Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].N1([C:39]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:40])CCNCC1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:39]([N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:40])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(N1CCCCC1)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N5CCCCC5)CC4)cc3c2)CC1
Yield: 95 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and piperazin-1-yl-piperidin-1-yl-methanone to afford the desired product as a light-brown foam (95%). MS (ISP): 495.5 (M+H)+
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]([O:27]C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:10]2[CH:29]=[CH:30][CH:31]=[CH:32][C:9]=2[N:8]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[CH2:3]([C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:10]2[CH:29]=[CH:30][CH:31]=[CH:32][C:9]=2[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 43 %

Procedure:
1M Aqueous sodium hydroxide solution (6.5 ml) was added to a solution of methyl 4'-[(2-butyl-1H-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate (A) (2.0 g) in ethanol (20 ml). The solution was heated under reflux for 3 hours and then volatile material was removed by evaporation. The residue was dissolved in water (20 ml) and the solution acidified to pH 4 with 20% aqueous citric acid. The precipitated solid was collected and dried under high vacuum to give 4'-[(2-butyl-1H-benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acid (0.83 g), as a white powder, m.p. 225°-227° C.; NMR (d6 -DMSO): 0.9(t,3H), 1.4(m,2H), 1.7(m,2H), 2.85(t,3H), 5.5(s,2H), 7.15(m,4H), 7.3(m,3H), 7.4-7.7 (complex m,5H); 12.6(br, 1H); mass spectrum (positive chemical ionisation; hereinafter referred to as "+ve CI" ): 385 (M+H)+, 384 (M+), 355, 342, 298, 211, 165, 145, 132, 77; microanalysis found: C,77.2; H,6.5; N,7.0; C25H25N2.025 H2O requires: C,77.2; H,6.2; N,7.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=O.[H][H]>[Ni].C(O)C>[NH2:1][C:4]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1N
Yield: 65 %

Procedure:
A mixture of 25 parts of ethyl 2-nitro-4-(phenylmethoxy)benzoate and 160 parts of ethanol was hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 2,2'-oxybispropane. After cooling, the product was filtered off and dried, yielding 14.5 parts (65%) of ethyl 2-amino-4-(phenylmethoxy)benzoate (4).
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:8]=[C:9]([C:13](SC)=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]>CO>[NH2:16][C:15]1[NH:3][N:2]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=2)[C:14]=1[C:17]#[N:18]
Reactant: NN
Reactant: CSC(=C(C#N)C#N)c1cccc([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Product: N#Cc1c(-c2cccc([N+](=O)[O-])c2)n[nH]c1N
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
0.24 ml (4.8 mmol) of hydrazine hydrate is added dropwise to 1.00 g (4.08 mmol) of 3-(3-nitro-phenyl)-3-methylmercapto-2-cyano-acrylonitrile in 5.3 ml of methanol and the reaction mixture is then boiled for 1.5 hours. The reaction mixture is then cooled in ice-water and the precipitate is filtered off and washed with diethyl ether/isopropanol (2:1), yielding 5-amino-3-(3-nitro-phenyl)-1H-pyrazole-4-carbonitrile; TLC: Rf =0.4 (methylene chloride:methanol=10:1); TRet (Grad20-100)=10.8; MS: (M)+ =229, (M-NO2)+ =183.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)C>[C:14]([C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1)#[N:15]
Reactant: C1CNCCN1
Reactant: N#Cc1cccnc1Cl
Solvent: CCO
Product: N#Cc1cccnc1N1CCNCC1
Yield: 72.3 %

Procedure:
A mixture of piperazine (0.5 mol) and 2-chloro-3-cyanopyridine (0.1 mol) in absolute ethanol (225 ml) was heated at reflux for 16 hours. The cooled mixture was filtered to remove precipitated piperazine hydrochloride and the filtrate evaporated in vacuo. The residue was diluted with water (200 ml), made basic (pH>10) with 5N sodium hydroxide and extracted with ether (5×300 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo affording 13.6 g of a white solid (72.5% yield); mp 99°-103° C. Spectral data are consistent with the assigned structure. This material was used without further purification.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(N2CCCCC2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1N1CCC(N2CCCCC2)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Subsequently, ammonium chloride (0.7 g) and iron powder (3.8 g) were added to a mixed solvent of water (30 ml) and ethanol (120 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-piperidinopiperidin-1-yl)benzonitrile (6.2 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (4.8 g), melting point: 110–112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:6]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([N:17]3[CH2:18][CH2:19][CH:14]([C:7]4[C:8](=[O:13])[NH:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)[CH2:15][CH2:16]3)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)c(C3CCN(c4cc(C(=O)N5CCc6cc(F)ccc65)ncn4)CC3)cc2c1

