Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[N+:3]([CH3:6])([O-:5])=[O:4].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>>[N+:3]([CH:6]=[CH:12][C:8]1[O:7][CH:11]=[CH:10][CH:9]=1)([O-:5])=[O:4]
Reactant: O=Cc1ccco1
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])C=Cc1ccco1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a 20% potassium hydroxide solution (25 mL) at 0° C. was added nitromethane (2.7 mL, 50 mmol) over 5 min followed by the slow addition via syringe pump of 2-furaldehyde (4.1 mL, 50 mM). The resulting brown solution was stirred vigorously for an additional 10 min at 0° C. then poured into an ice cold 50% HCl solution. The precipitate was collected via filtration, thoroughly washed with water, taken up in MeOH, solvents removed under reduced pressure, taken up in CHCl3 and filtered to remove any material that did not dissolve to give 2-(2-nitrovinyl)furan (10% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([NH2:16])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.CCN(CC)CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@@:4]([NH2:16])([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@](N)(CSCc1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid methyl ester (30.7 g, 127.3 mmol) prepared in Step A was dissolved in DCM. Et3N (26.4 g, 190 mmol) and (BOC)2O (27.7 g, 127.3 mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove DCM, and was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][O:25][CH2:26][C:27]([CH3:31])([OH:30])[C:28]#[CH:29]>>[CH:19]1([C:13]2[N:8]3[CH:9]4[CH2:10][CH:11]([C:5]5[CH:4]=[C:3]([F:23])[C:2]([C:29]#[C:28][C:27]([OH:30])([CH3:31])[CH2:26][O:25][CH3:24])=[CH:22][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:12]4)[CH2:20][CH2:21]1
Reactant: NC(=O)c1nc2n(c1C1CC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)COC
Product: COCC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C1CC1

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-cyclopropyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-methoxy-2-methylbut-3-yn-2-ol to give the titled compound. MS+410.2. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=7.5 Hz, 1H), 7.47 (br s, 1H), 7.25 (d, J=10.1 Hz, 1H), 6.98 (br s, 1H), 5.68 (s, 1H), 5.26 (m, 1H), 3.68 (m, 1H), 3.39 (m, 2H), 3.37 (s, 3H), 3.14 (m, 2H), 1.81-1.59 (overlapping m, 3H), 1.45 (s, 3H), 0.99 (m, 2H), 0.67 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 77 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), 5 mL of acetone, and 5 mL of acetonitrile. The resulting mixture was refluxed under stirring at 79-75° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 99.3%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)(=[O:20])=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Nc1cccc2cccnc12
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccccn1
Yield: 66 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (100 mg, 0.69 mmol), pyridine-2-sulfonyl chloride (Intermediate 18) (196 mg, 1.107 mmol) gave the title compound (130 mg, 65%) after purification by column chromatography with n-hexane/EtOAc (17:3) as the eluent.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.[F:12][C:13]1[CH:14]=[C:15]([CH:20]2CCC(=O)[CH2:22][CH2:21]2)[CH:16]=[C:17]([F:19])[CH:18]=1>O>[F:12][C:13]1[CH:14]=[C:15]([CH:20]2[CH2:9][CH2:8][CH:7]([CH:11]=[O:10])[CH2:22][CH2:21]2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=C1CCC(c2cc(F)cc(F)c2)CC1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=CC1CCC(c2cc(F)cc(F)c2)CC1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To dried MTP 10.0 g (29.2 mmol), THF 100 ml was added, and potassium-t-butoxide 3.30 g (29.4 mmol) was added. The mixture was stirred for about one hour. To the reactant, a THF solution (50 ml) of the above 4-(3,5-difluorophenyl)cyclohexanone 5.0 g (23.8 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 150 ml was added to the reactant, the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). The resulting purified material was stirred in mixture solvent of 3N-hydrochloric add 200 ml and acetone 200 ml for 5 hours at room temperature, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4-(3,5-difluorophenyl)cyclohexanecarboaldehyde 5.0 g (22.3 mmol). The yield was 93.7% from 4-(3,5-difluorophenyl) cyclohexanone.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[C:23](I)[C:24]([CH3:28])=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[CH3:30][NH:31][C:32]1[N:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[N:33]=1>O1CCOCC1>[CH2:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:37]5[CH:38]=[C:39]6[C:34](=[CH:35][CH:36]=5)[N:33]=[C:32]([NH:31][CH3:30])[N:41]=[CH:40]6)[C:24]([CH3:28])=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: Cc1ccc2c(Nc3ccc4c(c3)CCC4)ncnc2c1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5ccc6c(c5)CCC6)ncnc34)ccc2n1
Temperature: 180 °C

