Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH3:10].[CH:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]=1[O:9][CH3:10]
Reactant: CCCCCCC=O
Reactant: COc1c(Br)cccc1Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCC(O)c1cccc(Br)c1OC
Temperature: 40 °C
Yield: 79 %

Procedure:
To a THF solution of 2,6-dibromoanisole (10 g, 37.6 mmol) was added Mg (0.90 g, 37.6 mmol), and the mixture was heated and stirred at 40° C. Under ice-cooling, n-heptanal (47.2 g, 41.3 mmol) was added dropwise. Aqueous hydrochloric acid solution was added to the reaction mixture, this was extracted with ethyl acetate, and the solvent was distilled off to obtain 8.95 g of a compound (1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[S:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:18]4[CH:19]=[CH:20][S:16][CH:17]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])=[CH:5][CH:6]=1
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)cs1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Yield: 13 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(3-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, followed by methanol:ethyl acetate=1:9) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 38.4 mg (13.0%) of the desired product as a solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11].[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C@H:9]([NH:8][C:45](=[O:46])[C@@H:44]([NH:43][C:41](=[O:42])[O:40][C:36]([CH3:38])([CH3:37])[CH3:39])[CH3:48])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C@@:16]2([CH3:19])[CH2:18][O:17]2)=[O:15])=[O:11])=[CH:33][CH:32]=1
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To (S)-2-amino-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (2.07 mmol) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (782 mg, 4.14 mmol), HATU (1.82 g, 4.77 mmol), and DMF (7 mL). The mixture was cooled to 0° C. and DIEA (3.54 mL, 20.7 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-80% ethyl acetate/heptane) provided tert-butyl ((S)-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (897 mg, 89%) as a colorless solid. MS (EI) for C26H37N3O6, found 488.4 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][C:8]1([CH2:21][NH2:22])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)CC)C.O1CCCC1>C(OCC)C>[CH3:1][N:2]([CH3:6])[C:3]([NH:22][CH2:21][C:8]1([CH3:7])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
Dimethylcarbamic chloride (3.95 g) is added to a solution at 0° C. of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine (7.9 g, described in Example 3), triethylamine (3.7 g) and tetrahydrofuran (200 ml) over a period of 5 minutes. The mixture is stirred at 0° to 5° C. for 30 minutes and at 25° C. for 18 hours. Diethyl ether (200 ml) is added, the mixture is filtered and the filtrate is evaporated. The residue is crystallized from diethyl ether to obtain the title compound (9.0 g); mp 153°-155° C.; ir (CHCl3) 3450-3250 and 1635 cm-1 ; nmr(CDCl3) δ1.51(s) and 2.69(m).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13]>C(O)(=O)C>[CH3:9][C:10]1[CH:11]=[C:12]([CH3:13])[N:6]2[N:5]=[C:4]([CH2:7][OH:8])[N:3]=[C:2]2[N:1]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (9.5 g, 50 mmol) from Step 1 above in acetic acid (200 mL) was added 2,4-pentanedione (5.13 mL, 50 mmol). The mixture was heated to reflux for 4 hours, and then cooled to room temperature. The product was isolated by removing the solvent by rotary evaporation (8.5 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN(CCO)CCO)ccc21
Yield: 63.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (37.6 mg, 0.0922 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with diethanolamine (0.035 mL, 0.37 mmol), acetic acid (0.106 mL, 1.85 mmol) and sodium triacetoxyborohydride (98 mg, 0.46 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[di(2-hydroxyethyl)aminomethyl]indol-2-yl)isoindolinone (29.2 mg, yield 64%).
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12]1>C1COCC1>[CH:20]1([NH:19][C:18](=[O:10])[NH:17][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 13 (52 mg, 0.058 mmol), HOBT (10 mg, 0.065 mmol) and DCC (16mg, 0.079 mmol) in THF (2 ml) was stirred for 1 hour at room temperature and filtered to remove resulting dicyclohexyl urea. The filtrate was concentrated and the residue was dissolved in 1 ml of 50% aqueous dioxane. To the mixture was added a solution of D-3,4-dihydroxyphenylalanine (D-DOPA) (24 mg, 0.12 mmol) and triethylamine (20 μl, 0.14 mmol) in 1 ml of 50% aqueous dioxane. The mixture was stirred for 1 day at room temperature and then dioxane was removed under reduced pressure. To the residue was added 50 ml of H2O and the mixture was acidified with 1N HC1 to pH 2. The precipitate formed was collected by filtration and chromatographed on a column of C-18 silica gel (Bondpak C18, 20 i.d. ×200 mm). The column was eluted with 30-40% acetonitrile-1/1000N HC1 and the desired fraction was concentrated and lyophilized to give 4'N-CBZ protected title compound (23 mg, yield 37%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>CN(C)C=O>[NH2:12][C:11]1[N:3]=[CH:4][N:5]=[C:6]2[C:10]=1[N:9]=[CH:8][N:7]2[CH:14]=[CH:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2C=CCCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
3.4 g of sodium hydride were added to 9.6 g of adenine in 270 ml of dimethylformamide and the mixture was stirred for 2 hours and 30 minutes. 20 g of N-(4-bromobutyl)-phthalimide were added and the mixture was stirred at ambient temperature for 74 hours, followed by filtering. The solvent of the filtrate was evaporated and the precipitate was washed with ether, with water, with ethanol, then again with ether and dried. The residue was dissolved in methanol at 65° C. and chilled to obtain 15.00 g of the expected product.
Reaction SMILES: COC(C1CC(=O)[N:7](C2C=CC(O)=CC=2)[CH2:6]1)=O.FC1C=C(F)C(F)=CC=1CBr.C[O:30][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[CH:52]=[C:51]([F:53])[C:50]([F:54])=[CH:49][C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=O>>[CH3:6][NH2:7].[CH3:6][NH:7][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[CH:52]=[C:51]([F:53])[C:50]([F:54])=[CH:49][C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=[O:30]
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cc(F)c(F)cc3F)cc2)C1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: Fc1cc(F)c(CBr)cc1F
Product: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cc(F)c(F)cc3F)cc2)C1

