Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:24][C:25]([F:28])([F:27])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:24][C:25]([F:27])([F:28])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A mixture of ethyl 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3.0 g), 1N aqueous sodium hydroxide solution (20 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (2.60 g, yield 93%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 288-290° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](Cl)=[O:12])=[CH:10][C:5]=2[O:4][C:3]1=[O:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([Cl:24])[CH:17]=1.C([O-])(O)=O.[Na+]>COCCOC.[Zn].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>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:14])[O:4][C:5]=3[CH:10]=2)=[O:12])=[C:18]([Cl:24])[CH:17]=1
Reactant: Cn1c(=O)oc2cc(C(=O)Cl)ccc21
Reactant: Clc1cc(Br)ccc1CBr
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: COCCOC
Product: Cn1c(=O)oc2cc(C(=O)Cc3ccc(Br)cc3Cl)ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid (1.0 g, [CAS Reg. No. 140934-94-7]) in CH2Cl2 (14 mL) were added two drops of DMF and oxalylchloride (0.71 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-carbonyl chloride). To a suspension of zinc powder (677 mg) in 1,2-dimethoxyethane (8 mL) was added tetrakis(triphenylphosphine)palladium(0) (60 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (8 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-chloro-benzene (1.47 g, [CAS Reg. No. 89720-77-4]) in 1,2-dimethoxyethane (10 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. Ethyl acetate (20 mL) was added to the resulting precipitate and the suspension was stirred for 1 hour at r.t. The solid was filtered off and dried in vacuo. The title compound was obtained as an off-white solid (747 mg, 38%). MS (neg. ion, m/e)=380.2 [(M−H)−].
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[NH2:18])[C:9]1=[O:19])[CH3:7])(=O)C.C(Cl)Cl.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:18][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:19])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propyl acetate (100 mg, 0.0004 mol) in methylene chloride (2 mL, 0.03 mol) was added 3,4-dichlorophenyl acetic acid (120 mg, 0.00058 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (360 mg, 0.00096 mol) and N,N-diisopropylethylamine (300 μL, 0.002 mol). The reaction mixture was stirred overnight at room temperature. The mixture was then purified by column chromatography using an ethyl acetate:hexane (0-40%) gradient. The combined pure fractions were reduced in vacuo and taken up in methanol (3 mL, 0.07 mol), potassium carbonate (200 mg, 0.001 mol) and a few drops of water were added, and the mixture was stirred at room temperature for one hour. This was followed by purification using column chromatography (ethyl acetate:hexane, 0-100%) thus producing the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@@H:14]([OH:15])[CH2:13][C@@H:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1.C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([O:16][Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:19])[C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2cc(Br)c(C)s2)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A mixture of alcohol 4 (3.591 g, 4.9 mmol), 4A molecular sieves (2.5 g), and NMO (867 mg, 7.4 mmol) in dichloromethane (10 mL) was treated with TPAP (117 mg, 0.33 mmol). After 1 h, the mixture was filtered through celite and the filtrate evaporated in vacuo. Purification by flash chromatography (5% ethyl acetate/hexanes→7.5%) gave 5 (2.984 g, 4.1 mmol, 84%).
Reaction SMILES: FC1CCCC1.Cl.[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32][CH:33]([OH:35])[CH2:34][CH:15]3[C:14]=2[CH:13]=1>C1COCC1.O>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=3)[CH:16]3[CH2:32][C:33](=[O:35])[CH2:34][CH:15]3[C:14]=2[CH:13]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Agent: Cl
Agent: FC1CCCC1
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CC32)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of Preparation 45 (0.012 g) in THF (20 mL) and H2O (1 mL) add HCl solution (2 mL, 3 N in H2O), and stir the mixture overnight. Pour the mixture into satd. NaHCO3 and extract with Et2O (2×50 mL) and EtOAc (2×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, and concentrate to afford crude Preparation 27 as a light yellow solid. Purify the crude material by MPLC (0% to 25% to 50% EtOAc/hexanes) to afford Example 23 (0.010 g, 90%) as a white solid. 1H NMR (CD3OD) δ 7.22 (d, J=8.0 Hz, 2H), 6.85 (m, 1H), 6.79 (m, 3H), 6.64 (m, 1H), 5.22 (s, 1H), 3.54 (m, 1H), 2.67 (m, 1H), 2.56 (m, 1H), 2.26 (m, 2H), 2.13 (m, 2H), 1.84 (dd, J=3.9, 14.