Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=1.Cl>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[O:10][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=1
Reactant: COc1cc(O)cc(F)c1
Reactant: Cc1cc(F)ccc1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(F)cc(Oc2ccc(C=O)c(C)c2)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
A 0° C. solution of 3-fluoro-5-methoxy-phenol (2.40 g, 16.9 mmol) in dry DMF (20 mL) is treated with a 60% suspension of NaH (0.74 g, 18.5 mmol) and then stirred for 15 minutes under N2. A solution of 4-fluoro-2-methyl-benzaldehyde (2.33 g, 16.9 mmol) in DMF (10 mL) is added dropwise, and the mixture is warmed to 60° C. for 4 hours. The mixture is cooled and acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 6/1 hexanes/ethyl acetate to afford 1.40 g (32%) of the title compound. Rf=0.41 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C15H13O3F 260, found 261 (M+1, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 66.8 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-octane (183 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-octyl-1H-pyrazole (134 mg, 56%) as a clear oil.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].[C:16]([NH2:25])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[CH2:26](N(CC)CC)C>C(O)C>[OH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([NH:25][CH2:26][N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:24]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Reactant: NC(=O)c1ccccc1O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CON1C(=O)CC2(CCN(CNC(=O)c3ccccc3O)CC2)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione.hydrochloride (0.55 g), salicylamide (0.32 g), p-formaldehyde (0.11 g) and triethylamine (2 ml) in ethanol (20 ml) was stirred for 15 hours at room temperature. Then, the solvent was evaporated off under reduced pressure, and the residual oily product was subjected to a silica gel column chromatography (eluent; ethyl acetate), and the solvent for the solution containing the desired product was evaporated off under reduced pressure. The residual solid was recrystallized from ethyl ether to obtain 0.52 g of colorless crystals, m.p. 96° to 99° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([C:12]([O:11][CH3:10])=[O:22])=[CH:14][CH:15]=2)=[O:18])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a 3-necked round-bottomed flask equipped with a magnetic stir bar were added anisole (31 mL, 30.8 g, 0.285 mol.) and terephthalic acid monomethyl ester chloride (19.6 g, 0.099 mol.). The flask was equipped with a powder addition funnel and nitrogen inlet. The powder addition funnel was charged with AlCl3 (40.2 g, 0.301 mol.). The reaction mixture was cooled in an ice-water bath and the AlCl3 was added slowly, portionwise with stirring, under a nitrogen atmosphere. The ice-water bath was removed and the stirred reaction mixture was allowed to warm to room temperature for 3.5 h. The viscous reaction mixture was cooled in an ice-water bath and ice was added very slowly portionwise (Note: significant HCl was released upon addition of ice) followed by the slow addition of ice-water. The reaction mixture solidified upon quenching. The solid was filtered, washed with water, and allowed to stand overnight at RT. The solid washed with water and triturated with hexanes (2×) to give a pink solid. The crude product was recrystallized from EtOAc to give a white solid. The solid was dried to give 16.0 g (60%) of compound 23 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 3.84 (s, 3 H), 3.88 (s, 3 H), 7.08 (d, J=8.8 Hz, 2 H), 7.74 (d, J=8.8 Hz, 2 H), 7.77 (d, J=8.3 Hz, 2 H), 8.08 (d, J=8.3 Hz, 2 H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][N:20](COCC[Si](C)(C)C)[C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1>>[CH:1]1([NH:7][C:8]([C:19]2[NH:20][C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[N:18]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1

Procedure:
