Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([C:10](C(OC)C2N(C)C3C(=O)C4C=CC(C)=CC=4OCC=3C=2)=[O:11])OC)=[CH:5][C:4]2[CH2:32][O:33][C:34]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:35]=3[C:36](=[O:37])[C:3]1=2.[BH4-].[Na+].Cl.Cl(O)(=O)(=O)=O>CCOCC.C(Cl)Cl.CO>[CH3:1][N:2]1[C:6]([CH2:7][CH:10]=[O:11])=[CH:5][C:4]2[CH2:32][O:33][C:34]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:35]=3[C:36](=[O:37])[C:3]1=2
Reactant: COC(C(=O)C(OC)c1cc2c(n1C)C(=O)c1ccc(C)cc1OC2)c1cc2c(n1C)C(=O)c1ccc(C)cc1OC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc2c(c1)OCc1cc(CC=O)n(C)c1C2=O
Temperature: 25 °C

Procedure:
To a stirred, cold mixture of [1,7-dimethyl]-4,10-dihydro-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole-2-yl-methoxymethyl ketone (3.0 g, 0.01 m) and methanol is added sodium borohydride (0.114 g, 0.003 m) over ca. 15 minutes. The reaction mixture is allowed to warm slowly to room temperature over several hours. Excess dilute hydrochloric acid and methylene chloride are added, the layers separated, and the methylene chloride layer concentrated in vacuo to the corresponding crude alcohol which is dehydrated with pyridine-phosphorus oxychloride to yield the intermediate, an enol-ether. This is taken up in ether and treated with perchloric acid (Ber. 95 (1962) 2514) to yield 1,7-dimethyl-4,10-dihydro-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole-2-acetaldehyde, which is oxidized according to Example 24 to give I.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C:8]([NH2:33])=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
A mixture of 3-phthalimido-3-(3-cyclopentyloxy-4-methoxyphenyl)propionic acid (2.05 g, 5.00 mmol), 1,1'-carbonyldiimidazole (0.91 g, 5.5 mmol) and 4-dimethylaminopyridine (trace) in tetrahydrofuran (20 mL) was stirred for 1.5 hours under nitrogen at approximately 25° C. To the solution was added ammonium hydroxide (1.07 mL, 16.0 mmol, 28-30%) and stirring was continued for 1.5 hours. A small amount of solid forms during this time. The mixture was concentrated to half its volume and a white solid precipitated. The mixture was filtered, washed with a small amount of tetrahydrofuran, air dried, and dried in vacuo (60° C.,<1 mm) to afford 1.27 g of the product. The product was further purified by flash column chromatography (silica gel, 5% methanol/methylene chloride) and the resulting white solid was dried in vacuo (60° C., <1 mm) to afford 1 g (49%) of the product: mp 165°-166° C.; 1H NMR (CDCl3) δ 7.85-7.61 (m, 4H), 7.16-7.04 (m, 2H), 6.85-6.75 (m, 1H), 5.80 (dd, J=5.8, 10.4 Hz, 1H), 5.66 (br s, 1H), 5.54 (br s, 1H), 4.82-4.70 (m, 1H), 3.80 (s, 3H), 3.71 (dd, J=10.4, 15 Hz, 1H), 3.06 (dd, J=5.8, 15 Hz, 1H), 2.06-1.51 (m, 8H); 13C NMR (CDCl3) δ 171.8, 168.3, 149.8, 147.7, 133.9, 131.8, 131.3, 123.3, 119.9, 114.6, 111.8, 80.4, 56.0, 51.6, 37.9, 32.7, 24.1; Anal. Calcd for C23 H24N2O5. Theoretical: C, 67.63; H, 5.92; N, 6.86. Found: C, 67.25; H, 5.76; N, 6.68.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13]O)[CH2:11][C@H:10]([CH2:15][CH2:16][C:17]2([CH3:22])[O:21][CH2:20][CH2:19][O:18]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:48]I>CC#N>[CH2:1]([N:8]1[C@H:12]([CH2:13][I:48])[CH2:11][C@H:10]([CH2:15][CH2:16][C:17]2([CH3:22])[O:21][CH2:20][CH2:19][O:18]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CC[C@H]2C[C@@H](CO)N(Cc3ccccc3)C2=O)OCCO1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC1(CC[C@H]2C[C@@H](CI)N(Cc3ccccc3)C2=O)OCCO1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-4 (2.0 g, 6.26 mmol), PPh3 (2.63 g, 10.0 mmol), imidazole (725 mg, 10.6 mmol) and CH3CN (30 mL) at 0° C. was added I2 (2.39 g, 9.39 mmol) in five portions over 15 minutes. After 20 minutes, the reaction was warmed to 50° C. for 30 minutes and then poured into 200 mL 1:1 EtOAc/hexanes. The solution was washed with 10% sodium bisulfite, sat NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 11-5 as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][N:14]([CH3:20])[C:15](=[O:19])[C:16]=2[CH3:18])[NH:11]C1=O.[H-].[Na+].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.[OH-].[Na+].Cl>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:17]1[C:12]([NH:11][S:27]([CH:24]2[CH2:26][CH2:25]2)(=[O:29])=[O:28])=[CH:13][N:14]([CH3:20])[C:15](=[O:19])[C:16]=1[CH3:18]
