Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 4a (11.22 g, 39.3 mmol) and 4-mercaptophenol (4.96 g, 39.3 mmol) in 100 mL of EtOH was treated with Na2CO3 and heated overnight under efflux. Cooled to room temperature and quenched with water. Extracted with EtOAc. Dried over MgSO4, filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 25% EtOAc/hexane giving a red oil (8.65 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[CH2:17]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:28][CH2:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCCCN1CCC(CN)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(CC)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 3 of EXAMPLE 5 from 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 10, Step 2) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>CCO.N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: COc1cc(F)c(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc(F)c(/C=C/C(=O)O)cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A 250 mL round bottom flask was charged with 2,5-difluoro-4-methyoxybenzaldehyde (commercially available from Manchester Organics Ltd., UK) (18.45 g, 107.2 mmol), malonic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.27 g, 117.9 mmol), and 10:1 EtOH/pyridine (27 mL). The mixture was stirred overnight at 70° C. under a reflux condenser and cooled to 0° C. for 2 hours. The precipitated solid was filtered, rinsed with ether, and dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>>[F:1][CH2:2][C@H:3]1[CH2:8][N:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](CF)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CF)CN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 of example 1 was followed using cis (+/−)-tert-butyl 5-(fluoromethyl)piperidin-3-ylcarbamate and 4-chloro-3-nitropyridine yielding cis (+/−)-tert-butyl 5-(fluoromethyl)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate. LCMS (m/z): 355.1 (MH+); LC Rt=2.41 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:35]>ClCCl.C(OCC)(=O)C>[ClH:35].[ClH:35].[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C@H:9]3[CH2:10][NH:11][CH2:12][CH2:13][NH:8]3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2ccc([C@H]3CNCCN3)cc2)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4′-methoxybiphen-4-yl)-piperazine (1.46 g, 3.12 mmol) in dichloromethane (8 mL) was added 4 N hydrogen chloride in ethyl acetate (8 mL) at room temperature. After stirring for 1 h, the precipitate was collected and dried in vacuo to afford (S)-2-(4′-methoxybiphen-4-yl) piperazine dihydrochloride (1.00 g, 94%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[C:12]([CH3:18])[N:11]=1>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O>[Br:17][C:13]1[C:12]([CH3:18])=[N:11][C:10]([N:4]2[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]2)=[CH:15][C:14]=1[CH3:16]
Reactant: Cc1cc(Cl)nc(C)c1Br
Reactant: Cc1cc[nH]n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccn(-c2cc(C)c(Br)c(C)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 3-methylpyrazole (156 mg, 1.90 mmol) in DMF (2 ml) was added NaH (60% dispersion in oil, 76 mg, 1.9 mmol) and the reaction stirred at room temperature for 30 min. before adding 2-chloro-5-bromo-4,6-dimethylpyridine (227 mg, 1.03 mmol) as a solid in one portion. The mixture was heated to 85° C. for 2 d then cooled and diluted with EtOAc (35 ml) and brine (20 ml). The organic layer was washed with brine (2×15 ml) and water (1×10 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel (Hexanes/Et2O, 9:1) to afford 3-bromo-2,4-dimethyl-6-(3-methyl-pyrazol-1-yl)-pyridine (172 mg, 63%) as a white crystalline solid. 1H NMR (CDCl3) δ 2.36 (s, 3H), 2.44 (s, 3H), 2.65 (s, 3H), 6.23 (d, 1H, J=3 Hz), 7.62 (s, 1H), 8.41 (d, 1H, J=3 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:5]=[C:4]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=2)[C:3]=1[CH3:41].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:50]1(B(O)O)[CH2:52][CH2:51]1.C1(C)C=CC=CC=1>O>[CH:50]1([C:2]2[CH:7]=[C:6]([C:8]3([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:5]=[C:4]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([CH2:39][CH3:40])=[CH:37][CH:38]=3)[C:3]=2[CH3:41])[CH2:52][CH2:51]1
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(Br)c2C)cc1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(C3CC3)c2C)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A flask charged with 1-bromo-3-(4-ethylbenzyl)-2-methyl-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (0.30 g), potassium phosphate (0.38 g), cyclopropylboronic acid (50 mg), toluene (2 mL) and water (1 mL) is flushed with Ar for 5 min. Then, palladium acetate (11 mg) and tricyclohexylphosphonium tetrafluoroborate (36 mg) are added. The flask is tightly sealed and the mixture is stirred at 100° C. overnight. After cooling to room temperature, the mixture is diluted with water and ethyl acetate and treated with charcoal. After filtration, the organic layer is separated, washed with brine and dried (magnesium sulphate). The solvent is removed under reduced pressure and the resulting crude product is submitted to deacetylation without further purification.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.CN(C)C1C=CC=CC=1.C(OCC)C>O1CCCC1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: C=CC(=O)OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