Using essentially the same procedure as Example 25, Step B-C, but using cyclohexyl isocyanate (0.027 mL, 0.21 mmol) in Step B, 4,5-di-(4-chlorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)imidazole (36 mg, 0.086 mmol) from Example 25, Step A was converted to the SEM intermediate and then to the title compound with TBAF.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4]>Cl.C(OCC)(=O)C>[CH3:32][N:2]([CH3:1])[C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)N(C)C)C2)cc(OC)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCNC(C(=O)N(C)C)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A mixture of N,N-dimethyl 1-tert-butoxycarbonyl-4(3,4,5-trimethoxybenzoyl)piperazine-2-carboxamide (2.0 g) and 3N HCl - ethyl acetate (20 ml) is stirred for 30 minutes at room temperature. The reaction mixture is concentrated, and the concentrate is poured into a saturated aqueous solution of potassium carbonate, followed by extraction with dichloromethane. The organic layer is dried and concentrated to afford N,N-dimethyl 4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxamide (1.5 g) as colorless crystals, m.p. 167-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([CH2:9]O)=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([CH2:9][Cl:20])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)CCn1c(CO)nc2cc(Br)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)CCn1c(CCl)nc2cc(Br)ccc21
Yield: 101.3 %

Procedure:
To a solution of [5-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-yl]-methanol (1.32 g, 4.44 mmol) in DCM (20 mL) was added thionyl chloride (1.06 g, 8.88 mL) at 0° C. The final solution was stirred at 0° C. for 1 h. The solvent was evaporated and the residue triturated with EtOAc and filtered to give 1.42 g (91%) of 5-bromo-2 chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[NH:17]1[CH2:21][CH2:20][N:19]=[C:18]1S(O)(=O)=O>C(#N)C>[C:13]([C:11]1[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([NH:1][C:18]2[NH:19][CH2:20][CH2:21][N:17]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: CC(C)(C)c1cc(N)cc2c1SCC2(C)C
Solvent: CC#N
Product: CC(C)(C)c1cc(NC2=NCCN2)cc2c1SCC2(C)C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a 0.33 g (1.3 mmol) solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]thiophene in 10 mL of acetonitrile at RT is added 0.2 g (1.3 mmol) of imidazoline-2-sulfonic acid, (Maryonoff et al., (J. Org. Chem., 1986, 51, 1882). The reaction is then refluxed overnight. On cooling to RT, pure guanidine precipitates out of solution and is filtered from the solution to give 155 mg (40%) of product.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[S:13].C(N(C(C)C)C(C)C)C>>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[N:7]=[C:12]=[S:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N=C=S
Yield: 47.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-tert-butylaniline (5.0 g, 0.033 mol), thiophosgene (3.80 g, 0.033 mol) and N-ethyl di-isopropyl amine (8.5 g, 0.066 mol) to afford 3.0 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29](/[CH:31]=[CH:32]/[C:33]4[S:34][CH:35]=[C:36]([CH:38]([CH3:40])[CH3:39])[N:37]=4)[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>>[CH3:41][N:2]([CH3:1])[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29](/[CH:31]=[CH:32]/[C:33]4[S:34][CH:35]=[C:36]([CH:38]([CH3:39])[CH3:40])[N:37]=4)[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:6]1)=[O:4]
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(C(=O)N(C)C)C4)nc3c2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCCC(C(=O)N(C)C)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
The tert-butyl (E)-3-(2-{3-[(dimethylamino)carbonyl]piperidino}-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-2-propenoate (71.0 mg, 0.123 mmol) obtained in (B) was added with trifluoroacetic acid (3.0 ml) and stirred at room temperature for 2 hours. The trifluoroacetic acid in the reaction mixture was evaporated under reduced pressure, and the residue was neutralized with 0.1 N sodium hydroxide and phosphate buffer (pH 7-8) and extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (chloroform:methanol and chloroform:methanol:water, 8:3:1, v/v, lower layer) to obtain the title compound (39.0 mg, 61%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:18](OC)=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13](OC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCNCC1>C1(C)C=CC=CC=1.C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:18]=[O:19])[CH:11]=[C:12]([CH:17]=1)[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Oc2ccccc2)cc(C(=O)OC)c1
