)O)c2)c1=O

Procedure:
By the method of Example 2, phenylacetic acid is reacted with 5,6-diamino-1-[2-(3-carboxyphenyl)ethyl]-3-propyluracil to yield 8-benzyl-3-[2-(3-carboxyphenyl)ethyl]-1-propylxanthine. In turn, 5,6-diamino-1-[2-(3-carboxyphenyl)ethyl]-3-propyluracil is made by the synthetic methods of Example 1, starting with 3-carboxyphenethylamine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+2]>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)c1cccc(Br)n1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1cccc(Br)n1
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
To a stirring solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (1.01 g, 4.15 mmol) in chloroform (27 mL) was added manganese oxide (14.24 g, 0.16 mol) portion-wise over 4 h. The mixture was then left to stir for an additional 3.5 h and was then filtered through celite placed directly on the top of a SPE (silica, 20 g cartridge) eluting with chloroform. The filtrate was reduce under vacuum and then purified further by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 100:1 to 5:1) afforded the title compound as an oil (625 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl.CCOCC>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CCCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperidine-1-carboxylate (0.0313 g, 0.0605 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with ether, and the precipitated solid was collected by filtration, and washed with ether. The resulting solid was dissolved in a small volume of water, and the solution was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[3-(piperidin-4-yl)propyl]benzofuran-3(2H)-one (0.0223 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[O:21][CH3:22])/[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[O:21][CH3:22])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1OC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCCC[C@H]1O/N=C(\C(=O)O)c1csc(N)n1

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(trans-2-methoxycyclohexyloxyimino)acetate (1.79 g) was hydrolysed with IM sodium hydroxide (10.75 ml) in ethanol (20 ml) as described in Example 4e. After acidification of the aqueous phase to pH 2-3 the water was removed under reduced pressure. The residue was extracted with hot ethanol and concentrated to dryness to give a brown foam. Trituration with ethyl acetate gave the title compound as a buff coloured solid (0.904 g). νmax (KBr) 3302, 3207, 1628, 1534, and 1450 cm-1 ; δH ((CD3)2SO) inter alia 1.00-2.00 (8H, m), 3.00-3.33 (4H, m and s), 3.90-4.30 (1H, m), 6.87 (1H, s), and 7.28 (3H, br. s). [Mass spectrum: +ve ion (thioglycerol) MH+ (300), MNa+ (322)].
Reaction SMILES: Cl[C:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:19])[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2.[N-:26]=[N+:27]=[N-:28].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[N:26]([C:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:19])[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(Cl)c2cccnc2)CCN(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(N=[N+]=[N-])c2cccnc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
5-(2-Chloro-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (crude) (700 mg) was dissolved in DMF (4 mL). Sodium azide (975 mg, 15 mmol) was added and reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was diluted with water, basified with aqueous NaHCO3 solution and was extracted with EtOAc (200 mL). The organic layer was washed with water (6×50 mL), dried over anhydrous sodium sulfate and evaporated in vacuo to obtain the crude product that was purified by reverse phase HPLC to obtain 1 mg of 5-(2-azido-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.56 (m, 2H), 8.11 (dd, 1H), 7.6 (t, 1H), 7.2 (s, 1H), 6.85 (m, 2H), 4.67 (d, 1H), 4.47 (d, 1H), 4.39 (s, 2H), 3.84 (m, 1H), 3.48 (m, 1H), 3.34 (m, 1H), 3.12 (s, 3H), 3.12 (m, 1H), 2.36 (s, 3H), 2.03 (s, 3H). Separation by chiral HPLC provides enantiomers V-3a-b.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[C:6]2[C:7](=[O:22])[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:2][C:3]1[CH:23]=[C:6]2[C:7](=[O:22])[NH:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)=[CH:10][N:5]2[N:4]=1
Reactant: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cn2nc(CCl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]c(-c3ccc(OC(F)(F)F)cc3)cn2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 18.9 mg (0.055 mmol) 2-chloromethyl-6-(4-trifluoromethoxy-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one in 0.5 ml THF is flushed with nitrogen. 3.5 mg (0.092 mmol) Lithiumaluminiumhydride is added and the reaction mixture is stirred for 5 hours at room temperature. Then 1 ml THF, 3.5 μl water, 3.5 μl 15% aqueous NaOH solution and 10.5 μl water are added successively. The resulting suspension is stirred for 30 minutes at room temperature. The precipitate is filtered off and washed with THF and ethanol. The filtrate is evaporated and purified by preparative HPLC to give 2-methyl-6-(4-trifluoromethoxy-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one as colourless crystals; HPLC/MS 2.53 min (B), [M+H] 310;
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.O1[CH2:42][CH2:41]OCC1>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:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:13]3[CH:14]=[N:15][CH:11]=[CH:41][CH:42]=3)=[CH:30][CH:29]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Reactant: C1COCCO1
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
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3cccnc3)cc2)nc1