Reactant: Cc1c(=O)n(C)cc2[nH]c(=O)n(-c3ccc(I)cc3F)c12
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To the solution of 1-(2-fluoro-4-iodophenyl)-5,7-dimethyl-1H-imidazo[4,5-c]pyridine-2,6(3H,5H)-dione (23 mg, 0.0576) dissolved in dry DMF (2 mL) cooled to below 0° C. under an ice-bath, was added NaH (60% in mineral oil) (5.0 mg, 0.125 mmol). The cooling bath was removed after addition and the solution was allowed to stir at room temperature for 1 hour. The same solution was re-cooled to −5° C. in a dry-ice/acetone bath, and added cyclopropanesulfonyl chloride (28 mg, 0.20 mmol) dissolved in dry THF (0.5 mL) slowly. The mixture was allowed to warm to room temperature and stirred was and additional 16 hours. The reaction mixture was cooled to 0° C., additional NaH (60% in oil) (5.0 mg, 0.125 mmol), followed by cyclopropanesulfonyl chloride (15 mg, 0.11 mmol) were added. The solution was stirred at room temperature for additional 5 hours. To the same reaction mixture was added aqueous NaOH (1N) (5 mL). The mixture was heated to 65° C. for 40 minutes. After cooled to room temperature, aqueous HCl (1N) (25 mL) was added to acidify the solution, which was extracted with EtOAc (15 mL×3). The combined organic layers was washed with brine, dried (MgSO4), and concentrated under the reduced pressure to give a residue, which was HPLC purified. (9.6 mg, 35% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]([S:15](Cl)(=[O:17])=[O:16])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[CH2:9][NH:10][S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CN)c1cccc(Br)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1cccc(Br)c1
Yield: 31 %

Procedure:
2-(3-Bromophenyl)propylamine (9.7 g, 45.3 mmol) was combined with isopropylsulfonyl chloride (6.1 mL, 54.4 mmol), and DBU (10.2 mL, 68 mmol) in a manner analogous to the procedure described in example 2 to provide the final title compound, [2-(3-bromophenyl)propyl][(methylethyl)sulfonyl]amine, (4.5 g, 31%) as a white crystalline solid. Electron spray M.S. 320 (M*−H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: N#Cc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To 10 mL of a chloroform solution containing 58 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyanoquinoxalin-2(1H)-one and 35 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 11 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 67 mg of sodium triacetoxyborohydride was added, and stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=5:1] to give 43 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-cyanoquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N+:26]([O-])([OH:28])=[O:27]>C(O)(C(F)(F)F)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)c1ncc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc2c1O

Procedure:
2.0 g of 4-Hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester, Example D-7f, was dissolved in 15 ml of TFA. 0.375 ml of fuming nitric acid was added slowly to the solution, and the resultant mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under vacuum, and the resultant residue was purified by column chromatography on silica gel, eluting with 0-20% ethyl acetate in dichloromethane. The crude product obtained was triturated with methanol to produce 1.0 g of white solid; MS (+): m/z 383.01 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@H:19]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[C:20]1=[O:33]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@H:19]2[C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=3[CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[C:20]2=[O:33])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCN1CCc2cc(F)ccc2[C@H](N)C1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCN1CCc2cc(F)ccc2[C@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C1=O

Procedure:
Following General Procedure C above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-(S)-amino-3-ethyl-7-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (General Procedure 6-A), the title compound was prepared. Purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[S:8]([O:11][C:12]1[C:13]([NH2:32])=[CH:14][C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=2[CH:31]=1)(=[O:10])=[O:9].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:34][C:7]([F:6])([F:33])[S:8]([O:11][C:12]1[C:13]([N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:15]2[O:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=2[CH:31]=1)(=[O:10])=[O:9]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(OS(=O)(=O)C(F)(F)F)cc12
