Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].N([O-])=O.[Na+].CCOC([S-])=[S:30].[K+].[OH-].[K+]>Cl.O.C(O)C>[SH:30][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)CCCOc1c(N)cccc1C(=O)OCC
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCOc1c(S)cccc1C(=O)O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of ethyl 3-amino-2-(3-ethoxycarbonyl-propoxy)benzoate (8.93 g) in conc. hydrochloric acid (4.8 ml) was cooled in an ice bath. To this solution was added dropwise a solution of sodium nitrite (2.11 g) in water (5 ml) at 5° C. On the other hand, a solution of potassium xanthogenate (5.83 g) in water (7.6 ml) was heated at 50° C. To this solution was added dropwise the above solution of the diazonium salt at 50-55° C. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate. After an additional extraction with ethyl acetate, the combined extracts were dried over magnesium sulfate and evaporated in vacuo to give the crude material, which was then dissolved in ethanol and 85% potassium hydroxide (9.10 g) was added to the solution. After the mixture was heated to reflux for 1.5 hours, it was cooled in an ice bath and acidified with conc. hydrochloric acid. The mixture was then extracted with ethyl acetate (x 3). The combined extracts were dried over magnesium sulfate and evaporated in vacuo to give 3-mercapto-2-(3-carboxypropoxy)benzoic acid (7.08 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.I[CH2:23][CH2:24][CH3:25].[Na]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:23][CH2:24][CH3:25])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1
Reactant: CCCI
Agent: [Na]
Solvent: C1CCOC1
Product: CCCN(c1cncc(Cl)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate (0.20 g, 0.64 mmol) in tetrahydrofuran (3 mL) at 0° C. was added 1-iodopropane (1 mL, 10 mmol) and sodium hyrdride (0.051 g, 1.3 mmol). The reaction mixture was warmed to room temperature then stirred at 60° C. After 1.5 h, the reaction mixture was cooled to room temperature and quenched with water (10 mL). The reaction mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)(propyl)amino]piperidine-1-carboxylate as a yellow oil. LRMS (ESI) calculated for C17H27ClN4O2 [M+Na]+, 377.2; found 377.1.
Reaction SMILES: [OH:1]O.[CH:3]1=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1>C(O)(C)(C)C>[CH:3]12[O:1][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: C1=CCCCCCC1
Reactant: OO
Agent: C1=C\CCCCCC/1
Solvent: CC(C)(C)O
Product: C1CCCC2OC2CC1
Temperature: 30 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
Hydrogen peroxide (30%, 2 ml) was added to a mixture of the catalyst from Example 48 (0.04 g) and cis-cyclooctene (1.4 g, 11.5 mmol) in tert-butanol (10 ml) at 30° C. under an atmosphere of nitrogen. The reaction mixture was stirred at 30° C. for 48 h under nitrogen. The catalyst was filtered off and washed well with ether (80 ml). The combined organic layers were washed well with water (2×40 ml) and then dried over magnesium sulphate. After filtration the solvent was removed under reduced pressure −20° C. at 50 mm of Hg—to afford 9-oxabicyclo[6.1.0] nonane as a white solid (0.95 g, 65%). M.p. 51° C., lit. m.p. 53–56° C.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1[CH:7]=O.C([O-])(=O)C.[Na+].Cl.[NH2:21][OH:22]>O>[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1[CH:7]=[N:21][OH:22]
Reactant: NO
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C=NO)c(C)c1
Yield: 85 %

Procedure:
To 120 ml of ethanol and 60 ml of water were added 29.6 g (0.2 mole) of 2,4,6-trimethylbenzaldehyde, 32.8 g (0.4 mole) of sodium acetate and 20.7 g (0.3 mole) of hydroxylamine hydrochloride, and the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was added to 500 ml of water. The precipitated crystals were collected by filtration to give 28 g (0.17 mole) of 2,4,6-trimethylbenzaldoxime.
Reaction SMILES: O1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:21])[CH2:12][NH:13]C(=O)OC(C)(C)C)=[C:4]2C=C1.[ClH:22].[O:23]1CCO[CH2:25][CH2:24]1>C(O)C>[ClH:22].[NH2:13][CH2:12][C:11]([NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:25]=[CH:24][O:23][C:4]=12)=[O:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccnc2occc12
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: NCC(=O)Nc1ccnc2ccoc12
Temperature: 25 °C

