Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][CH2:2][C:3](=[N:14][OH:15])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12]
Reactant: NO
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C(CCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
2-Chloro-2′,4′-difluoroacetophenone (3.09 g, 16.2 mmol) was dissolved in ethanol (30 ml). The solution was added under ice-cooling successively with hydroxylamine hydrochloride (1.23 g, 17.7 mmol) and sodium acetate (1.45 g, 17.7 mmol), and the mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and washed with an aqueous sodium bicarbonate solution and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration, and the solvent was evaporated under reduced pressure. The residue was suspended in hexane and dried to obtain the title compound as colorless solid (2.29 g, yield: 69%).
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH:14]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:35][CH2:36][CH2:37][NH2:38].O.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][CH2:6][C@H:7]([NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15](/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=2)[CH:14]=1)[C:8](=[O:9])[NH:38][CH2:37][CH2:36][OH:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
(S)-3-t-butoxy-2-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}propionic acid (25 mg), 2-hydroxyethylamine (9 μL), benzotriazol-1-ol monohydrate (19 mg), and (3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (25 mg) were dissolved in 2 mL of N,N-dimethylformamide, and then, N,N-diisopropylethyl-amine (53 μL) was added to the solution. The solution was stirred overnight at room temperature. Then, 2-hydroxyethylamine (9 μL), benzotriazol-1-ol monohydrate (19 mg), and (3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (25 mg) were added again to the solution, and the solution was further stirred overnight. After removal of the solvent under reduced pressure, to the obtained residue was added water, and the mixture was extracted three times with dichloromethane. The respective organic layers were combined, whereafter the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with dichloromethane. The filtrate and the washings were combined, and dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 44 mg (76%) of N-[(S)-2-t-butoxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzamide.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:10]([O:12]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=[N:47]C=2C=1.N[C@H](C(O)=O)CC1C=CC=CC=1.C1(SC)C=CC=CC=1>CN(C=O)C>[NH2:1][C@H:2]([C:10]([NH2:47])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCC1c2ccccc2-c2ccccc21
Reactant: On1nnc2ccccc21
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CSc1ccccc1
Product: NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 1 h

Procedure:
Fmoc-Phe-OPfp (0.5 mmol) and HOBt (0.5 mmol) were added to a suspension of resin B (prepared from 185 mg, 0.1 mmol of the Fmoc-derivative) in DMF (5 ml) and the mixture was shaken for 1 hour. The resin was successively washed with DMF (5 ml×5), then treated with 20% piperidine in DMF (5 ml) for 15 min. The treated resin was washed with DMF (5 ml×5) and CH2Cl2 (5 ml×5) and dried in vacuo; yield 179 mg. The dried resin (5 mg) was treated with 1M thioanisole/TFA-m-cresole (100 μl-10 μl) at 28° C. for 60 min. H-Phe-NH2 liberated was determined by TLC scanner. The latter treated resin was subjected to 6N HCl hydrolysis. No Phe was detected by amino acid analyser. This result shows that phenylalanine had been cleaved almost completely from the resin. It was therefore established that resin B is useful as an amide precursor for amino acids and that the thioanisole-containing solution described above is a superior cleavage reagent.
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:17]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:15]4[C:4]([CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12]2)=[CH:5][CH:6]=[C:7]3[CH:8]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)Cl
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 142 %