Agent: CN1CCNCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1cc(C=O)cc(Oc2ccccc2)c1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of dimethyl 5-phenoxyisophthalate (0.143 g, 0.50 mmol) in toluene (12 mL) was added drop-wise a solution of Red-A1 (60% in toluene, 0.673 mL, 2.0 mmol) and 1-methylpiperazine (0.243 mL, 2.2 mmol) in THF at 5° C., and the resulting mixture was stirred for 2 h. The reaction was quenched with H2O (4 mL), and then extracted with EtOAc (20 mL). The organic layer was washed with H2O (10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Purification by flash column chromatography (10% EtOAc/hexanes) afforded the desired product (0.094 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 10.04 (s, 2H), 8.08 (s, 1H), 7.72 (t, J=1.5 Hz, 2H), 7.46-7.40 (m, 2H), 7.28-7.24 (m, 1H), 7.09-7.06 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH2:13][CH2:14][CH2:15][OH:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH3:17])[CH2:13][CH2:14][CH2:15][O:16][C:10]1=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(CCCO)C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C)CCCOC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.3 %

Procedure:
2-(t-Butyloxycarbonyl)amino-2-methyl-5-hydroxypentanoic acid (3.0 g, 0.012 mol) and EDC (2.56 g, 0.013 mol) were dissolved in DMF (20 mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated to dryness, and the residue was partitioned between EtOAc (30 mL)-H2O (30 mL), the organic layer separated, washed with brine and dried (Na2SO4). Filtration, concentration, and chromatography (SiO2, EtOAc: hexane, 1:3) gave 0.86 g (31%) of the title compound. 1H NMR (CDCl3) δ5.1 (br s, 1H), 4.35-4.55 (m, 2H), 2.49-2.64 (m, 1H), 1.78-2.1 (m, 3H), 1.45 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: C(F)(F)=C(Cl)F.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:10]=[CH:11][C:12]2[CH:18]=[C:17]([C:19](O)=[O:20])[C:16]3[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=3[O:14][C:13]=2[CH:26]=1>>[F:27][C:8]([F:7])([F:28])[C:9]1[CH:10]=[CH:11][C:12]2[CH:18]=[C:17]([CH2:19][OH:20])[C:16]3[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=3[O:14][C:13]=2[CH:26]=1
Reactant: O=C(O)C1=Cc2ccc(C(F)(F)F)cc2Oc2ccccc21
Agent: FC(F)=C(F)Cl
Product: OCC1=Cc2ccc(C(F)(F)F)cc2Oc2ccccc21
Yield: 75.2 %

Procedure:
Preparation analogous to Example 12 f) from 3-trifluoromethyl-dibenz[b,f]oxepine-10-carboxylic acid. Product crystallised from tert-butyl methyl ether/hexane; yield: 75.2%; white crystals: TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.31; 1H-NMR (CDCl3, 200 MHz): 2.76 (sbr, 1H); 4.72 (s, 2H); 6.96 (s, 1H); 7.16-7.48 (m, 7H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH2:12])=[C:3]1[C:13]1[CH:14]=[C:15]([NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=1>CO>[CH2:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[C:13]1[CH:14]=[C:15]([NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=1)[CH3:12]
Reactant: C=Cc1c(-c2cncc(NS(=O)(=O)CC)c2)n(C)c2ccccc12
Solvent: CO
Product: CCc1c(-c2cncc(NS(=O)(=O)CC)c2)n(C)c2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A flask is charged with ethanesulfonic acid [5-(1-methyl-3-vinyl-1H-indol-2-yl)-pyridin-3-yl]-amide (35 mg, 0.082 mmol) and MeOH (5 mL). The flask is evacuated and flushed with N2 thrice. Pd/C (4.36 mg) is added and the reaction stirred under H2 overnight at 50° C. The reaction is filtered over celite and the celite layer is washed thoroughly with MeOH. The filtrate is concentrated in vacuo. The crude is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) followed by HPLC purification using Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to afford the pure product ethanesulfonic acid [5-(3-ethyl-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 1.27 (t, J=7.6 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 3.25 (q, J=7.3 Hz, 2H), 3.66 (s, 3H), 7.09-7.17 (m, 1H), 7.23-7.31 (m, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.83 (t, J=2.3 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H). HRMS: (ESI) m/z 344.1435 [(M+H)+ Calcd for C18H21N3O23 344.1427].
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.Cl.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([CH:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[NH:4][C:5](=[O:8])[NH:6][N:7]=2)[CH2:24][CH2:25]1)=[O:19]
Reactant: O=C(Cc1ccccc1F)C1CCNCC1
Reactant: O=c1[nH]nc(CCl)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(Cc1ccccc1F)C1CCN(Cc2n[nH]c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
After adding 150 mg of 5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one, 335 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride and 180 mg of anhydrous potassium carbonate to acetonitrile, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (23 mg, 7% yield).