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Methanesulfonyl chloride (146 μL, 1.873 mmol) was added to a stirring solution of 6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (270 mg, 0.624 mmol) and DIEA (500 μL, 2.86 mmol) in DCM (6.3 mL) at 25° C. It was allowed to stir for 1 hour and then diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. It was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (300 mg, 82%). LC-MS retention time: 1.49 min; m/z (MH+): 589. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 mM where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:23])([CH2:21][CH3:22])[CH2:17][C:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:23])([CH2:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CC(=O)[O-])c1ccnc(OC)c1COCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(O)(CC(=O)O)c1ccnc(OC)c1COCc1ccccc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
Tertiobutyl 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoate (40 g; 100 mmol) is treated with trifluoroacetic acid (150 ml) and the reaction medium is agitated for 18 hours at 20° C. After evaporation of the trifluoroacetic acid, methylene chloride (200 ml) is poured in and a saturated solution of sodium bicarbonate is introduced until the pH −7.5-8. After decantation, the aqueous phase is washed with 100 ml of methylene chloride. The pH of the aqueous phase is then adjusted to 1 by the addition of a solution of 6N hydrochloric acid. The product is then extracted from the aqueous phase with methylene chloride (2 times 200 ml). The solution is dried over magnesium sulphate and concentrated. The 3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid (31.1 g; 90 mmol) thus obtained, taken up in isopropyl alcohol (30 ml), is treated with a solution of quinidine (29.2 g; 90 mmol) in isopropyl alcohol (30 ml) at 50° C. under agitation until complete dissolution. Then the reaction medium is left so that temperature reduces to 40° C., the agitation is stopped and the temperature allowed to drop to 20° C. The medium is taken to 0° C. without agitation then maintained at this temperature for 16 hours. Then the temperature is allowed to rise to 20° C. and agitation is carried out until crystallization. The medium is diluted with isopropyl alcohol then filtered. The precipitate is rinsed with isopropyl alcohol. The salt of the (+) enantiomer precipitates (m=26.6 g) while the salt of the (−) enantiomer remains in solution in the isopropyl alcohol. Thus the filtrate is recovered which is concentrated in order to produce an oil (34 g) which is used without other purification in the following stage.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42]([OH:44])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:47](CC)CC)C.ClC(OC(C)C)=O.N>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[C:42](=[O:44])[NH2:47])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(N)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 0.17 h

Procedure:
To a solution of 0.51 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) in 1 ml of dichlormethane are added 1.2 ml of triethylamine and 0.79 ml of isopropyl chloroformate. The reaction mixture is stirred for 10 minutes, followed by addition of 2 ml of conc. ammonia 25%. After an additional 10 minutes the reaction mixture is diluted with dichloromethane, washed with 0.5N hydrochloric acid and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.50 (dichlormethane-methanol 9:1); Rt=4.50.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2

Procedure:
The titled compound was prepared following the procedure B using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and hexanoyl chloride as a colorless oil (88%). 1H NMR (CDCl3, 300 MHz) δ 7.70 (d, J=2.3 Hz, 1H), 7.44 (m, 4H), 7.16 (m, 4H), 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H) 4.88 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.06 (t, J=7.5 Hz. 2H), 1.75 (s, 6H), 1.61 (m, 4H), 1.36 (m, 2H), 1.23 (m, 4H), 0.94 (t, J=7.3 Hz, 3H), 0.85 (t, J=6.8 Hz, 3H). M+ (ESI): 538.4 HPLC, Rt: 5.95 min (Purity: 98.2%).