0.8 ml of acryloyl chloride was added to a solution of 2.2 g of 4-{2-[4-(6-Hydroxy-hexyloxy)-phenyl]-ethyl}-phenol (L) and 1.23 ml of N,N-dimethylaniline in 20 ml of tetrahydrofuran, cooled in an icebath. The mixture was stirred for 3 hours at room temperature. 40 ml of diethylether was added which was extracted twice with 20 ml of 2.4N hydrochloric acid and once with 20 ml of brine. It was dried over magnesium sulphate and evaporated. 1.65 g of 4-{2-[4-(6-acryloyloxy-hexyloxy)-phenyl]-ethyl}-phenol (N, 64%) was obtained after washing with 15 ml of pentane.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>C1COCC1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:8])[CH2:21][O:22]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2Cl)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and the reaction mixture was stirred for 10 min. after which the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29](O)=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:61][C:62](=[O:66])[C@H:63]([CH3:65])[NH2:64])C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(#N)C.CO.[Pd]>[OH:38][C@@H:23]([C@H:22]([OH:39])[C@H:21]([OH:40])[C@@H:20]([NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:11])[CH2:41][OH:42])[C:24]([NH:26][C@H:27]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:28][C:29]([NH:64][C@H:63]([C:62]([OH:66])=[O:61])[CH3:65])=[O:30])=[O:25]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)N[C@@H](C)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.5 %

Procedure:
To absolution of (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionic acid (200 mg), L alanine benzyl ester p-toluenesulfonate (238 mg) and N-hydroxy-5-norbornene-2,3-dicarboxyimide (183 mg) in acetonitrile (10 ml) were added N,N′-dicyclohexylcarbodimide (140 mg) and triethylamine (0.094 ml) and the mixture was stirred at room temperature for 15 hours. The formed insoluble solid was filtrated off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated brine, followed by drying over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was dissolved in methanol (10 ml) and stirred at room temperature with 10% palladium on activated carbon (60 mg) under hydrogen atmosphere for 3 hours. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to afford the title compound (58 mg).
Reaction SMILES: [Li]CCCC.[N+:6]([CH2:9][CH2:10][CH3:11])([O-:8])=[O:7].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.C(Cl)Cl>[C:13]1([CH:12]([OH:19])[CH:9]([N+:6]([O-:8])=[O:7])[CH2:10][CH3:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CCC[N+](=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(C(O)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58.4 %

Procedure:
n-BuLi (1.6 M in hexane, 6.24 mL) was added dropwise with stirring to a solution of nitropropane (0.9 mL, 10 mmol) in THF (12 mL) at -78° C. After 15 minutes a solution of TiCl3 (OPriso) (5 mmol) in THF (2 mL) and CH2Cl2 (3 mL) solution was added. After a further 15 minutes benzaldehyde (0.5 mL, 5 mmol) was added and the mixture allowed to warm up to room temperature (~ 30 min.). Stirring was continued for a further 3.5 hours at room temperature and the mixture was quenched with an aqueous slurry of disodium EDTA (1.86 g, 5 mmol) and extracted with Et2O (3×75 mL). The combined Et2O fractions were washed with dilute hydrochloric acid (2 M, 75 mL), aqueous sodium bicarbonate (75 mL) and water (75 mL), dried and evaporated in vacuo. Flash column chromatography (SiO2 , hexane:Et2O, 6:1 v.v] gave 1-phenyl-2-nitro-butan-1-ol (0.57 g, 61%) erythro:threo ratio 6:1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[OH-].[Na+].[CH3:13][C:14]([CH3:16])=[O:15]>[Cl-].[Na+]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=Cc1c(F)cccc1F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C=Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2,6-difluorobenzaldehyde (10.0 g, 70 mmol) in acetone (85 mL) was added sodium hydroxide (1 N solution, 106 mL). After stirring at room temperature for 1.5 h, the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with chloroform (2×150 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (0 to 20% gradient of ethyl acetate in hexanes as eluant) to afford the title product as a solid (8.1 g).
