Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH2:37])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH:37][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NNC(=O)N1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
Morpholine-4-carbonyl chloride (297 mg, 1.99 mmol) was added dropwise over a period of 10 minutes to a solution of DMAP (24 mg, 0.199 mmol) and pyridine (0.16 mL, 1.99 mmol) in dry DCM (5 mL). The mixture was stirred at 0° C. for 20 minutes then, a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide hydrochloride (0.65 g, 1.99 mmol) in dry DCM (2.0 mL) was added over a period of 10 minutes. The mixture was stirred at 0° C. for 15 min and was then allowed to warm to rt and was stirred overnight. The reaction mixture was diluted with DCM (10 mL), and washed with 1N HCl (10 mL), and saturated sodium chloride (10 mL), then was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (0 to 1:100 MeOH/DCM, containing 1% TEA) to give N′-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)morpholine-4-carbohydrazide (0.38 g, 47%) as a white solid. ESI-MS (EI+, m/z): 404.19 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+:25].[Na+]>CC(C)=O.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[Na+:25]
Reactant: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.6 %

Procedure:
(2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]-carbamoyl]oxirane-2-carboxylic acid (48.59 g) was dissolved in acetone (245 mL), and sodium carbonate (8.51 g) dissolved in water (32.9 mL) was slowly added. The solution was stirred at room temperature to 50° C. for three hours until the deposited inorganic salt was dissolved. While the temperature was kept, acetone (200 mL) was dropped and a seed crystal was placed in the solution, and then the solution was stirred for 30 minutes. Acetone (510 mL) was again dropped, and the solution was stirred for 1 hour while the temperature was kept. While the solution was gradually cooled to room temperature, it was stirred overnight. The precipitated crystalline product was collected by filtration, washed with a mixture of 3% water-acetone (70 mL), dried in air to obtain white solid sodium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (46.1 g, 87.9%). The NMR data of the solid product were the same as those in Example 9.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2c(F)cccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)-1,3-difluorobenzene (0.56 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.40 g, 55%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1CCN2C(=NCCC2)CC1.[O:21]1CCOC[CH2:22]1>>[O:21]=[C:22]1[O:1][N:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:9]1
Reactant: CCOC(=O)C(=N)NO
Reactant: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1noc(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(hydroxyamino)-2-iminoacetate (2 g, 15.14 mmol) in dioxane (15.00 mL) is added CDl (2.7 g, 16.65 mmol) and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring for 1 hour at 80° C., the reaction is quenched with 1N HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g). HPLC retention time=0.72 minutes (condition B); MS 159.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:23])=[O:22])[CH:16]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C[C@H](NC(=O)c3cccc(-c4ccc(OC)cc4)c3)C(=O)O)cc2)cc1
Yield: 85 %