Procedure:
A mixed solution of 150 g of pyrene, 75.52 g of t-butyl chloride and 742 ml of dichloromethane was cooled to 0° C. under a nitrogen stream, and 98.9 g of aluminum chloride was added. After this mixed solution was stirred at room temperature for 3 hours, 1100 ml of water was added, and this was extracted with 1100 ml of dichloromethane. The organic layer was washed with 750 ml of water three times, dried with magnesium sulfate, and evaporated, and this was purified by methanol washing, and filtered. After the resultant was vacuum dried, 272 g (content 79.2%) of 2-t-butylpyrene was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@@H:8]([N:15]1[CH2:21][C:20](=[O:22])[C:17]2([CH2:19][CH2:18]2)[C:16]1=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.O>C1COCC1>[CH3:7][C@@H:8]([N:15]1[CH2:21][CH:20]([OH:22])[C:17]2([CH2:18][CH2:19]2)[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@H](c1ccccc1)N1CC(=O)C2(CC2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1CC(O)C2(CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a suspension of LiAlH4 (0.995 g, 26.2 mmol) in THF (40 mL) was added a solution of 5-((R)-α-methylbenzyl)-4,7-dioxo-5-azaspiro[2.4]heptane (3.0 g, 13.1 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs, then warmed up to 50° C. and continued to stir for 6 hrs. The reaction mixture was then cooled to 0° C. and ethyl acetate (10 mL) and water (10 mL) were added. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:3 (v/v) 2-butanol/n-hexane) to afford the title compound as colorless oil (2.4 g, 85%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=[O:30]>>[CH:37]([C:34]1[CH:35]=[CH:36][C:31]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:32][CH:33]=1)([CH3:39])[CH3:38]
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(4-isopropylphenyl)-1-butanone: ESMS m/e: 435.2 (M+H)+.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(Cl)(=O)C.[CH3:8][N:9]([C:13]([NH2:15])=[NH:14])[CH2:10][CH2:11][OH:12].[C:16](O)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[C:16]([O:12][CH2:11][CH2:10][N:9]([CH3:8])[C:13]([NH2:15])=[NH:14])(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CN(CCO)C(=N)N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCCN(C)C(=N)N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 12.44 mL (175 mmol) of acetyl chloride and 35 mL of dry DCM. The flask is charged with 41.00 g (350 mmol) of Creatinol and 175 mL of dry DCM, and cooled with an ice-water bath to about 0° C., under a nitrogen atmosphere. The acetyl chloride solution is then added slowly with stirring, over a period of 15 minutes, to the Creatinol solution. The solution is stirred for another 10 minutes, after which 15.38 g (60 mmol) of Palmitic acid is added in one portion and the reaction is slowly heated to about 65° C. for about 10 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 2/5) to yield pure 2-(1-methylguanidino)ethyl palmitate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][O:14][C:15]=1[CH3:16])=O.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C.ClCCl>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[CH:7][N:8]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1ncc2ccccn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (pyridin-2-ylmethyl)-amide (0.293 g, 1 mmol) in dichloroethane (5 mL) was added phosphorus oxychloride (0.47 mL, 5 mmol) via a syringe and the resulting mixture heated under reflux overnight. After cooling to room temperature, the mixture was diluted with dichloromethane. Cold saturated sodium bicarbonate (15 mL) was then added slowly and the mixture was vigorously stirred for 15 min. The organic layer was separated and the aqueous was extracted with dichloromethane. The combined extracts were washed with water, dried over sodium sulphate, and evaporated. Purification by preparative HPLC on reversed phase [0.1% aq. ammonia (25%)] afforded the title compound (0.13 g, 47%) as an orange solid. MS: m/e: 276.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:18]([Si:17]([O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Br

Procedure:
At room temperature, 5.0 g (24.87 mmol) of 4-bromo-3,5-dimethylphenol, 2.03 g (29.84 mmol) of imidazole and 6.23 g (32.33 mmol) of chloro(triisopropyl)silane are stirred in 20 ml of dimethylformamide overnight. Saturated sodium bicarbonate solution is then added, and the mixture is extracted three times with diethyl ether. The combined organic phases are washed with water and dried with sodium sulphate, and the solvent is removed under reduced pressure. This gives 7.5 g (84% of theory) of 4-bromo-3,5-dimethylphenyl triisopropylsilyl ether.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@@H:22]([OH:24])[CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C1COCC1.CO.[OH-].[Li+]>O>[CH3:29][C:27]([CH3:28])([CH3:30])[C:26]#[C:25][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]2[CH2:21][C@@H:22]([OH:24])[CH2:23]2)[C:11]([CH:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@@H](O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2C[C@@H](O)C2)CC1
Temperature: 60 °C

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (400 mg, 0.93 mmol) in a 3:2:1 mixture of THF:MeOH:water (20 mL) was treated with lithium hydroxide (4.5 mL, 1.0 M aqueous solution) and heated to 60° C. for 2 hours. The organic volatiles were evaporated under reduced pressure and remaining solution was acidified with 10% HCl(ac). A white precipitate was collected by vacuum filtration, washed with water, and dried to afford 290 mg (74% yield) of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid as a white powder. MS (m/z): 415.8 [M−H]−; HPLC retention time: 4.10 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)=[O:4].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)[C:36](=[O:37])[CH2:35][C:30]1[NH:29][C:28]2[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=2[S:32](=[O:33])(=[O:34])[N:31]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)c(Cl)c1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1

