Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH:15]=[C:14]([CH3:13])[CH:18]=[N:17]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2cc(C)cn2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, 4-methyl-pyrazole and cesium carbonate in NMP. EI-MS m/e (%): 246 (M+, 85), 245 ([M—H]+, 100).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH3:27])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH2:26]([C:22]1[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1)[CH3:27]
Reactant: CCc1cccc(N)n1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)n1
Temperature: 68 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 68° and 75° C., to a solution of 2-amino-6-ethylpyridine (2.45 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 68° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 15 minutes and then stirred at a temperature of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (6.5 g) is thereby obtained, which is dissolved in boiling acetonitrile (75 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(6-ethyl-2-pyridyl)- 3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.3 g) in the form of cream-coloured crystals, m.p. 150° C., is thereby obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.[CH2:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](OCC)=[O:27])[CH2:22][CH2:21]1)[CH3:19]>CCCCCC.C(O)(=O)C>[O:27]=[C:26]([C@H:23]1[CH2:24][CH2:25][C@H:20]([CH2:18][CH3:19])[CH2:21][CH2:22]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCOC(=O)[C@H]1CC[C@H](CC)CC1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H](C(=O)CP(=O)(OC)OC)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, 47 ml. of a 1.25 M solution of n-butyllithium in n-hexane were added dropwise to a solution of 7.64 g. of dimethyl methylphosphonate in 120 ml. of tetrahydrofuran at -70° C. After one hour of stirring at -70° C., a solution of 5.63 g. of ethyl trans-4-ethylcyclohexanecarboxylate [c.f. N. L. Allinger and L. A. Freiberg, J. Org. Chem., 31, 894, (1966)] in 30 ml. of tetrahydrofuran was added dropwise at -70° C., and the mixture was stirred at the same temperature for one hour and further stirred at -5° C., for one hour. The reaction mixture was then acidified with acetic acid and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation to give 5.0 g. of the title compound having the following physical characteristics:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:22][N:21]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:20](=[O:39])[CH:19]=1.CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:22][N:21]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:20](=[O:39])[CH:19]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1ccc(Cn2nc(-c3ccccc3)c(Cl)cc2=O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(-c3ccccc3)c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (121 mg, 0.60 mmol) in THF (3 mL) at room temperature under argon was added NaH (24 mg, 0.60 mmol). After stirring at room temperature under argon for 30 minutes, 5-chloro-2-(4-methoxybenzyl)-6-phenylpyridazin-3(2H)-one (163 mg, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for three days. EtOAc (10 mL) and brine (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 138.9 mg (56.3%) of tert-butyl-4-(1-(4-methoxybenzyl)-6-oxo-3-phenyl-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9H) 1.62-1.82 (m, 2H) 1.80-1.98 (m, 2H) 3.16-3.57 (m, J=5.27, 5.27 Hz, 4H) 3.76 (s, 1H) 4.35-4.64 (m, 1H) 5.26 (s, 2H) 6.21 (s, 1H) 6.84 (d, J=8.79 Hz, 2H) 7.33-7.53 (m, 5H) 7.64 (dd, J=6.81, 3.30 Hz, 2H). MS (ESI) 492 (M+H).
Reaction SMILES: COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.[SH:19][C:20]1[S:24][C:23]([CH3:25])=[N:22][N:21]=1.CC(O[CH2:30][C:31]1[CH2:40][S:39][C@@H:34]2[C@H:35]([NH2:38])[C:36](=[O:37])[N:33]2[C:32]=1[C:41]([OH:43])=[O:42])=O.N>C(#N)C>[NH2:38][CH:35]1[C:36](=[O:37])[N:33]2[C:32]([C:41]([OH:43])=[O:42])=[C:31]([CH2:30][S:19][C:20]3[S:24][C:23]([CH3:25])=[N:22][N:21]=3)[CH2:40][S:39][C@H:34]12
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A 14.8 g quantity of DCPA was cooled at 14° C., and 1.59 g of 5-mercapto-2-methyl-1,3,4-thiadiazole was added to it, whereby the mixture reached at the temperature of 25° C. and dissolved. 6.0 ml of acetonitrile was added and the solution was cooled at 15° C., to which 2.72 g of 7-ACA and 10.0 ml of acetonitrile were added, followed by stirring at 25° to 27° C. for 30 minutes. The reaction solution was poured into 80 g of ice-water, which was placed in a refrigerator overnight, adjusted to pH 4.0 with 25% aqueous ammonia and stirred for 1.0 hour under ice-cooling. The resultant precipitate was recovered by filtration, washed with 50 ml each of cold water and acetone successively, and dried, thereby affording 2.40 g of 7-amino-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:13].[OH-:14].[Na+].[OH:16]O.Cl>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:16])=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:13]
Reactant: N#CC1(c2ccc(Br)c(F)c2)CC1
Reactant: [OH-]
Reactant: OO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1(c2ccc(Br)c(F)c2)CC1
Temperature: 25 °C