Procedure:
(2S)-(3-Bromo-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid methyl ester (100 mg, 0.22 mmol) was reacted with 4-methoxy-phenyl-boronic acid (204 mg, 1.4 mmol) according to general procedure D yielding the title compound (90 mg, 83%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]([CH:12]([OH:15])[C:13]#[N:14])[CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=1)[CH3:2].[CH3:17][OH:18].[ClH:19]>C(OCC)C.O1CCOCC1>[ClH:19].[CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]([CH:12]([OH:15])[C:13](=[NH:14])[O:18][CH3:17])[CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(CC)cc(C(O)C#N)c1F
Reactant: CO
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOc1cc(CC)cc(C(O)C(=N)OC)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 118E (630 mg, 2.93 mmol) in anhydrous diethyl ether (10 mL) at 0° C. was added MeOH (1.2 mL) and 4.0 N HCl in dioxane (2.9 mL). The mixture was stirred at 0° C. for 30 min and then at rt over night. Solvent was removed to give methyl 2-(3-ethoxy-5-ethyl-2-fluorophenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (5.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude was purified by column chromatography to give 118F (632 mg, 89% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (t, J=7.69 Hz, 3H) 1.43 (t, J=7.03 Hz, 3H) 2.58 (q, J=7.76 Hz, 2H) 3.76 (s, 3H) 4.04-4.13 (m, 2H) 5.37 (s, 1H) 6.68-6.81 (m, 2H).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18][CH:17]=2)[CH2:12][C:11]1([F:52])[F:51])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][C:19]1[C:20]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:35])[CH:23]=2)=[N:21][C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]([F:51])([F:52])[CH2:12]2)=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(OC(=O)c4ccccc4)C(F)(F)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2CCC(OC(=O)c3ccccc3)C(F)(F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(6-(4-(benzoyloxy)-3,3-difluorocyclohexyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)-2-fluorobenzoate (670 mg, 0.921 mmol) in DCM (12 mL) at RT was added TFA (4.96 mL, 64.4 mmol). The resultant mixture was stirred at RT for 2 hours. The mixture was concentrated, diluted with EtOAc, neutralized with NaHCO3 twice, then brine, the organic layer was separated, dried and concentrated to afford the crude product, which was used at the next step directly. (434 mg, 0.921 mmol, 100% yield). LC-MS (m/z): (MH+) 472.1, at 0.942 min. 1H NMR (400 MHz, DMSO) 6 ppm: 1.07 (t, J=7.04 Hz, 2H) 1.83 (t, J=10.17 Hz, 2H) 2.16 (d, J=5.09 Hz, 1H) 2.29-2.45 (m, 2H) 3.02 (br. s., 1H) 3.16-3.44 (m, 9H) 5.22-5.52 (m, 1H) 5.73 (s, 1H) 6.24 (s, 2H) 7.44-7.75 (m, 5H) 7.89 (t, J=7.83 Hz, 1H) 7.94-8.07 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CO>N1CCCC1>[C:11]([N:18]1[CH2:19][CH2:20][C:21]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
The examples listed in Table 1 were prepared according to Schemes 1-37. The synthesis of compounds 1A-1U is outlined in Scheme 1. The 2′-hydroxyacetophenone derivatives 1.1a-1.1m were condensed with 1-Boc-4-piperidone 1.2 in neat pyrrolidine (method 1A) at room temperature or in refluxing methanol in the presence of pyrrolidine (method 1B) to provide N-Boc-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one derivatives 1.3. Conversion of the ketones 1.3 to the enol triflate derivatives 1.5 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Suzuki type coupling of the enol triflate derivatives 1.5 with either 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 (commercially available from Combi-Blocks Inc.) or 2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0) (method 1C) or palladium, 10 wt. % (dry basis) on activated carbon (method 1D), lithium chloride, and an aqueous solution of sodium carbonate afforded compounds 1.8 which were converted to the final products (compounds 1A-1T) under acidic conditions (method 1E: anhydrous HCl, diethyl ether, room temperature or method 1F: neat trifluoroacetic acid, room temperature). Demethylation of compound 1G using boron tribromide provided the corresponding phenolic derivative (compound 1U). The boronate derivative 1.7 was prepared in 4 steps from 2,5-dibromopyridine 1.9. Treatment of 2,5-dibromopyridine with n-butyllithium provided the corresponding lithiated derivative, which reacted with carbon dioxide to provide 5-bromopyridine-2-carboxylic acid 1.10. Treatment of the carboxylic acid derivative 1.10 with oxalyl chloride furnished the acyl chloride 1.11, which reacted with diethylamine 1.12 to provide 5-bromo-2-(N,N-diethylaminocarbonyl)-pyridine 1.13. Conversion of the aryl bromide 1.13 to the corresponding boron derivative 1.7 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2].
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH2:9]([NH2:15])[CH2:10][O:11][CH2:12][CH2:13][OH:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:15]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[CH3:6]
Reactant: CC(=O)CCC(C)=O
Reactant: NCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1CCOCCO
Yield: 90.2 %

Procedure:
A solution of 0.95 moles of 2,5-hexanedione, 0.95 mole of diglycolamine, and 1.4 g of p-toluenesulfonic acid in 400 ml of toluene was refluxed in a flask fitted with a Dean-Stark trap. After removal of the required amount of water, distillation yielded 157 g of N-(hydroxyethoxyethyl)-2,5-dimethylpyrrole with b.p.=110° C. at 13 mm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCOCC2)ccc1Br
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-3-methylbenzoic acid (5.00 g) in dry THF (60 ml) was added dropwise at -5° to +5° to 1,1'-carbonylbis[1H-imidazole](4.90 g) and stirred under nitrogen over 10 min. Stirring was continued at +23° for 4 h, and morpholine (6.1 ml) added dropwise over 1 min. After 16 h the solution was evaporated, treated with aqueous 2M hydrochloric acid (80 ml), and extracted with ethyl acetate (4×75 ml). The combined, dried organic extracts were washed with aqueous saturated sodium bicarbonate (100 ml), dried and evaporated. A solution of the residual oil in dichloromethane (60 ml) was adsorbed onto silica gel (Merck 7734) and the mixture applied as a plug to a flash column of silica gel (Merck 9385). Gradient elution with ethyl acetate:hexane (3:7→6:4) afforded the title compound as a cream solid (5.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[NH2:18].[C:19](Cl)(Cl)=[S:20]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[N:18]=[C:19]=[S:20]
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a solution of 4.8 g of 5-(4-chloro-3-aminophenyl)-3-(2-furyl)-1,2,4-oxadiazole in 400 ml of tetrahydrofuran, 5 ml of triethylamine and 2.1 g of thiophosgene are added. After stirring at room temperature for 4 hours, the reaction mixture is filtered and evaporated to dryness in vacuo. The residue is crystallized from petroleum ether to yield 1.5 g (27%) of the title product, m.p. 131°-132°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)CN
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)CNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and isobutylamine (37 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile] to give an anti-form compound (8 mg) and a syn-form compound (6 mg).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:28])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>ClCCl>[CH:1]1([C:6]2[C:7]([O:28][C:37]([O:39][CH3:40])=[O:38])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
Tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (596 mg, 1.53 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (388 mg, 535 μL, 3.84 mmol) then treated dropwise with methyl chloroformate (178 μL, 2.301 mmol). The reaction was stirred for 5 min at room temperature and then concentrated in vacuo to tert-butyl 4-(5-cyclopentyl-4-(methoxycarbonyloxy)-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (680 mg, 99% yield). The material was used without purification. LC/MS m/z 447.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([N:19]=[C:20]=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: CCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 65.7 %