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([N+:33]([O-:35])=[O:34])[CH:26]=2)[CH:20]=1.O>O1CCCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([C:21]2[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=[CH:23][N:22]=2)=[CH:26][C:27]=1[N+:33]([O-:35])=[O:34])[CH3:4]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 101 mg) in tetrahydrofuran (10 ml) was added a solution of diethylphosphonoacetic acid ethyl ester (0.535 ml) dropwise at 0° C., and the mixture was stirred at 5° C. for 30 minutes. Then to the resultant mixture was added a solution of 4-(4-methoxypyridin-2-yl)-2-nitrobenzaldehyde (543 mg) in tetrahydrofuran (10 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 4-(4-methoxypyridin-2-yl)-2-nitrocinnamic acid ethyl ester (557 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:41][C:42]([C:44]2([NH:59]C(=O)OC(C)(C)C)[CH2:49][CH2:48][N:47]([C:50]3[C:51]4[CH:58]=[CH:57][NH:56][C:52]=4[N:53]=[CH:54][N:55]=3)[CH2:46][CH2:45]2)=[O:43])[CH2:16][C:17]2[N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1>O.CO>[NH2:59][C:44]1([C:42]([NH:41][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[O:43])[CH2:49][CH2:48][N:47]([C:50]2[C:51]3[CH:58]=[CH:57][NH:56][C:52]=3[N:53]=[CH:54][N:55]=2)[CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)NC(Cc2ncc[nH]2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
Trifluoroacetic acid (5 mL, 64.90 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 89) (310 mg, 0.38 mmol) at room temperature and the resulting solution stirred for 30 minutes. Water (5-6 drops) was then added and stirring continued for a further 30 minutes. The resulting solution was diluted with methanol and applied to a 10 g SCX column which was then eluted with MeOH followed by 2N NH3 (in MeOH). Product-containing fractions were combined and concentrated by evaporation then triturated with MeCN/DMF (1:1) to give a pale yellow ppt. The precipitate was collected by filtration, washed with MeCN and dried under vacuum to afford 4-amino-N-(1-(4-chlorophenyl)-2-(1H-imidazol-2-yl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (130 mg, 72.8%) as a cream solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([C@@H:13]3[CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[N:14]3[C:28](=[O:48])[C@@H:29]([CH2:36][N:37]([CH:46]=[O:47])[O:38]CC3C=CC=CC=3)[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1.O>CO.[OH-].[OH-].[Pd+2]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([C@@H:13]3[CH2:17][CH2:16][NH:15][N:14]3[C:28](=[O:48])[C@@H:29]([CH2:36][N:37]([CH:46]=[O:47])[OH:38])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccc3[nH]nnc3c2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ccc2[nH]nnc2c1
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of phenylmethyl (3S)-3-[(1H-1,2,3-benzotriazol-5-ylamino)carbonyl]-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-pyrazolidinecarboxylate (87.2 mg, 0.133 mmol) in methanol (2.7 ml) was added 20% palladium hydroxide on carbon, 50% water (18.73 mg, 0.133 mmol). The mixture was hydrogenated under balloon pressure for 3 h, and was then filtered through a 0.2 μm PTFE membrane. The solution was concentrated in vacuo, and the residue was azeotroped with EtOAc (10 mL). The residue was triturated with 30% EtOAc in hexanes, and the solid was collected by vacuum filtration to give (3S)—N-1H-1,2,3-benzotriazol-5-yl-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-3-pyrazolidinecarboxamide (43.2 mg, 0.101 mmol, 75% yield) as a white solid. LC/MS: (M+H)+: 430.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1.[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][OH:26])[CH:19]=1)[CH2:16][NH2:17]>C(O)C.[Pt]=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][OH:26])[CH:19]=2)[CH3:12])=[CH:6][CH:5]=1
Reactant: COCc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Agent: O=[Pt]
Solvent: CCO
Product: COCc1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-methoxymethylphenyl)propan-2-one (0.46 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (0.45 g) in ethanol (50 ml) was refluxed 0.5 hours, cooled to ambient temperature and hydrogenated at atmospheric pressure using platinum oxide as catalyst. The solution was filtered, evaporated, the residue taken up in ethyl acetate and filtered again. Removal of the solvent gave an oil which was crystallised and recrystallised from benzene to give the title compound, mp 81°-92°, as a 53:47 mixture of diastereoisomers.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[CH2:14]([N+:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]>CO>[C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[CH2:14]([N+:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15].[CH2:14]([N+:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Yield: 92 %

Procedure:
Terephthalic acid (2.5 g, 0.015 mol) was titrated with a 40% aqueous solution of tetraethylammonium hydroxide (11.3 mL). The solvent was evaporated to obtain a hard residue which was dissolved in methanol. The methanol was evaporated to obtain 5.8 g, 92% yield of salt. FIG. 43 shows a 1H NMR spectrum and FIG. 44 shows a 13C NMR spectrum of the salt in DMSO-d6.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)=[N:13][N:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49].Cl>CN(C=O)C.O>[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:46][CH2:47][C:48](=[O:49])[N:50]3[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=4[C:63]([F:64])([F:66])[F:65])[CH2:54][CH2:55]3)=[O:22])=[CH:23][CH:24]=2)=[N:13][N:12]=1
Reactant: Cc1nnc(-c2ccc(C(=O)O)cc2)o1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