Procedure:
Tert-Butyl 2-(furo[2,3-b]pyridin-4-ylamino)-2-oxoethylcarbamate (350 mg, 1.2 mmol) was placed in ethanol (96%) (3.0 ml) and hydrogen chloride in dioxane (5.0 ml, 20.00 mmol) was added after which the resulting mixture was stirred at room temperature over night. The solids were filtered off, washed subsequently with EtOH and diethylether and dried in a stream of air. 230 mg of a white powder was obtained (1.01 mmol, 84%). MS (ESI) m/z=191.9 [M+1]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:27][S:26](=[O:29])(=[O:28])[CH2:25][C:24]=2[CH:30]=1>>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[NH:27][S:26](=[O:29])(=[O:28])[CH2:25][C:24]=3[CH:30]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)N2
Product: O=C(Nc1ccc2c(c1)CS(=O)(=O)N2)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-amino-1,3-dihydro-2,1-benzisothiazole-2,2-dioxide [J. Het. Chem., 23, 1645. (1986)] according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 181-182° C. (isopropanol)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])[CH3:13].N1CCCCC1.C(Cl)Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:13]/[C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:14])=[CH:2]1
Reactant: CC(=O)c1cccnc1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CO
Product: O=C(/C=C/c1c[nH]c2ccccc12)c1cccnc1
Temperature: 25 °C

Procedure:
Indole-3-carboxaldehyde (100 mg, 0.69 mmol) was added to a dried 100 mL round bottom flask and dissolved in anhydrous methanol (5 mL). 3-Acetyl-pyridine (113 μL, 1.03 mmol, 1.5 equiv.) and piperidine (69 μL, 0.7 mmol) were added and the reaction stirred under reflux. After twelve hours, the reaction was cooled to room temperature, upon which a precipitate formed. The solid was filtered, yielding 54 mg. However, there was significant aldehyde present on a crude NMR. This mixture was dry-loaded onto silica and purified by column chromatography (methylene chloride:methanol 9:1), producing 33 mg pure, yellow solid (19%). NMR: 1H NMR (600 MHz, d6-DMSO): δ 12.004 (s, 1H, N—H), 9.292-9.289 (d, J=1.8, 1H, pyr-H2), 8.808-8.797 (dd, J1=4.8, J2=1.8, 1H, pyr-H6), 8.467-8.447 (dt, J1=7.8, J2=2.1, 1H, pyr-H4), 8.174 (s, 1H, indole-H2), 8.154-8.140 (dd, J1=6.6, J2=1.8, 1H, indole-H4), 8.120-8.095 (d, J=15.0, 1H, C═CH), 7.665-7.639 (d, J=15.6, 1H, C═CH), 7.607-7.585 (m, 1H, pyr-H5), 7.506-7.492 (dd, J1=6.9, J2=1.5, 1H, indole-H7), 7.268-7.223 (qd, J1=6.6, J2=1.5, 1H, indole-H5,6). 13C NMR (150 MHz, d6-DMSO): δ 187.9, 152.7, 149.3, 139.9, 137.6, 135.7, 134.1, 133.7, 125.1, 123.9, 122.9, 121.3, 120.7, 115.0, 112.9, 112.5. Melting Point: 192-194° C. TLC (methylene chloride:methanol 9:1) Rf=0.26. Elemental analysis calculated for C16H12N2O: C, 77.40; H, 4.87; N, 11.28. found: C, 77.00; H, 4.80; N, 11.12.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[O:9]=[C:10]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][C:12]#[N:13]>>[CH3:6][N:4]([CH:3]=[C:11]([C:10](=[O:9])[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[C:12]#[N:13])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)c1ccco1
Product: CN(C)C=C(C#N)C(=O)c1ccco1

Procedure:
A 50 ml portion of dimethylformamide dimethylacetal was added to 25 g of solid β-oxo-2-furanepropanenitrile. This exothermic reaction produced yellow crystals. After one hour the volatiles were removed under reduced pressure and the residue was dissolved in methylene chloride. This solution was passed through a short pad of hydrous magnesium silicate. The eluate was refluxed with the gradual addition of hexane to the point of turbidity. Cooling and filtration gave 35.2 g of the desired compound, mp 117°-125° C.
Reaction SMILES: C[O:2][C:3]1[CH2:21][CH2:20][C@@:19]2(C)[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2C=C)[CH:4]=1.O.O.C(O)(=O)C(O)=O>CC(C)=O>[CH3:23][C@:15]12[CH2:16][CH2:17][C@H:18]3[C@@H:8]([CH2:7][CH2:6][C:5]4[CH2:4][C:3](=[O:2])[CH2:21][CH2:20][C:19]=43)[C@@H:9]1[CH2:10][CH:11]=[CH:12]2
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)=O
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=C(CCC(=O)C3)[C@H]1CC2
Reaction time: 6 h
Yield: 75.5 %