Procedure:
25 mg (70 μmol) 6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one, 20 mg (70 μmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 50 μL (0.29 mmol) DIPEA were stirred in 2 mL DMF overnight at RT. Then the reaction mixture was diluted with DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][SiH:26]([CH3:28])[Cl:27]>ClCCl.C(O)(C)C>[C:1]1([C@@H:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[CH2:8][CH2:9][Si:26]([Cl:27])([CH3:28])[CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[SiH](C)Cl
Reactant: C=C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)O
Product: C[Si](C)(Cl)CC[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Reaction time: 6 h

Procedure:
1 g (3.06 mmol) of amide 5 was dispersed in an inert atmosphere in 10 ml of dry dichloromethane. 12 mg of H2PtCl6.xH2O was dispersed in 0.25 ml isopropanol and the obtained brown suspension was added to the reaction mixture. Afterwards, 10 ml of dimethylchlorosilane (92 mmol) was added and the reaction mixture was stirred on a reflux temperature for six hours. The transparent yellow solution was evaporated to paste remain which was dissolved in 5 ml of dry dichloromethane and again evaporated until dry.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:39][CH2:40][CH3:41])[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:38]=1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:39][CH2:40][CH3:41])[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:24]=[CH:23][C:22]=3[N+:21]([O-:6])=[CH:20][C:19]=2[N:38]=1)[CH3:13]
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCCCN4CCCC4=O)cc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCCN4CCCC4=O)cc3c21
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
3-Chloroperoxybenzoic acid (50% pure, 1.8 g, 5.26 mmol) was added to a solution of 1-[3-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)propyl]-pyrrolidin-2-one (2.9 g, 5.26 mmol) in chloroform (50 mL). After 30 minutes, saturated aqueous sodium carbonate (20 mL) was added to the solution and the resulting mixture was allowed to stir for 1 hour. The layers were separated and the aqueous layer was extracted with chloroform (3×50 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 1-4% methanol in dichloromethane) to yield 1.56 g of 1-(3-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}propyl)pyrrolidin-2-one as a tan foam.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[C:8]([C:11](=[CH:17]N(C)C)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[CH3:9]>C(O)C>[CH3:9][C:8]1[N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[N:7]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C
Yield: 87.5 %

Procedure:
tert-Butylhydrazine hydrochloride (33.6 grams, 0.27 mole) and α-acetyl-α-(dimethylaminomethylene)acetic acid, ethyl ester (50 grams, 0.27 mole) were added to 150 ml. of ethanol and the resulting reaction mixture was refluxed for two hours. The reaction mixture was then cooled, and the solvent was removed in vacuo. The residue was taken up in 300 ml. of ether, washed with water, washed with saturated sodium bicarbonate, washed with saturated brine, and dried using sodium sulfate and filter paper. The solvent was then removed in vacuo. The residue was distilled at 110° C. at 1.2 mm mercury pressure to provide 49.7 grams of 5-methyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 88.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12]>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1cc(CO)ccc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)ccc1Cl
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv; commercially available) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0° C. After 1 h the reaction was cooled to −78° C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CC[N:15]([CH:19]([CH3:21])[CH3:20])C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1(N)CC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:15][CH:19]2[CH2:21][CH2:20]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)NC1CC1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 18.0 g (79.0 mmol) 2-(4-bromo-phenyl)-propionic acid (Bioorg. Med. Chem. Lett. 2010, 20, 887) and 68.4 mL (393 mmol) DIPEA in 90 mL DMF, 50.5 g (157 mmol) TBTU are added. The mixture is stirred for 15 min at 0° C. After that time, 16.3 mL (236 mmol) cyclopropylamine are added and the mixture is stirred for 16 h at rt. After that time, iced water is added and the mixture is extracted with EtOAc. The organic layer is washed with brine and dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; hexane/EtOAc 7:3) to yield the desired product.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:37])[C@H:11]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:12][C:13](=[O:29])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])C1C=CC=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10](=[O:37])[C@H:11]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:12][C:13](=[O:29])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)NO)cc1
Reaction time: 9 h

Procedure:
N-(Toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-benzyloxyamide (see Example 43 (159)) was dissolved in MeOH (10 mL) and 5% Pd/BaSO4 (52 mg) was added. The mixture was hydrogenated at 50 psi H2 for 9 h. The mixture was filtered through a pad of diatomaceous earth and evaporated in vacuo to give a residue which was purified by silica gel chromatography (92:8 CH2Cl2/MeOH) to give the title compound as an oil.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)C>C1COCC1.CO>[OH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][CH2:7][C:6]([OH:18])=[O:5])=[O:17]
Reactant: CCOC(=O)CNC(=O)c1cccc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
LiOH (75 mg in 2 mL water) was added to (3-hydroxy-benzoyl amino)-acetic acid ethyl ester (100 mg, 0.45 mmol) in a mixture of THF and MeOH mixture. This was followed by the addition of to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The THF and MeOH were then evaporated under reduced pressure and the resulting residue was acidified to pH 2 using 10% citric acid solution. The product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (3-hydroxy-benzoyl amino)-acetic acid in 89% yield. 1H NMR (DMSO-D6): δ 12.4 (s, 1H), 9.6 (s, 1H), 8.7 (t, 1H), 7.2 (d, 3H), 6.9 (m, 1H), 4.0 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)cc1OC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 56.2 %

