Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9](O)=[O:10].N1C=CC=CC=1>ClCCl>[Br:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:4])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CC(Br)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CC(Br)C(=O)Cl
Reaction time: 20 h

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[N:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:7][C:8]1[N:9]=[C:10]([S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Sc1nc[nH]n1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(Sc2nc[nH]n2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 14.4 %

Procedure:
A mixture of 3-mercapto-1H-1,2,4-triazole (200 mg), 2,6-dibromopyridine (560 mg), anhydrous potassium carbonate (420 mg) and N,N-dimethylformamide (1 ml) was heated and stirred for 3 hours on an oil bath at 100° C. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica-gel column chromatography with 5 to 30% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (73 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([CH3:40])[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]([CH3:40])[C:37]([OH:39])=[O:38])=[CH:34][CH:35]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(COc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared by treating 4-(2-benzyl-7-trifluoromethyl-2H-indazole-3-yl)-phenol (20 mg, 1 eq) with 2-(4-bromomethyl-phenyl)-propionic acid (39 mg, 3 eq) and potassium carbonate (37 mg, 5 eq) in DMF (2 mL) at 150° C. overnight. After cooling, water was added and the pH adjusted to 1 (aq. HCl, 2M) followed by extraction with dichloromethane. Purification by preparative HPLC gave the desired product in 45% yleld.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9][C:10]=1[OH:14]
Reactant: Oc1cccc(CN2CCOCC2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1cc(CN2CCOCC2)ccc1Br

Procedure:
3-(Morpholin-4-ylmethyl)phenol (9.65 g) in glacial acetic acid (60 ml) was treated over 2 h with bromine (2.88 ml) in acetic acid (8 ml), evaporated to near dryness, water (100 ml) added and basified with 0.880 ammonia, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated to dryness to give an oil, which was purified by column chromatography eluting with 1:1 ether/isohexane to give the desired product as an oil (4.75 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.[C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][C:24]([C:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:20])=[CH:23][CH:22]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 96 h

Procedure:
A 135 g. portion of aluminum chloride is dissolved in 500 ml. of nitrobenzene, the solution being held below 10°C. by external cooling. A finely ground mixture of 50 g. of succinic anhydride and 75 g. of biphenyl is added to the stirred solution, the temperature being held below 10°C. It is then held at room temperature for 4 days. After pouring the reaction mixture into a solution of 150 ml. of concentrated hydrochloric acid in one liter of ice water, the nitrobenzene is removed by steam distillation. The solid is collected, dissolved in 4 liters of 3% hot sodium carbonate solution, clarified and reprecipitated by the addition of excess 6N sulfuric acid solution. The crude product is collected, dried, and recrystallized from ethanol to give the pure product, melting point 185°-187°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH3:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH3:22][O:21][CH2:20][C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=1
Reactant: COCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=Cc1cccnc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCc1nc2c(N)nc3ccccc3c2n1CCCCNCc1cccnc1
Reaction time: 0.08 h
Yield: 15.3 %

Procedure:
To a round-bottomed flask containing 1-(4-aminobutyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 33.4 mmol) was added methanol (160 mL) followed by acetic acid (40 mL). The reaction was stirred for 5 minutes and pyridine 3-carboxaldehyde (5.4 g, 50.1 mmol) was added and the reaction was stirred overnight at ambient temperature. Sodium cyanoborohydride (1 M in THF, 33.4 mL, 33.4 mmol) was added to the resultant imine in portions over 10 minutes. After 45 minutes the solvent was evaporated to afford an oil. To the oil was added saturated aqueous sodium bicarbonate (200 mL) and the aqueous layer was washed with ethyl acetate (200 mL) and dichloromethane (200 mL). The product was extracted from the aqueous with 20% methanol (2×100 mL) in dichloromethane. The organic layers were combined and the solvent evaporated to afford crude 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (about 2 g). The aqueous layer was again extracted with 20% dimethylformamide (2×100 mL) in dichloromethane. The organic layers were combined and the solvent evaporated to afford crude 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (about 2 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1.CCOCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extractd 2× with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:10](=[C:4]2[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:33][C:34]#[N:35])=[CH:15][CH:16]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(O)cc2)CC(C)(C)C1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCC#N)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
The O-alkylation procedure described for 190 was used. To a stirred suspension of 4,4′-[(3,3,5,5-tetramethylcyclohexylidene) methanediyl]diphenol (219) (0.600 g, 1.78 mmol), K2CO3 (0.368 g, 2.67 mmol), and acetone (60 mL) was added bromoacetonitrile (0.200 mL, 2.85 mmol) under a nitrogen atmosphere at RT. The reaction mixture was refluxed for 3 h, cooled to RT and filtered. Standard work-up followed by purification afforded 0.196 g (29%) of the title compound 229 as a white solid along with 0.38 g (52%) of the bis-alkylated compound 2,2′-[[(3,3,5,5-tetramethylcyclohexylidene) methanediyl]bis(benzene-4,1-diyloxy)]diacetonitrile. In addition, 0.10 g of unreacted starting material (219) was recovered. 1H NMR (300 MHz, CDCl3): δ 7.15 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.75 (s, 2H), 2.00 (s, 2H), 1.98 (s, 2H), 1.31 (s, 2H), 0.95 (s, 12H). LCMS (ESI): m/z 374 (M−H)−. Anal. Calcd for C25H29NO2, C, 79.96; H, 7.78; N, 3.73; Found: C, 79.95; H, 7.84; N, 3.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1.F[B-](F)(F)F.[O:24]=[N+:25]=[O:26].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([N+:25]([O-:26])=[O:24])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: Cc1cn2ccnc(-c3ccc(Cl)cc3Cl)c2n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 1323.8 %