Reaction SMILES: C([O:8][C:9](=[O:55])[C@H:10]([CH2:51][CH:52]([CH3:54])[CH3:53])[NH:11][C:12](=[O:50])[C@H:13]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:14][C:15](=[O:42])[C@H:16]([CH3:41])[NH:17][C:18](=[O:40])[CH2:19][NH:20][C:21](=[O:39])[C@H:22]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.[OH-].[Na+]>CO>[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:20][CH2:19][C:18]([NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:55])=[O:8])[CH2:51][CH:52]([CH3:53])[CH3:54])=[O:50])[CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:42])[CH3:41])=[O:40])=[O:39])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=1)=[O:25])([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
18.9 Parts N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanyl-L-phenylalanyl-L-leucine benzyl ester is dissolved in 70 parts methanol and the solution cooled to 10° C. Then, 90 parts by volume of a 1N sodium hydroxide solution is added dropwise with stirring while maintaining the temperature below 20° C. After standing at room temperature for 1 hour, the methanol is removed by evaporation under reduced pressure. The solution is washed once with ethyl ether to remove benzyl alcohol and the aqueous layer acidified with 90 parts by volume of a 1 N hydrochloric acid solution. The solid which results is filtered and washed with water to afford N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanyl-L-phenylalanyl-L-leucine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[N:12](C)[C:11]([CH2:16][CH2:17][CH2:18][C:19]3[CH:33]=[CH:32][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=3)=[N:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13](=[O:14])[N:12]=[C:11]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([OH:27])=[O:26])=[CH:32][CH:33]=3)[NH:10]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3ccc(C)cc3)c(=O)n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Cn2[nH]c(CCCc3ccc(OC(C)(C)C(=O)O)cc3)nc2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.3 %

Procedure:
A 4-neck flask was equipped with overhead stirring apparatus and thermometer probe. The flask was charged with 2-(4-{3-[1-(4-Methylphenylmethyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}phenoxy)-2-methyl-propionic acid, ethyl ester (800 g, 1.828 moles), and toluene (4000 mL) followed by 1N NaOH (4023 mL, 2.194 mol, 1.2 eq). The resulting mixture was stirred at ambient temperature for 5 h. The mixture was transferred to a 22-L bottom outlet flask and layers separated. The aqueous layer from the above layer separation was charged to the flask and acidified to pH 2 with concentrated HCl (337 mL). Ethyl acetate was added (8000 mL) and the mixture was transferred to a 22-L bottom-outlet flask. The layers were separated and the organic solution was transferred to a 22- L 3-neck round-bottom flask equipped with a distillation head and overhead stirring apparatus. The mixture was concentrated by distillation of the ethyl acetate to approximately 4000 mL, and fresh ethyl acetate (3600 mL) was added to the reaction vessel. Distillation was continued until 3600 mL of distillate were recovered. Heating was stopped and the mixture was allowed to cool slowly to 60-65° C., at which point seed crystals (0.8 g) of the desired product were added. The flask contents were allowed to cool slowly until crystallization initiated (55-57° C.), then the mixture was cooled to 0-5° C. and stirred for 1 h. The product was filtered, washed with cold ethyl acetate, and dried in vacuo at 55° C. to afford the title compound as a white solid (713.6 g, 95.3%). 1H NMR (DMSO-d6, 500 MHz): δ 1.46 (s, 6 H), 1.79 (m, 2 H), 2.25 (s, 3H), 2.35 (t, 2 H), 2.47 (t, 2 H), 4.70 (s, 2 H), 6.71 (d, 2H), 7.03 (d, 2H), 7.10 (m, 4 H). 13C NMR (DMSO-d6), δ 20.6, 25.0, 25.5, 27.7, 47.0, 78.3, 118.6, 127.4, 127.7, 128.9, 128.9, 134.4, 134.5, 136.4, 145.9, 153.4, 154.3, 175.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-1-Benzyl-3-hydroxy-4-methylpyrrolidine (6.81 g) was dissolved in dichloromethane (70 mL). While the solution was chilled in a dry ice/acetone bath, triethylamine (5.21 mL) was added, followed by dropwise addition of methanesulfonyl chloride (2.89 mL) and stirring for 1 hour. Subsequently, water (50 mL) was added and the mixture was allowed to warm to room temperature. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The dichloromethane layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (180 mL). To this solution, tetrabutylammonium cyanide (23.9 g) was added and the mixture was refluxed for 7 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (300 mL). This solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to give cis-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil (4.61 g).