Reaction SMILES: [CH2:1]([S:5]([N-:8][Si](C)(C)C)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:13]([O:17][C:18]([NH:20][C@H:21]([C:26](F)=[O:27])[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C1C=CC=CN=1)C>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:5]([NH:8][C:26](=[O:27])[C@H:21]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)[N-][Si](C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Agent: CN(C)c1ccccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-butanesulfonyl-N-trimethylsilylamide (prepared according to the procedure described in Example 8) (0.64 g, 3.06 mmol), t-butoxycarbonylisoleucine fluoride (0.475 g, 2.04 mmol), and dimethylaminopyridine (110 mg, 0.9 mmol) in tetrahydrofuran (7 ml) is stirred at room temperature for 2 hours. The mixture is diluted with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material is chromatographed on silica gel with ethyl acetate/hexane (4:1) to give N-butanesulfonyl-(t-butoxycarbonyl)isoleucineamide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([N:25]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:18]=[CH:19][C:20]=2[O:21][CH:22]([F:24])[F:23])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([N:25]3[CH2:30][CH2:29][N:28]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:18]=[CH:19][C:20]=2[O:21][CH:22]([F:23])[F:24])[CH2:12][CH2:11]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OCC3CC3)c2)CCN1
Product: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OCC3CC3)c2)CCN1C(=O)Cc1c[nH]cn1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-isobutyl-piperazine (Example 37, Compound 125) as starting materials. Product as an off-white solid (14%). LC/MS (Method B) 2.94 min, [M+1]+ 463.0. Potency class B.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C(O)=O.[CH:16]1([NH:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH:16]1([N:22]2[C:1]([OH:7])=[CH:2][C:3]([CH3:5])=[N:23]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: Cc1cc(O)n(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
A solution of ethyl acetoacetate (26 g) and cyclohexylhydrazine oxalate (40 g) in ethanol (100 ml) was heated at sufficient temperature and in a manner to allow removal of the ethanol by distillation. The temperature was gradually raised to about 130°, and heating was continued at this temperature for 4 hours, during which time by-product water and additional ethanol were continuously removed by distillation. The reaction mixture, after cooling to room temperature, was dissolved in methylene chloride and extracted with a saturated solution of sodium bicarbonate. The methylene chloride layer was dried and concentrated to give a viscous residue, which was induced to crystallize upon trituration with diethyl ether. The solid was collected to give 2-cyclohexyl-3-hydroxy-5-methylpyrazole (16.5 g), m.p. 153°. The assigned structure of the product as consistent with its infrared spectrum.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:9]([N+:10]=1[O-])=[CH:8][CH:7]=[CH:6][N:5]=2.C[Si]([C:16]#[N:17])(C)C.CN(C)C(Cl)=O.[OH-].[Na+]>C(Cl)Cl>[C:16]([C:6]1[N:5]=[C:4]2[S:3][C:2]([CH3:1])=[N:10][C:9]2=[CH:8][CH:7]=1)#[N:17]
Reactant: Cc1sc2ncccc2[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc2ccc(C#N)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step 3 (4.706 g, 28.3 mmol) in 60 mL of CH2Cl2 was added trimethylsilyl cyanide (7.6 mL, 57 mmol) and the mixture was stirred at room temperature for 30 min. Dimethylcarbamyl chloride (5.2 mL, 56 mmol) was then added and the mixture was heated to reflux overnight. At 0° C., 2N NaOH (60 mL) was added and the mixture was stirred at this temperature one hour. The product was extracted in EtOAc, dried over Na2SO4, and purified by flash chromatography on silica with EtOAc: toluene 10:90; yield: 4.50 g, (91%).