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (300 mg) synthesized in Example 402-1 and (3-diethylboryl)pyridine (76 mg) were dissolved in dioxane (2.6 mL) and sodium carbonate (2 mol/L, 1.3 mL), tetrakis(triphenylphosphine)palladium (30 mg) was added, and the mixture was refluxed for 2 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (223 mg) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[NH2:47][CH2:48][CH2:49][CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:47][CH2:48][CH2:49][CH2:50][N:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: NCCCN1CCCC1
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCN4CCCC4)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 53.5 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (40 mg, 0.096 mmol), N,N-diisopropylethylamine (0.050 mL, 0.29 mmol), and catalytic DMAP in 2.5 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.069 mL, 0.116 mmol). After 6 min at rt, 1-(3-Aminopropyl)pyrrolidine (16.0 mg, 0.125 mmol) was added and the reaction stirred at rt for 4 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The sample was triturated with EtOAc, and the filtrate chromatographed eluting with CHCl3/MeOH plus triethylamine to give the title compound as a light beige solid (27 mg, 53%). 1H NMR (CDCl3) δ: 8.50 (s, 1H), 8.36-8.44 (m, 2H), 8.10 (s, 1H), 7.58 (s, 1H), 7.46-7.54 (m, 2H), 7.32-7.39 (m, 1H), 7.22-7.31 (m, 2H), 7.10 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 4.46 (s, 2H), 3.53-3.61 (m, 4H), 3.22 (t, J=5.4 Hz, 2H), 2.77-2.97 (m, 7H), 1.82-1.99 (m, 6H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:18])[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)Nc1ccc(CCOC(C)=O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)OCCc1ccc(NC(C)=S)cc1
Yield: 142.3 %

Procedure:
4-Acetamidophenethyl acetate (10.0 g, 45.2 mmol) and phosphorus pentasulfide (10.0 g, 22.5 mmol) were suspended in toluene (200 ml). The suspension was refluxed for 40 min. After cooling the supernatant was decanted into a separatory funnel and washed with 50% aqueous Na2CO3 solution (70 ml) and then with water (70 ml). The organic toluene layer was dried over anhydrous sodium sulfate overnight. The dried toluene solution was concentrated to dryness to give a yellowish solid (7.6 g, 71%). This solid was used for next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=2)[N:5]([CH3:20])[C:4]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=[O:22])#[CH:2]>CO.[Pd]>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=2)[N:5]([CH3:20])[C:4]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:25][CH2:24]1)=[O:22])[CH3:2]
Reactant: C#Cc1nc(-c2cccc(CCCCCC)c2)n(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1cccc(-c2nc(CC)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of 0.13 g (0.29 mmol) of [5-ethynyl-2-(3-hexyl-phenyl)-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 13) in 5 ml of MeOH was treated with 0.031 g (0.03 mmol) of Pd—C (10%) and the reaction mixture was then hydrogenated with H2 (1 bar) at RT for 2 hours. After removal the catalyst by filtration, the solvent was evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.12 g (92%) of the title compound as light yellow oil. MS: 451.1 (MH+).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])[O:15]C)[N:9]=1)[C:2]([NH2:4])=[NH:3]>C(O)C.O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14]([NH2:17])=[O:15])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1nc(CSCCC(N)=O)cs1
Yield: 67.5 %

Procedure:
In a mixture of 30 ml of ethanol and 30 ml of water was dissolved 5.0 g of methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate and after allowing to stand the solution for 20 hours at 40° C., the solvent was distilled off under reduced pressure. The residue formed was purified by a column chromatography using a mixture of chloroform and methanol and recrystallized from methanol to provide 3.2 g 3-(2-guanidinothiazol-4-ylmethylthio)propionamide showing a melting point of 193°-194° C. (decompd.).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O)O.C([Zn]CC)C.[C:14]1([C:20]#[C:21][Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(#N)C1C=CC=CC=1.CCCCCCCCCCCCC>C1COCC1>[C:1]1([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [Li]C#Cc1ccccc1
Reactant: Oc1ccccc1O
Agent: CCCCCCCCCCCCC
Agent: CC[Zn]CC
Solvent: C1CCOC1
Solvent: N#Cc1ccccc1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of catechol (0.440 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with diethylzinc (4 ml; 4.00 mmol; 1.0 M in THF) and the resulting solution was allowed to warm to room temperature for 20 min. Solvent was removed in vacuo, then phenylethynyllithium (4.0 ml; 4.00 mmol; 1.0 M THF) was added at room temperature and the resulting mixture was stirred for 30 min. This solution was then added to a room temperature mixture of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0282 g; 5 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol). The reaction mixture was then heated to 65° C. and stirred for 6 days; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.08 mmol (54% yield) of diphenylacetylene and 0.41 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][NH:42][CH2:41][CH2:40]2>CN(C)C=O>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)([CH2:4][CH2:3][CH2:2][N:42]2[CH2:41][CH2:40][C:39]3[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH2:43]2)[C:6]#[N:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(C(C#N)(CCCCl)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Temperature: 95 °C
Reaction time: 12 h

Procedure:
To a solution of 3.20 g of α-(3-chloropropyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile in 30 mL of dimethyl formamide, under argon, is added 2.78 g of potassium carbonate, 79.5 mg of potassium iodide, and 1.84 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. The reaction mixture is then heated at 95° C. for 4 hours, then allowed to cool and stir at ambient temperature for 12 hours. The solvent is evaporated from the mixture under vacuum at 45° C. The residue is partitioned between diethyl ether and water. The organic solution is dried with magnesium sulfate, filtered and evaporated to give the crude product. The product is chromatographed on a column of silica gel and is eluted with ethyl acetate providing 1.6 g of the desired product, after evaporation of the solvent, as an orange gum.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][OH:24])=[C:29]([O:37][CH3:38])[CH:30]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1cc(C(=O)O)ccc1OCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc(OCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (5)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4151.) as brown solid (38%). MS 512 (MH+).