Procedure:
2 M Aqueous sodium carbonate (857 μl, 1.7 mmol), tetrakis (triphenylphosphine)palladium (0) (99 mg, 86 μmol), N-(2,3-dihydro-1H-inden-5-yl)-8-iodo-7-methylquinazolin-4-amine hydrochloride (250 mg, 571 μmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (326 mg, 1142 μmol) and dioxane (5 mL) were added to a microwave vial. The reaction mixture was heated in a microwave at 180° C. for 20 min. The solid residue was filtered off through Celite® and washed with methanol and DCM. The filtrate was concentrated and purified by flash chromatography (0-10% MeOH in DCM) to give 6-(4-(2,3-dihydro-1H-inden-5-ylamino)-7-methylquinazolin-8-yl)-N-methylquinazolin-2-amine as an off-white amorphous solid. MS (M+H)+ 433.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:3][C:2]=1[O:1][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of benzyl (3-hydroxy-4-methylphenyl)carbamate (83.1 g, 321 mmol) in N,N-dimethylformamide (300 mL) were added cesium carbonate (157 g, 482 mmol) and 2-chloro-5-nitropyridine (50.9 g, 321 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (1 L), and the obtained aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with saturated brine (100 mL) and purified by basic silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/hexane (1:1) to give the title compound (91.8 g, 75%) as a pale-yellow solid.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.I[CH2:13][CH3:14].Cl>CN(C)C=O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOCc1ccc(Br)cc1
Reaction time: 2 h
Yield: 49.4 %

Procedure:
NaOH (0.1 g, 2.4 mmol) was added to 2 ml of degassed dimethylformamide and 4-bromobenzylalcohol (0.3 g, 1.6 mmol) was further added slowly. Iodoethane (0.14 ml, 1.76 mmol) was added at room temperature followed by stirring for 2 hours. The mixture was added with 50 ml of 2N c HCl and extracted with 50 ml of ethylacetate. The organic layer was washed twice with 50 ml of H2O. After concentration under vacuum and column chromatography (ethylacetate/n-hexane, 1/10), the title compound (0.17 g, 48%) was obtained as yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:8]=1.[CH2:22]([NH2:34])[CH2:23][C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][NH:34][CH:11]([CH3:12])[CH2:10][CH2:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C#Cc2ccccc2)c(CCC(C)=O)c1
Reactant: COc1ccc(CCN)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CCC(C)NCCc2ccc(OC)c(OC)c2)c1
Yield: 90.2 %

Procedure:
4-[5-Methoxy-2-(phenylethynyl)phenyl]-2-butanone (0.5 g, 1.8 mmole), the product of Example 1d, and homoveratryl amine (0.33 g 1.8 mmole) were combined in 10 mL of absolute methanol. With stirring, sodium cyanoborohydride (0.21 g, 3.3 mmole) was added in three portions. During this addition, the pH was adjusted to 6 with glacial acetic acid. After stirring for 5 hr, the reaction mixture was concentrated in vacuo and the resulting residue dissolved in methylene chloride. The methylene chloride solution was washed with 1N sodium hydroxide, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.72 g of the title compound as a golden oil. The free base was dissolved in absolute methanol (5 mL) and treated with oxalic acid (0.2 g). After stirring for several hours, ether (50 mL) was added and the solution was cooled and filtered to give 1.0 g of the title compound as the oxalate salt.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-phenylphenol (5.00 g), methyl bromoacetate (3.1 ml) and potassium carbonate (8.1 g) in DMF was stirred at room temperature. After five hours, the reaction mixture was diluted with water (100 ml) and then extracted with ether. The combined organic layers were washed with aqueous sodium carbonate followed by brine and then dried, filtered and evaporated to give crude methyl (3-phenylphenoxy)acetate (7.2 g) as a pale yellow liquid, 1H NMR (CDCl3) delta 3.8 (3H,s), 4.7 (2H,s), 6.8-7.6 (9H,m) ppm.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]5[O:31][CH2:32][O:33][C:27]=5[CH:26]=4)[CH2:23][CH2:22][C:21]([C:34]([O:36]C)=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]5[O:31][CH2:32][O:33][C:27]=5[CH:26]=4)[CH2:23][CH2:22][C:21]([C:34]([OH:36])=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc3c(c2)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc3c(c2)OCO3)cc1
Yield: 89.1 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g). To the solution was added 1N sodium hydroxide solution (6 ml), and the mixture was refluxed for 2 hours, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.26 g) as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[CH2:10]1OCOCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:4]([C:3]1([CH3:7])[CH2:8][O:9][CH2:10][O:1][CH2:2]1)(=[O:6])[CH3:5]
Reactant: CC(=O)C(C)(CO)CO
Reactant: C1OCOCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C1(C)COCOC1