Procedure:
8-(2,4-Dichlorophenyl)-2-methylimidazo[1,2-a]pyrazine (0.10 g, 0.36 mmol) was dissolved in acetonitrile (0.36 mL), then nitronium tetrafluoroborate (72 mg, 0.54 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give 8-(2,4-dichlorphenyl)-2-methyl-3-nitroimidazo[1,2-a]pyrazine (1.54 g) as a yellow oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@@H:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:37])[CH3:38])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: CC(C)S(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: CC(C)S(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and propane-2-sulfonic acid [5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide (which was obtained in Example 27) according to the procedure of Example 73 as a white solid; mp>175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.25(d, J=6.8 Hz, 6 H), 1.30–1.55 (m, 2 H), 1.80–2.00(m, 2 H), 2.60–3.70(m, 9 H), 4.47(dd, J=9.7, 3.9 Hz, 1 H), 4.58(dd, J=8.7, 3.4 Hz, 1 H), 6.75–6.90(m, 3 H), 6.90–7.10(m, 3 H), 7.26(d, J=2.0 Hz, 1 H); MS (ES) m/z: 563.0 (MH+, 100%); HRMS Calcd. for C26H35N4O6S2 (MH+): 563.1992. Found: 563.1985.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[OH:18][CH2:19][CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[N:21]([CH2:20][CH2:19][OH:18])[CH:22]=[CH:23]5)=[O:32])=[CH:40][CH:39]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3c(ccn3CCO)c2)cc1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5c(ccn5CCO)c4)cc3)[nH]c2c1

Procedure:
Compound 674 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(1-(2-hydroxyethyl)-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C27H26N4O4: 471.20; found: 471.05.
Reaction SMILES: [Li+].[I-].Cl[C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](COC3C=CC4C(=O)N(C5CCCC5)SC=4C=3)[CH:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([O:12]C)=[O:11].O>N1C=CC=CC=1>[C:6]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)cc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 110.4 %