Procedure:
4-fluoro-2-nitroaniline (1.56 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) were stirred in toluene (5 ml) at 80°-90 C. for 5 hrs. This solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous MgSO4, and the solvent was distilled off. The resulted crystals were washed with hexane to give 1-(4-fluoro-2-nitrophenyl)-3-heptylurea (1.95 g, 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:31]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (21.4 mg, 0.078 mmol) in CH2Cl2 (2 mL) was added 2,4-difluorophenyl isocyanate (0.10 μL, 0.084 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 124 as a colorless solid (30.2 mg, 73%). LCMS m/z (%)=430 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.94 (bs, 1H), 8.46 (bs, 1H), 8.09-8.00 (m, 1H), 7.45 (d, J=1.80 Hz, 1H), 7.42 (dd, J=8.89, 2.72 Hz, 1H), 7.34-7.26 (m, 1H), 7.09 (d, J=8.94 Hz, 1H), 7.06-6.99 (m, 1H), 6.24 (d, J=1.83 Hz, 1), 3.97 (t, J=6.32 Hz, 2H), 3.65 (s, 3H), 2.23 (t, J=7.07 Hz, 2H), 2.10 (s, 6H), 1.78-1.69 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:26]([NH:25][CH3:23])=[O:27])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CNC(=O)NCCSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Reaction time: 8 h

Procedure:
62.2 mg (0.2 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile are suspended in 0.4 ml of DMF, and 14.2 mg (0.2 mmol) of ethyl isocyanate are added at room temperature. The mixture is stirred overnight, filtered and purified by preparative HPLC.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][C:5]1[S:6][C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][C@@H:25]4[CH2:27][O:26]4)=[C:18]([CH2:28][CH3:29])[CH:17]=3)[N:12]=2)=[CH:8][C:9]=1[CH3:10])[CH3:2].Cl.C[O:34][C:35]([CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:36]>>[CH2:1]([N:3]([CH2:4][C:5]1[S:6][C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][C@@H:25]([OH:26])[CH2:27][N:39]4[CH2:40][CH2:41][CH:37]([C:35]([OH:34])=[O:36])[CH2:38]4)=[C:18]([CH2:28][CH3:29])[CH:17]=3)[N:12]=2)=[CH:8][C:9]=1[CH3:10])[CH2:30][CH3:31])[CH3:2]
Reactant: COC(=O)C1CCNC1
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H]1CO1
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H](O)CN1CCC(C(=O)O)C1

Procedure:
The title compound is prepared starting from diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (30 mg, 68 μmol) and rac-pyrrolidine-3-carboxylic acid methyl ester hydrochloride (56 mg, 340 μmol) in analogy to Example 203; LC-MS*: tR=0.76 min; [M+1]+=557.17; 1H NMR (D6-DMSO): δ 1.03 (t, J=7.0 Hz, 6H), 1.21 (t, J=7.5 Hz, 3H), 1.90-1.98 (m, 2H), 2.22 (s, 3H), 2.34 (s, 3H), 2.43-2.49 (m, 1H), 2.58 (q, J=7.0 Hz, 4H), 2.67-2.77 (m, 5H), 2.80-2.95 (m, 2H), 3.73 (s, 2H), 3.74-3.77 (m, 1H), 3.78-3.84 (m, 2H), 3.91-3.98 (m, 1H), 7.72 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:16][CH:9]2[CH2:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH2:12][CH:8]2[CH:7]1[CH2:17][O:18][CH3:19])=[O:4].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)C>[CH:13]([N:11]1[CH2:12][CH:8]2[CH:7]([CH2:17][O:18][CH3:19])[CH:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH2:16][CH:9]2[CH2:10]1)([CH3:14])[CH3:15]
Reactant: COCC1C(NC(=O)CN)CC2CN(C(C)C)CC21
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCC1C(NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)CC2CN(C(C)C)CC21

Procedure:
A mixture of 2-amino-N-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)acetamide, 4-chloro-6-trifluoromethylquinazoline (see Armarego et al., J. Chem. Soc. B, 1967, 449) and triethylamine in ethanol is heated at reflux until the reaction is complete. The solution is concentrated under vacuum yielding a residue. The residue is purified by reverse phase HPLC and lyophilization providing the title product.