Procedure:
A suspension of 4-bromo-3-fluorophenylcyclopropanenitrile (21 mmoles) in methanol (10 ml) is added with a 35% NaOH aqueous solution (40 ml) and a 35% H2O2 aqueous solution (3 ml), then is refluxed for 4 hours, cooled at room temperature and added with 2N HCl (250 ml). The precipitated solid is collected by filtration and redissolved in a 5% NaHCO3 aqueous solution (300 ml). The insoluble fraction is filtered off and the clear filtrate is acidified to pH=2 with 2N HCl. The product precipitates as a white solid, which is recovered by filtration and dried under vacuum.
Reaction SMILES: [C:1](=[O:4])([OH:3])[OH:2].[C:5](Cl)([CH3:7])=[CH2:6].[N+:9]([C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1](=[O:3])([O:2][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1)[O:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)Cl
Reactant: O=C(O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=C(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To isopropenyl chloride carbonate (6.68 g) were added 4-nitrophenol (5 g) and chloroform (150 ml), and thereto was added drowpise pyridine (2.9 ml) under ice-cooling over a period of 20 minutes. Then, the mixture was stirred under ice-cooling for 15 minutes, then warmed to room temperature, and further stirred overnight. After the reaction was completed, the reaction solution was washed succesively with 1N aqueous hydrochloric acid solution, water and a satureated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to give the title compound (1.41 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.O.B1([O-])O[O:20]1.O.O.O.O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[N:10]1[CH:11]=[C:7]([C@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:20])[CH:8]=[N:9]1
Reactant: C1=C(c2cnn(C3CCCCO3)c2)CCCC1
Reactant: [O-]B1OO1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O[C@H]1CCCC[C@@H]1c1cnn(C2CCCCO2)c1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of the 4-cyclohex-1-en-1-yl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (775 mg, 3.34 mmol) prepared in Example 33a in THF (4 mL), a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added with cooling on ice, and the reaction solution was stirred for 30 minutes with cooling on ice. To the reaction solution, a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added again, and the mixture was stirred at room temperature for 90 minutes. To the reaction solution, water (5 mL) and subsequently sodium perborate tetrahydrate (1.00 g, 6.50 mmol) were added, and the mixture was stirred for 5 hours. To the reaction solution, sodium thiosulfate (2.0 g) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (dichloromethane/methanol=97:3) to yield the title compound (590 mg, 71%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[NH:4][C:5]([C@@H:7]1[CH2:11][C:10](=[N:12][O:13][CH3:14])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[NH:4]1[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=2[N:1]=[C:5]1[C@@H:7]1[CH2:11][C:10](=[N:12][O:13][CH3:14])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CON=C1C[C@@H](C(=O)Nc2ccccc2N)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CON=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Yield: 97.4 %