Procedure:
Estra-2,5(10), 16-triene-3-methyl ether (2) (646.3 mg, 2.390 mmole), dissolved in 50 ml of acetone was hydrolyzed for 6 h at room temperature using oxalic acid dihydrate (0.84 g, 6.7 mmole). The reaction mixture was quenched with 25 ml of saturated sodium bicarbonate and then extracted twice with 25 ml portions of ethyl acetate. The combined organic extracts were washed twice with 25 ml of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane to give product (462.5 mg, 1.804 mmole, 75%), m.p. 112-116 C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]3C(=O)C4=CC=CC=C4C3=O)=[N:8][C:7]=2[CH:28]=1.O.NN>C(O)C>[NH2:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:28][C:7]=2[N:8]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
To a mixture of 0.41 g of N-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}phthalimide and 5 ml of ethanol, 0.3 ml of hydrazine monohydrate was added and stirred at room temperature for 1.5 hours. To the reaction mixture, ethanol was added and filtrated, and the filtrate was concentrated. The residue was diluted with ethyl acetate, and washed with water and then with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 2-(3-aminopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 52”).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH3:19][C:20]([SH:23])([CH3:22])[CH3:21].CN(C=O)C.CC(C)([O-])C.[Na+]>C1COCC1.CC(OC)(C)C>[C:20]([S:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16])([CH3:22])([CH3:21])[CH3:19]
Reactant: Cc1cc(-c2ccc(F)c(C(F)(F)F)c2)ccn1
Reactant: CC(C)(C)S
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(SC(C)(C)C)c(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Reaction time: 17 h
Yield: 100.6 %

Procedure:
To a solution of 4-(4-Fluoro-3-trifluoromethyl-phenyl)-2-methyl-pyridine (51.0 g, ˜200 mmol) in THF (100 mL) were carefully added at room temperature 2-methyl-2-propanethiol (23.5 g, 260 mmol) and DMF (29.2 g, 400 mmol). Sodium-tert-butoxide solution 25% in THF (96.1 g=106 mL, 250 mmol, Chemetall) was added over 50 min and the beige suspension was stirred at 50° C. for 17 h. The brownish suspension was transferred into a separatory funnel, filled with TBME (500 mL), and washed with water (500 mL) and with 10% brine (500 mL). The two aqueous layers were extracted with TBME (300 mL) and the combined organic layers were dried (Na2SO4). Filtration and evaporation (45° C./≧10 mbar) afforded crude title product (65.5 g, 100.6%) as a brown oil which was used without purification in the next step. 1H NMR (CDCl3, 400 MHz) δ 1.39 (s, 9H), 2.65 (s, 3H), 7.33 (d, J=5.1 Hz, 1H), 7.39 (s, 1H), 7.73 (dd, J1=8.1 Hz, J2=1.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.96 (d, J=1.9, 1H), 8.60 (d, J=5.4, 1H). ESI-MS (m/z) [M+H]+326 (100).
Reaction SMILES: C[O:2][C:3]([C:5]1([N:14]([CH3:27])[C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:12][N:11]([CH3:13])[N:8]1[CH2:7][CH2:6][C:5]2([N:14]([CH3:27])[C:15](=[O:26])[CH:16]([C:17]3[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:3]2=[O:2])[CH2:10][CH2:9]1
Reactant: COC(=O)C1(N(C)C(=O)Cc2c(C)cc(C)cc2C)CCN(N(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C2C(=O)N(C)C3(CCN(N(C)C)CC3)C2=O)c(C)c1
Temperature: 3 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
750 mg 1-Dimethylamino-4-{methyl-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (from Step 3) is dissolved in 35 ml N,N-dimethylformamide, cooled in an ice bath to 3° C., and 672 mg potassium t-butoxide is added. The mixture is allowed to warm to room temperature and stirred for 18 hours. Then half saturated aqueous ammonium chloride solution is added, and the pH adjusted to 5.5 by the addition of aqueous hydrochloric acid. The mixture is extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated. The residue is purified by chromatography on silica gel, with ethyl acetate as a solvent. Thus, 210 mg 8-Dimethylamino-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione is obtained as a solid, mp>195° C. 1H-NMR (CDCl3): 6.86 ppm (s, 2H), 3.12 ppm (m, 2H), 2.86 ppm (s, 3H), 2.84 ppm (m, 2H), 2.42 ppm (s, 6H), 2.30 ppm (m, 2H), 2.23 ppm (s, 3H), 2.17 ppm (s, 6H), 1.85 ppm (m, 2H).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(C(C)C)CC)(C)C.Cl[C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]>CN(C)C=O>[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15](=[O:16])[NH:4][CH2:1][C:2]#[CH:3])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of propargylamine (250 μL, 3.645 mmol) in diisopropylethylamine (1.273 mL, 7.290 mmol), was added 9-fluorenylmethyl chloroformate (Fmoc), dissolved in 7 mL dimethylformamide. The mixture was stirred under argon overnight at room temperature. After completion, the solution was reduced in vacuo. An ethyl acetate/water extraction procedure was performed to isolate the product; MS: 278.10 (m/z).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH:28]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@@H:29]([C:31](O)=[O:32])[CH3:30]>CN(C=O)C.CCOC(C)=O>[NH:28]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C@@H:29]([C:31]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:32])[CH3:30]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)N[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O