Procedure:
A solution of 3,3-bis(hydroxymethyl)-2-butanone (66.1parts) and s-trioxane (27 parts) in toluene (250 parts) containing p-toluenesulfonic acid (1.9 parts) is held under reflux while water of reaction is continuously removed (ca. 0.5 hr) by a Dean-Stark trap. The solution is cooled, neutralized by stirring with solid sodium bicarbonate and filtered Toluene is removed in vacuo and the residue distilled at 50-55° C. and 0.6 mm Hg. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C7H12O3 --Calculated: C, 58.3%; H, 8.4%. Found: C, 57.9%; H, 8.2%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)(C)C)(=O)[NH:16][NH2:17].CO.C([BH3-])#N.[Na+].[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:16][NH2:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NNC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzylpiperidin-3-one (2.0 g, 0.0089 mol), and tert-Butyl carbazate (1.17 g, 0.00886 mol) in Methanol (31 mL, 0.78 mol) was added Sodium cyanoborohydride (1.11 g, 0.0177 mol) portionwise at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was basified with 1N NaOH solution and a white precipitate crashed out of solution. The reaction mixture was filtered and the white solid was allowed to air dry to give 1-benzyl-3-hydrazinylpiperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[OH:38][C@H:39]1[CH2:43][CH2:42][N:41]([C:44]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][CH:47]=2)=[O:45])[CH2:40]1.CC1(C)C(C)(C)OB(C2C=CC(C(O)=O)=CC=2)O1.N1CC[C@H](O)C1>>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][CH3:16])[C:12]([C:10]1=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:49]3[CH:48]=[CH:47][C:46]([C:44]([N:41]4[CH2:42][CH2:43][C@H:39]([OH:38])[CH2:40]4)=[O:45])=[CH:51][CH:50]=3)=[CH:37][C:6]=2[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:9]1)=[O:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CC[C@H](O)C3)cc2)OC1(C)C
Agent: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: O[C@H]1CCNC1
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@H](O)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and (S)-(3-hydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone that was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (S)-pyrrolidin-3-ol. MS APCI (+) m/z 705 (M+1) detected.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:24]([OH:26])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:6])[CH3:3].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:43][N:44]([N:51]=O)C(N[N+]([O-])=O)=N>O1CCCC1>[N+:44](=[CH:43][C:24](=[O:26])[C@@H:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:27])[CH3:3])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)=[N-:51]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)C=[N+]=[N-]
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-[(1,1-dimethylethoxy)carbonyl]--O-benzyl-L-tyrosine in dry tetrahydrofuran (90 ml) cooled at -20° C. to -25° C. was added isobutyl chloroformate (8.7 ml, 67.3 mmol) followed by 4-methylmorpholine (6.8 ml, 67.3 mmol) and the mixture was stirred for 20 minutes. The precipitate was filtered and washed with dry tetrahydrofuran. The filtrate was cooled to -5° C. and poured into a diazomethane in ether solution (prepared from 1-methyl-3-nitro-1-nitrosoguanidine (29.7 g, 202 mmol) as described in Example 1 (d) at 0° C. The resulting yellow solution was kept at 0° C. for 2.0 hours, then at room temperature overnight. Nitrogen was then bubbled through the solution for 30 minutes, the solution diluted with ethyl ether (500 ml) and then washed with water, saturated sodium bicarbonate, and brine, and dried over magnesium sulfate. Concentration in vacuo afforded a yellow residue which was triturated with hexane (500 ml) to give 24.5 g of (S)-[3-diazo-2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]propyl]carbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:12][CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:53]=[CH:52][C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][C:49](O)=[O:50])=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)=[O:16])[C:10]#[CH:11].C(Cl)CCl>C(Cl)Cl>[CH2:9]([O:12][CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:53]=[CH:52][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][C:49]([O:1][N:2]3[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[O:50])=[CH:32][CH:33]=2)=[O:27])=[CH:24][CH:23]=1)=[O:16])[C:10]#[CH:11]
Reactant: O=C1CCC(=O)N1O
Reactant: C#CCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)O)cc2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C#CCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
N-hydroxysuccinimide (252 mg, 2.30 mmol) was added to a solution of 1-((4-(4-(3-(3-(prop-2-yn-1-yloxy)propanamido)propoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (1.25 g, 1.98 mmol) in anhydrous DCM (10 ml) was added followed by EDC (505 mg, 2.64 mmol). The reaction was stirred at r.t. for 2-3 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH gradient) to provide 1.16 g (1.63 mmol, 80% yield) of 2,5-dioxopyrrolidin-1-yl 1-((4-(4-(3-(3-(prop-2-yn-1-yloxy)propanamido)propoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 97.8 %

Procedure:
A solution of 2.03 g (6.36 mmol) of methyl(R)-3-(4-allylphenyl)-2-tert-butoxycarbonylaminopropionate (prepared as in Synlett, 2005, 12, 1877-1880) in 20 ml of dioxane/water (1:1, v/v) and 0.30 g (12.71 mmol) of lithium hydroxide was stirred at RT for 2 h and then neutralized with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over Na2SO4, filtered and concentrated. 1.90 g of the title compound were obtained.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([CH2:19][NH:20][OH:21])=[CH:17][CH:16]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O.Cl>O1CCOCC1>[OH:21][N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[CH:23][CH:22]=1)[C:29]([NH2:28])=[O:30]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCc1ccc(OCCc2noc(-c3ccccc3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N(O)Cc1ccc(OCCc2noc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of N-[4-[2-(5-phenyl-[1,2,4]-oxadiazol-3-yl)-ethoxy]-benzyl]-hydroxylamine (1.5 g, 4.82 mmol in dioxane (70 mL) was added trimethylsilylisocyanate (0.84 g, 7.23 mmol). After stirring for 2 hours at room temperature the mixture was poured into H2O, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether (after cooling to 0° C.), gave a white solid (1.2 g, 70% yield, m.p. 135°-136° C.).