Procedure:
A solution of the anilide compound from the previous step, e.g. tert-butyl (2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate (0.8 g, 2.3 mmol) in dichloromethane (30 ml) and acetic acid (3 ml) was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate (7 ml) was added to the reaction, the organic phase collected and dried over magnesium sulfate before filtering and removal of solvent in vacuo to give the desired product, e.g. tert-butyl (2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (740 mg, 97%) as an off-white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27])=O)(=O)OC.O.[NH2:31][NH2:32]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:32]=[N:31][C:4]3[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=3[CH:16]=2)=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:21]=1
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: NN
Reactant: COP(=O)(CC(=O)c1ccc(F)cc1C(F)(F)F)OC
Solvent: O
Product: CC1(C)Cc2cc(-c3ccc(F)cc3C(F)(F)F)nnc2C1

Procedure:
light yellow oil. MS (ESI): 311.0 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(4-Fluoro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][N:34]=1>C(Cl)Cl>[CH3:32][C:33]1[N:34]=[CH:35][C:36]([NH:39][C:40](=[O:41])[NH:1][C:2]2[C:7]3[N:8]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nc3c(N)cccc3o2)CC1
Reactant: Cc1ccc(N=C=O)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)Nc2cccc3oc(CN4CCN(C(=O)OC(C)(C)C)CC4)nc23)cn1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a room temperature solution of tert-butyl 4-((4-aminobenzo[d]oxazol-2-yl)methyl)piperazine-1-carboxylate (5.0 g, 15.1 mmol, 1.0 equiv) and triethylamine (2.1 g, 15.1 mmol, 1.0 equiv) in dry DCM (37 mL) was added 2-methyl-5-isocyanatopyridine (2.22 g, 16.6 mmol, 1.1 equiv) in dry DCM (37 mL) via cannula. After 1 h, the reaction mixture was filtered and washed with water (25 mL) and brine (25 mL). The solution was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel purification (5% MeOH/95% EtOAc—15% MeOH/85% EtOAc) provided the title compound as a white foam (7.03 g, 100%). LCMS [M+H]+=467.2.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N+:17]([O-])=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.C(O)CCC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1
Reactant: [H][H]
Reactant: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 86.1 %

Procedure:
33.2 g (0.1 mol) of 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole-N-oxide, 0.125 g of palladium carbon, 300 ml of a solvent mixture comprising toluene, butanol and water (ratio by volume of 1:1:1) and 5 g 50% dimethylamine were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature of the resultant mixture was increased to 50° C. under agitation, and agitation was continued until no more hydrogen gas was absorbed by the mixture. The pressure of hydrogen was always kept at 8 to 10 kg/cm2 during the reaction. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. The most part of solvent was distilled off, and the residual solid was washed with isopropyl alcohol and then dried to obtain 27.2 g of 2-(2'-hydroxy-3'-t-butyl- 5'-methylphenyl)-5-chlorobenzotriazole as a target substance (yield, 86.2%; melting point, 138° to 140° C.).
Reaction SMILES: [NH:1]([C:8](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.[F:33][C:34]([F:46])([F:45])[S:35]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>>[F:33][C:34]([F:46])([F:45])[C:5]([OH:7])=[O:6].[CH3:5][C@@H:2]1[N:1]([CH2:31][C:28]2[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=2)[C:8](=[O:9])[N:42]([C:41]2[CH:43]=[CH:44][C:38]([S:35]([C:34]([F:45])([F:33])[F:46])(=[O:36])=[O:37])=[CH:39][CH:40]=2)[C:3]1=[O:4]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=Cc1ccncc1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: C[C@H]1C(=O)N(c2ccc(S(=O)(=O)C(F)(F)F)cc2)C(=O)N1Cc1ccncc1
Product: O=C(O)C(F)(F)F