Procedure:
LiI (0.042 g, 0.32 mmol) was added to a solution of methyl 3-chloro-3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylate (0.158 g, 0.32 mmol) in pyridine (5 mL). The reaction mixture was refluxed for 12 h, and then cooled to room temperature. Excess solvent was removed under vacuum. The product was purified by HPLC using isopropanol:water as the solvent system to afford 3-chloro-3′-(2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylic acid as a colorless solid (70 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.82 (d, 1H, J=8.5 Hz), 7.80 (d, 1H, J=8.6 Hz), 7.71-7.76 (m, 4H), 7.49-7.47 (m, 2H), 7.05 (d, 1H, J=8.5 Hz), 5.23 (s, 2H), 4.83-4.81 (m, 1H), 2.02-1.99 (m, 21-1), 1.62-1.60 (m, 6H). LC-MS (ESI) Calcd for C26H22ClNO4S [M+H]+: 480.09. Found: 479.95. HRMS (ESI) calcd for C26H22ClNO4S [M+H]+: 480.1031. Found: 480.1031.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1cccs1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 431(M+1)
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[C:8]([CH:32]3[CH2:35][CH2:34][CH2:33]3)=[CH:9][C:10]([CH2:30][CH3:31])=[C:11]([CH:29]=2)[C:12]([N:14]2[CH2:19][CH2:18][C:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)([F:20])[CH2:16][CH2:15]2)=[O:13])=[N:4][N:3]=1.[OH-].[K+].[CH3:38]O>>[CH:32]1([C:8]2[C:7]([C:5]3[NH:1][C:2]([O:6][CH3:38])=[N:3][N:4]=3)=[CH:29][C:11]([C:12]([N:14]3[CH2:15][CH2:16][C:17]([C:21]4[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=4)([F:20])[CH2:18][CH2:19]3)=[O:13])=[C:10]([CH2:30][CH3:31])[CH:9]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CCc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: CCc1cc(C2CCC2)c(-c2nnc(OC)[nH]2)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 217.3, 200 mg, 0.420 mmol, 1.00 equiv) in methanol (20 mL). Potassium hydroxide (237 mg, 4.22 mmol, 10.0 equiv) was added to the reaction mixture. The resulting solution was stirred for 15 h at 70° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was diluted with 30 mL of H2O, then extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (49.0% CH3CN up to 63.0% in 8 min, up to 100.0% in 1 min, down to 49.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 20 mg (10%) of the title compound as a white. m/z (ES+) 488 (M+H)+. 1H-NMR (300 MHz, CD3OD): δ 7.72 (d, 2H), 7.64-7.61 (m, 2H), 7.39-7.25 (m, 2H), 4.85-4.78 (m, 1H), 4.00-3.93 (m, 4H), 3.54-3.49 (m, 2H), 3.28-3.22 (m, 1H), 2.80-2.65 (m, 2H), 2.26-1.84 (m, 10H), 1.45-1.27 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[F:21][C:22]([F:39])([F:38])[C:23]1[N:28]=[CH:27][C:26]([NH:29][NH:30]C(OC(C)(C)C)=O)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:26]2[CH:27]=[N:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=2)[N:30]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 69.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-[6-(trifluoromethyl)pyridin-3-yl]hydrazinecarboxylate (Intermediate-61, 0.431 g, 1.55 mmol), DCM (50 mL) and trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)C1CCOCC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(C3CCOCC3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-tetrahydro-pyran-4-carboxamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [C:1]([O-])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>CN(C)C=O>[OH:3][C@@H:2]([CH3:4])[C:1]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[O:5]
Reactant: CC(O)C(=O)[O-]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of sodium lactate (1.7 g., 15.0 mmole), diphenylphosphorylazide (3.6 ml., 1.1 eq.), and dry dimethylformamide (30 ml.) at 0° (ice-bath) in an argon atmosphere is treated with triethylamine (2.1 ml., 1.0 eq.) and L-proline, phenylmethyl ester, monohydrochloride salt (3.6 g., 15.0 mmole). After 24 hours, the reaction mixture is partitioned between ethyl acetate and water. The aqueous phase is back extracted, the organic extracts are combined, washed with 5% potassium bisulfate, brine, and evaporated. The residue (5 g.) is chromatographed on silica (130 g.) eluting with (1:1, ethyl acetate/hexane) to give 2.5 g. of 1-[(S)-2-hydroxy-1-oxopropyl]-L-proline, phenylmethyl ester as a white crystalline solid after evaporation; m.p. 86°-88° (isopropyl ether). TLC (silica gel; ethyl acetate) Rf =0.4.
Reaction SMILES: [H-].[Na+].P([O-])([O-])(O[CH:6]([CH2:9][CH3:10])[C:7]#[N:8])=O.CC([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=O>C1COCC1>[CH3:27][O:26][C:18]1[CH:17]=[C:16]([C:9]([CH3:10])=[CH:6][C:7]#[N:8])[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCC(C#N)OP(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(C)=CC#N)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a slurry of 60% NaH (1.46 g, 61.1 mmol) in THF at 0° C. was added 10.0 g (56.4 mmol) of ethyl(cyanomethyl) phosphate. A solution of 9.88 g (47.0 mmol) of 3,4,5-trimethoxyacetophenone in THF was added precipitating a yellow solid. The mixture was stirred at room temperature for 30 minutes, quenched with water, and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4), and evaporated in vacuo to afford 9.32 g (85%) of 16 as a yellow oil.