Procedure:
(1R,2S)-2-(3-Chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.12 g, 0.42 mmol) was dissolved in anhydrous N,N-dimethylformamide (4.2 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.154 g, 0.46 mmol) was added followed by N-methylmorpholine (0.101 mL, 0.92 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.088 g, 0.46 mmol) was added portionwise and the mixture was stirred at 25° C. for 15 h. The reaction mixture was quenched by pouring into 1.0 M aqueous hydrochloric acid solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo to afford the crude product, (1R,2S)-2-{(3-chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester, which was used directly in the next step without further purification. LC-MS (ESI) calcd for C24H26ClFN4O7S2 600.09, found 601.1 [M+H+].
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]=[CH:38][N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:4]=4)[CH:38]=[N:39][CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cc1OCCCCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-(4-phenyl-butoxy)-benzonitrile from step 2 (100 mg, 0.36 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23 Step 5 (188 mg, 0.36 mmol) in CH2Cl2 (2 ml) was added DIEA (136 μl, 0.78 mmol) followed immediately by the addition of Tf2O (90 μl, 0.53 mmol). The reaction mixture stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (2 ml) and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>ClCCl>[O:5]1[CH2:6][CH2:7][CH:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
Step A To a solution of 4-hydroxytetrahydropyran (4.5 g, 44 mmol) (Aldrich) in dichloromethane (90 mL) at 0° C. was added triethylamine (5.4 g, 53 mmol), and methanesulfonyl chloride (3.73 mL, 48 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 1 h, then at room temperature for 1.5 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid tetrahydropyran-4-yl ester as a white solid (Yield 8 g, 100%).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:34](N(C(C)C)CC)(C)[CH3:35].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([NH:7][C:6](=[O:5])[CH:34]=[CH2:35])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.5 %

Procedure:
[1-(4-Benzyloxycarbonylamino-benzyl)piperidin-4-yl]-carbamic acid tert-butyl ester (0.14 g, 0.32 mmol) was suspended in a 4M solution of HCl in Dioxane (5 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.28 ml, 1.6 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 100% DCM to 90% DCM, 10% Methanol) to give the title compound (0.012 g, 10% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]/[N:16]=[C:17](/[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][N:24]2[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]2)=[CH:21][CH:20]=1)\[NH2:18])=O.C([O-])(=O)C.[Na+]>CCO.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]1[O:15][N:16]=[C:17]([C:19]2[CH:33]=[CH:32][C:22]([CH2:23][N:24]3[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]3)=[CH:21][CH:20]=2)[N:18]=1
Reactant: COC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cnn(-c4ccccc4)c3N)cc2)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccc5)c4N)n3)cc2)C1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
To a suspension of (Z)-methyl 1-(4-(N′-(5-amino-1-phenyl-1H-pyrazole-4-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (102 mg, 0.227 mmol) in EtOH (3 mL) was added sodium acetate (37.3 mg, 0.455 mmol) as a solution in water (1 mL). The mixture was heated to 90° C. for 3 hr. The reaction mixture was transferred to a microwave vial and was then heated to 120° C. for 30 minutes. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (15 mL) and the combined organic layers were dried (MgSO4) and concentrated to afford an oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/hexane gradient. The pure fractions were concentrated to afford methyl 1-(4-(5-(5-amino-1-phenyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (70 mg, 0.163 mmol) as a colorless oil. HPLC retention time=1.35 (ethyl ester-1.42) minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS:(M+H)=431.23 (ethyl ester-445.25). (The product is a mixture of methyl ester and ethyl ester due to partial transesterification during the reaction. The mixture was carried on through the sequence.)
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]3[N:16]=[C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=4)[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6]1.[OH-].[Na+]>CO>[N:29]1([CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:17]3[N:18]=[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH2:4][C:3]([OH:34])=[O:2])[CH:9]=5)[N:15]4[N:16]=3)=[CH:21][CH:22]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-acetic acid methyl ester (0.51 g, 1.1 lmmol) in methanol (10 ml) was added sodium hydroxide (2N, 1 mL) and the mixture stirred for 3 hours at room temperature. All solvents were removed in vacuo to afford the title compound as a pale yellow solid. No further purification was required. Yield: 0.40 g, 80%; LCMS method: 2, RT: 2.36 min, MI: 448 [M+1].