DIPEA (180 mg, 0.24 mL, 1.4 mmol) was added drop wise to 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid (90 mg, 0.4 mmol) in DMF (3 mL). EDCI (92 mg, 0.48 mmol) and HOBT (65 mg, 0.48 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (150 mg, 0.4 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue purified by column chromatography (using silica gel of 60-120 mesh and 10% EtOAc in Hexane as eluent to afford 40 mg (19.9% yield) of 4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 96.6%. 1H NMR (CDCl3): δ 8.1 (d, 2H), 7.9 (m, 2H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 4.2 (m, 2H), 4.0 (m, 2H), 3.6 (m, 3H), 3.4 (m, 1H), 2.6 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.[C:27](OCC)(=O)[CH3:28]>C(O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)cc2c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2[N+](=O)[O-])c(OC)c1
Reaction time: 16 h

Procedure:
A solution of 1.2 (1.65 g, 4.63 mmol) in ethanol (20 mL) with several drops of concentrated sulfuric acid was heated to reflux overnight. After 16 h, HPLC indicated that no 1.2 remained and the ethanol was removed in vacuo on a rotary evaporator. The concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic layer was washed with water then brine, stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark oil. The desired product was isolated by trituration of the residue with ethyl acetate to yield the desired product as an orange solid. The filtrate from trituration was chromatographed on silica gel, eluting with an ethyl acetate/hexane gradient, to afford additional product. LC-MS ESI (pos.) m/z: 385.0 (M+H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:13])[CH:9]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(c2ccc(F)nc2)CN1
Agent: [Pd]
Solvent: CO
Product: O=C1CC(c2ccc(F)nc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 4-(6-fluoropyridin-3-yl)-1H-pyrrol-2(5H)-one(190 mg, 1.066 mmol) in MeOH (10 mL) under N2 atmosphere was added Pd—C (227 mg, 0.213 mmol). The reaction mixture was stirred under H2 balloon at room temperature for overnight. Reaction mixture was filtered through Celite, washed with MeOH. Filtrate was evaporated. Azeotrope with toluene (x=3). Yield was 80%. Proceed for next step. LCMS (m/z): 181.0 (MH+), 0.341 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[N:21]=[C:20]4[N:22]([CH3:36])[C:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]=5[C:19]4=[CH:18][CH:17]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[N:21]=[C:20]4[N:22]([CH3:36])[C:23]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]=5[C:19]4=[CH:18][CH:17]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
tert-Butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.14 g, 0.28 mmol) was treated with 1.25 M HCl in MeOH (7.0 mL), and the resulting suspension was stirred at ambient temperature for 18 h. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with saturated NaHCO3 solution (50 mL). The resulting layers were separated, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to dryness. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 0:100 over 20 column volumes and held for 34 column volumes) provided the title compound (75 mg, 67%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J=2.7 Hz, 1H), 7.92-7.78 (m, 3H), 7.69-7.62 (m, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.18 (dd, J=7.8, 2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 3.87 (s, 2H), 3.65 (s, 3H), 3.08 (t, J=5.7 Hz, 2H), 2.75 (t, J=5.4 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[CH:6]1.[OH-].[K+:25]>C(O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[CH:6]1.[K+:25]
Reactant: Cc1cccc(C)c1Cn1cc(C)c2ccc(CC(=O)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Cn1cc(C)c2ccc(CC(=O)[O-])cc21

Procedure:
To a solution of the compound [64] (226 mg) in ethanol (5 mL) was added an aqueous solution of 1N-potassium hydroxide (0.74 mL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (254 mg) as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH:16]1[C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[CH:14]=[C:15]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c([nH]1)CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c([nH]1)CNCC2
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.0 eq) in ethanol was added 10% Pd/C (w/w), and the reaction was carried under hydrogen atmosphere overnight. Reaction mixture was filtered through celite and concentrated to afford crude product which on purification afforded compound ethyl 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([CH2:13][C:14]2([CH3:17])[CH2:16][CH2:15]2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.CN(C(O[N:26]1N=[N:33][C:28]2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([CH2:13][C:14]2([CH3:17])[CH2:16][CH2:15]2)[C:10]([NH:33][CH2:28][C:27]#[N:26])=[O:12])=[CH:6][CH:7]=1
Reactant: CC1(CC(Sc2ccc(Br)cc2)C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(CC(Sc2ccc(Br)cc2)C(=O)NCC#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice cold solution of 2-[(4-bromophenyl)thio]-3-(1-methylcyclopropyl)propanoic acid (417 mg, 1.3 mmol), HATU (652 mg, 1.7 mmol), 2-aminoacetonitrile hydrochloride (171 mg, 1.8 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) dropwise. The resulting mixture was stirred at room temperature for 18 h and partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford 2-[(4-bromophenyl)thio]-N-(cyanomethyl)-3-(1-methylcyclopropyl)propanamide.