Reaction SMILES: C[Al](C)C.[NH4+:5].[Cl-].[CH2:7]([O:14][C:15]([N:17]1[CH2:22][C@@H:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:20][C@H:19]([C:32](OC)=[O:33])[C@@H:18]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]([N:17]1[CH2:22][C@@H:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:20][C@H:19]([C:32](=[O:33])[NH2:5])[C@@H:18]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@H](C(N)=O)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
Under an atmosphere of N2, a 2.0M solution of Me3Al in PhMe (Aldrich, 140 ml, 280 mmol) was added dropwise to a stirred and ice-cooled suspension of NH4Cl (14.92 g, 279 mmol) in dry PhMe (280 ml). After the addition was complete, the reaction mixture was allowed to stirr at room temperature for 30 minutes; at this point, solid NH4Cl disappeared completely, and the clear, homogeneous mixture resulted. To this was added a solution of (2R*,3S*,5S*)-1-benzyloxycarbonyl-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (13.88 g, 27.89 mmol) in dry PhMe (30.0 ml) dropwise at room temperature: on the addition, the reaction mixture became turbid. This was stirred and heated at a bath temperature of 50 C. overnight (ca. 20 hours). The turbid white reaction mixture was ice-cooled; and H2O (80.0 ml, 4.40 mol) was added carefully, wherein H2 gas evolved violently. The resultant white precipitates were filtered off by the aid of Celite, and washed with AcOEt (80 ml×5). The combined filtrate and AcOEt washings were washed with sat. NaCl aq. solution (×2), dried (MgSO4), and concentrated in vacuo to give a viscous colorless oil (13.76 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 100 g). Elution with n-hexane-AcOEt (5:1/2:1/1:1) gave title compound (11.10 g, 82.4%) as a colorless syrup. IRmax (film): 3405(s), 3340(s), 3200(s), 3100(w), 3070(m), 3045(m), 1735(m), 1675(br., v.s), 1610(s), 1498(s), 1160(s), 1100(s), 836(s), 775(s), 737(s) cm-1 ; 1H-NMR δ: 7.42-7.18(m, 10H), 5.83(d, J=5.1 Hz, 1H), 5.67(br.s, 1H), 5.47(br.s, 1H), 5.20(d, J=12.5 Hz, 1H), 5.13(d, J=12.5 Hz, 1H), 3.91(br.d, J=13.9 Hz, 1H), 3.63(dd, J=10.0, 6.8 Hz, 1H), 3.53(dd, J=10.0, 7.7 Hz, 1H), 3.08(dd,J=13.9, 7.7 Hz, 1H), 2.98(ddd,J=17.6, 5.1, 4.8 Hz, 1H), 2.25-1.91(m, 3H), 0.87(s, 9H), 0.02(s, 6H) ppm.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+]>CCO.O>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1CCC(=NO)CC1

Procedure:
4-Methylcyclohexanone (2.0 g, 17.8 mmol) was mixed with hydroxylamine hydrochloride (1.86 g, 26.8 mmol) and sodium acetate (2.63 g, 32.0 mmol) in a mixture of EtOH (20 mL) and water (12 mL). The mixture was refluxed for 5 h. All solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was used for the next step without further purification.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[CH:5]=1.[NH2:23][C@H:24]([C:40]([NH:42][C@H:43]([C:53]([C:55]([O:57][CH3:58])=[O:56])=[O:54])[CH2:44][O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.Cl.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl.C(Cl)(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:40]([NH:42][C@H:43]([C:53]([C:55]([O:57][CH3:58])=[O:56])=[O:54])[CH2:44][O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:41])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:31]=1)=[O:12])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[CH:5]=1
Reactant: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: Cn1cnc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1cn(C)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of Cbz-His(1-Me) (from Step 1 above, 0.36 g, 1.2 mmol), Tyr(OBn)-Ser(OBn)-CO2Me.HCl (from Example 8, Step 1 above, 0.60 g, 1.2 mmol), DCC (0.30 g, 1.4 mmol), and HOBT (0.19 g, 1.4 mmol) in CH2Cl2 was added Et3N (0.17 mL, 1.2 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with CHCl3, washed with saturated aqueous NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (1% MeOH:CHCl3) provided the title compound as a white solid, mp 161.5°-163.5° C.; FAB-MS 748 (m+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.CCCCCC>C(O)C>[C:1]([C:3](=[CH:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][OH:9])=[CH:20][CH:19]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(OCCO)cc1
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(C#N)=Cc1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (1.1 eq.) and 4-(2-hydroxyethoxy)benzaldehyde (1 eq.) were combined in ethanol (1.2 M). The reaction mixture was stirred at RT for 48. To this was then added an equal volume of hexane and the title compound was isolated by filtration as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:36]=[CH:37][CH:38]=2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:35])(=[O:34])[NH2:33])=[O:24])=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:36]=[CH:37][CH:38]=2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:33][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:34])=[O:35])=[O:24])=[CH:39][CH:40]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
In a stream of nitrogen and at 0° C., 0.27 ml (1.30 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.20 mmol) of 3-(4-chlorobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 4 and 293 mg (2.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 640 mg (yield: 93.0%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:17]=2)[N:12]=[C:11]([C:29]([O:31][CH3:32])=[O:30])[CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[N:17]=2)[N:12]=[C:11]([C:29]([O:31][CH3:32])=[O:30])[CH:10]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 18 g of methyl 4-(benzyloxy)-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridine-2-carboxylate dissolved in 200 ml of methanol with 200 ml of tetrahydrofuran was charged with 1.8 g of 20% palladium hydroxide on carbon catalyst, and the mixture was stirred at room temperature for 2 hours under hydrogen atmosphere at 1 atm. The reaction mixture was filtered and concentrated to give crude title compound.