Procedure:
To a solution of methyl 4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate (Intermediate-46, 0.070 g, 0.17 mmol) in dry toluene was added 3-(trifluoromethyl)aniline (0.043 g, 0.17 mmol) followed by addition of trimethyl aluminum (2M solution in toluene) (0.5 mL). The reaction mixture was refluxed for 1 hr under inert atmosphere. The reaction mixture was brought to RT and quenched with water. Few drops of dilute HCl were added and the reaction mixture was extracted with DCM and concentrated. The obtained product was purified with column chromatography to afford 0.050 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.46 (d, J=6.9 Hz, 1H), 7.54-7.65 (m, 4H), 7.72-7.76 (m, 3H), 7.94 (d, J=8.4 Hz, 1H), 8.24 (s, 1H), 10.51 (s, 1H), 12.85 (s, 1H); MS (m/z): 523.04 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH:44]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:55][C:52]2[CH:51]=[CH:50][C:49]([C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)=[CH:54][CH:53]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Reactant: Nc1ccc(-c2cccnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 60.2 %

Procedure:
DMAP (68 mg, 0.56 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (100 mg, 0.28 mmol) in DMF (2 mL) followed by EDCI (64 mg, 0.33 mmol) and HOBT (45 mg, 0.33 mmol). After 2 minutes, 4-pyridin-3-yl-phenylamine (55 mg, 0.18 mmol) was added and it was stirred at room temperature overnight. Cold water was then added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 55 mg (38.73% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(4-pyridin-3-yl-phenyl)-propionamide. LC/MS [M+H]+: 507.1, 90.55%. 1H NMR (300 MHz, DMSO-d6): δ 10.25 (d, 1H), 8.9 (bt, 1H), 8.5 (d, 1H), 8.1-8.0 (m, 1H), 7.7 (d, 5H), 7.52-7.3 (m, 4H), 3.8-3.46 (m, 8H), 3.2 (bt, 1H), 3.1 (bt, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:11])[CH3:10].[H-].[Na+].[CH2:14]([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O1CCCC1>[C:9]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[C:29]([O:28][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:30]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)N(Cc2ccccn2)C(C)=O)c1

Procedure:
The title compound prepared by the procedure of Example 27 using 0.462 g of product from Example 12 in 4 ml of dry tetrahydrofuran, 0.147 g of washed 50% sodium hydride and 1.03 g of product from Example 26 in 4 ml of dry tetrahydrofuran. The residue is purified by column chromatography (silica gel: 35% ethyl acetate/hexane) to give 0.178 g of the desired product as a yellow oil which crystallized on standing.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38](N4CCN(C)CC4)[CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:49][N:50]([CH3:67])[CH2:51][CH2:52][O:53][C:54]1[CH:55]=[N:56][C:57](C2C=CC(O)=CC=2)=[N:58][CH:59]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:37]=[CH:38][C:39]([C:57]4[N:56]=[CH:55][C:54]([O:53][CH2:52][CH2:51][N:50]([CH3:67])[CH3:49])=[CH:59][N:58]=4)=[CH:40][CH:41]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CN1CCN(c2cccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)CC1
Reactant: CN(C)CCOc1cnc(-c2ccc(O)cc2)nc1
Product: CN(C)CCOc1cnc(-c2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)nc1

Procedure:
The title compound 112D was prepared in a similar manner to the synthesis of compound 105 by substituting compound 87A with compound 112C: 1H NMR (DMSO-d6): δ 12.84 (s, 1H), 9.70 (s, 1H), 8.64 (s, 2H), 8.23 (d, J=8.85 Hz, 2H), 8.04 (d, J=7.93 Hz, 1H), 7.79 (d, J=8.24 Hz, 1H), 7.57-7.61 (m, 2H), 7.34-7.49 (m, 4H), 7.02 (t, J=8.85 Hz, 2H), 6.97 (d, J=8.85 Hz, 1H), 4.93 (s, 2H), 4.52-4.54 (m, 2H), 4.01 (t, J=6.41 Hz, 2H), 3.87 (t, J=5.95 Hz, 2H), 2.95 (t, J=5.8 Hz, 2H), 2.82-2.85 (m, 2H), 1.95-2.00 (m, 2H): ESI (+)/MS: 730 (M+H)+.