Procedure:
The compound is prepared from 0.025 mmol of resin, 0.075 mmol of N-Fmoc-L-Ala(OH), 0.125 mmol of 4-pyridinecarboxaldehyde and 0.0625 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 5.6 mg of expected product are obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]12[NH:13][CH:12]1[CH2:11][N:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=1[F:31])[CH2:9]2.C(N(CC)CC)C>ClCCl>[C:1]([N:13]1[CH:12]2[CH:8]1[CH2:9][N:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=1[F:31])[CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC4NC4C3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC4C(C3)N4C(C)=O)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Acetic anhydride (3.5 μL, 0.05 mmol) was added to a cooled (0° C.) solution of N-({(5S)-3-[4-(3,6-diazabicyclo[3.1.0]hex-3-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (12 mg, 0.036 mmol) in triethylamine (10 μL, 0.072 mmol) and dichloromethane (0.7 mL). After 1 hour, the solution was diluted with dichloromethane, and washed with dilute NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by pTLC (4% MeOH—CH2Cl2) provided the title compound.
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[C:21]([CH2:23][C:24](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:25])#[N:22]>C(Cl)Cl>[C:2]1([C@@H:14]2[CH2:15][CH2:16][C@H:17]([NH:20][C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:18][CH2:19]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n32)CC1
Agent: Cl
Solvent: ClCCl
Product: N#CCC(=O)N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine hydrochloride (0.106 g, 0.206 mmol, Example #D.1) in DCM (4 mL) was added TEA (0.086 mL, 0.62 mmol). The reaction mixture was sonicated until the reaction was homogeneous. To the reaction solution was added perfluorophenyl 2-cyanoacetate (0.078 g, 0.31 mmol, Preparation #6). The resulting solution was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by silica gel chromatography (40 g) eluting with a gradient of 0-20% EtOAc in DCM and then further purified by RP-HPLC (Table 2, Method e) to give N-(cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)-2-cyanoacetamide with 3 equiv NH4OAc as an excipient (0.025 g, 22%). LC/MS (Table 2, Method a) Rt=1.33 min; MS m/z: 324 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16]>>[NH:21]1[C:22]2[C:18](=[C:17]([NH:14][C:15]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=3)=[O:16])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1cccc2[nH]ccc12
Yield: 65.8 %

Procedure:
4-(Trifluoromethoxy)benzylamine (0.21 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound (0.23 g). mp 177° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.36 (d, 2H), 6.52 (m, 1H), 6.95 (m, 3H), 7.24 (t, 1H), 7.36 (d, 2H), 7.48 (d, 2H), 7.63 (dd, 1H), 8.32 (1H), 11.06 (s, 1H), 12.07. Found: C, 58.51, H, 3.98, N, 12.03.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]#N.S(=O)(=O)(O)[OH:14].[OH2:18]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:14])=[O:18]
Reactant: N#CCc1cc(Cl)cc(Cl)c1Cl
Reactant: O
Reactant: O=S(=O)(O)O
Product: O=C(O)Cc1cc(Cl)cc(Cl)c1Cl

Procedure:
A mixture of 6.9 grams (0.031 mole) of 2,3,5-trichlorophenylacetonitrile and 65 mL of water was stirred, and 65 mL of concentrated sulfuric acid was cautiously added. Upon completion of the addition the reaction mixture was heated to reflux, where it was stirred for about 2 hours. After this time the reaction mixture was cooled in an ice-bath and filtered. The collected solid was washed with water and then dissolved in ethyl acetate. The organic layer was washed with two portions of water and then with one portion of an aqueous solution saturated with sodium chloride. The organic layer was then dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 6.3 grams of 2,3,5-trichlorophenylacetic acid, mp 125°-133° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[Cl:8][C:7]1[C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccccn1
Product: Clc1cccnc1Oc1ccc2ncnc(Nc3ccccn3)c2c1

Procedure:
The compound of Example 88 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-dichloropyridine, 2-aminopyridine and 4-chloro-6-hydroxy-quinazoline.