Procedure:
2.69 Grams (5 m moles) of H-Phe-Arg(NO2)-CHA.HCl was dissolved in 10 ml of 1.5N-NEM/DMF, to this solution was added 1.73 g (5 m moles) of Z-D-Ala-SDP at 0° to 5° C., the reacted at room temperature for 18 hours. After the reaction was completed, the reaction mixture was diluted with 150 ml of AcOEt, the washed 3 times with 50 ml of cold 5%-hydrochloric acid and washed twice with 50 ml of an aqueous solution saturated with sodium chloride, then decolored and dried with activated carbon and anhydrous magnesium sulfate. After the drying, magnesium sulfate and activated carbon were removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure to obtain crude product of Z-D-Ala-Phe-Arg(NO2)-CHA, recrystallized from MeOH/AcOEt/n-hexane to obtain 2.8 g (80.0%) of Z-D-Ala-Phe-Arg(NO2)-CHA.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:29][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:3])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CC(C)CCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)CCNC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and isoamylamine (39.5 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3-methylbutyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.3 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH2:66]([O:68][CH2:69][CH2:70][NH2:71])[CH3:67]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:71][CH2:70][CH2:69][O:68][CH2:66][CH3:67])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCOCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.30 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.013 g (0.15 mmole) 2-Ethoxy-ethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 100:0-20:80) to give 0.040 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-ethoxy-ethyl)-3-methoxy-benzamide (I-40) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]4[C:17]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:18][O:19][C:20]=4[CH3:21])[C:11]3=[O:28])[C:9](=[O:29])[N:8]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:5]2=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]4[C:17]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:18][O:19][C:20]=4[CH3:21])[C:11]3=[O:28])[C:9](=[O:29])[N:8]([CH2:30][C:31]([OH:33])=[O:32])[C:5]2=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1CN1CCC2(C1=O)C(=O)N(CC(=O)OC(C)(C)C)c1ccc(Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1onc(-c2ccccc2)c1CN1CCC2(C1=O)C(=O)N(CC(=O)O)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
An ice-cold solution of tert-butyl [5-chloro-1′-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-2,2′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetate, intermediate 42 (80.00 mg; 0.15 mmol) in DCM (8.00 ml) was treated with trifluoroacetic acid (2.00 ml). After stirring at room temperature for 5 h, the solvents were removed in vacuo. Toluene was added twice and removed in vacuo to give the titla compound as a white solid in 91% yield (96.3% purity by HPLC). MS (ESI+): 466.3; MS (ESI−): 464.4
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH3:15])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2ccc(Br)cc2)cc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(-c2ccc(Br)cc2)nn1C
Yield: 22.4 %

Procedure:
A mixture of 3-(4-bromophenyl)-5-hydroxy-1-methylpyrazole (2.5 g), acetone (200 ml), potassium carbonate (1.6 g) and methyl iodide (1.4 g) was heated at reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate/toluene as eluent to give 3-(4-bromophenyl)-5-methoxy-1-methypyrazole (590 mg) as a solid, m.p. 71°-73° C.; NMR: 3.6(3H,s), 3.9(3H,s), 6.2(1H,s), 7.5-7.6(2H,d) and 7.6-7.7(2H,d).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH-:41])=[CH:35][CH:34]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:5])[OH:10].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH-:41])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1ccc(CC[NH-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
Fmoc-Asp(OtBu)-2-(4-methoxyphenyl)ethyl amide (5.44 g; 10 mmoles) was treated with 50% TFA/CH2Cl2 for 90 minutes at room temperature. The solvent was evaporated and the residue was triturated with ethyl ether/petroleum ether. The precipitate was dried and used without further purification.