Procedure:
The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 2,4,5-trifluorobenzyl bromide giving the (RS)-5-oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a white solid (83% of theory) which, thereupon, by treatment with methylamine yields the (RS)-5-oxo-1-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide as a light yellow solid; MS: m/e=379 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH:42][C:43](N1C=CN=C1)=[O:44]>CN(C=O)C.[Cl-].[Na+].O>[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH:42][C:43]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:44]
Reactant: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCNCC2)c(C)c1
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a warm (70° C.), stirred, solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidin-4-yl-amine (0.101 g, 0.28 mmol) and DIPEA (0.29 mL, 1.67 mmol) in DMF (3 mL) was added freshly prepared imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1 hour, the mixture was cooled to room temperature, diluted with brine (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were washed with water (5×10 mL), dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 102 mg (75%) of COMPOUND 274 as a white solid. 1H NMR (CDCl3) δ 1.60-1.79 (m, 2H), 1.96-2.03 (m, 5H), 2.27 (s, 3H), 2.66-2.75 (m, 3H), 3.85 (s, 2H), 4.26-4.30 (m, 4H), 6.69 (s, 2H), 7.22-7.26 (m, 2H), 7.32-7.37 (m, 1H), 7.53-7.62 (m, 2H), 7.75 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=8.7 Hz), 8.18 (s, 1H), 8.40 (d, 1H, J=6.0 Hz); 13C NMR (CDCl3) δ 18.32, 18.49, 27.57, 44.75, 54.92, 55.42, 58.07, 120.85, 126.62, 126.77, 127.23, 128.09, 130.13, 132.31, 133.26, 136.67, 139.17, 141.76, 145.51, 146.85, 154.35, 155.80, 159.42; ES-MS m/z 470 (M+H). Anal. Calcd. For C27H31N7O.1.0H2O: C, 66.51; H, 6.82; N, 20.11. Found: C, 66.34; H, 6.68; N, 19.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chlorophenyl boronic acid (1.08 g, 6.97 mmol) and 3-methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester (0.9 g, 3.48 mmol) were dissolved in dichloromethane. To this mixture was added copper acetate (0.63 g, 3.48 mmol), 4 Å molecular sieves and pyridine (0.56 mL, 6.97 mmol) and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo and dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%). ESI-MS m/z: 369 (M+1), UV retention time: 2.97 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[OH:18])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[O:18][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(F)cc1O
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Oc1cc(F)ccc1C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenyl)-1-(4-fluoro-2-hydroxy-phenyl)-ethanone (16.0 g, 60.6 mmol) in CH2Cl2 (300 ml) is added triethylamine (7.4 g, 72.7 mmol). A solution of isobutyryl chloride (7.1 g, 66.6 mmol) in CH2Cl2 (100 ml) is added slowly over 30 min. The reaction mixture is stirred at room temperature for 2 h. The organic phase is washed with 0.5 M HCl, water and brine and dried (MgSO4). The solvent is removed in vacuo, and the product is purified by flash chromatography on silica gel using iso-hexane:ethyl acetate (20:1 to 10:1) as the eluent to give the title compound.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:40])[C@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([C@H:29]([N:28]([CH3:40])[CH3:27])[CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CN(C)[C@H](Cc1ccccc1)C(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc([C@@H](Cc3ccccc3)N(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2R)-2-(dimethylamino)-3-phenylpropanoic acid, the title compound was obtained in 54% purity by HPLC. MS(ESI+): m/z=510.6.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-:18])(=O)=[O:16])=[CH:11][CH:10]=2)[CH2:5]CC[CH2:2]1.[Na+].S(Cl)([Cl:22])=O>CN(C)C=O>[CH3:2][CH:1]([CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([Cl:22])(=[O:18])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCCC2CCCC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(S(=O)(=O)Cl)cc1

Procedure:
A mixture of sodium 4(2-cyclopentylethoxy)-benzenesulfonate (2.5 grams, 8.6 mmole), thionyl chloride (15 mL), and a few drops of N,N-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the titled compound as an oil, 2.24 grams (90%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]23[N:16]([CH2:17][CH:18]=[CH2:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH:10]3[OH:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br.C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH2:26][O:20][C@H:10]2[CH2:11][CH2:12][C@H:13]3[N:16]([CH2:17][CH:18]=[CH2:19])[C@:9]2([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]3)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: C=CCN1C2CCC(O)C1(c1ccccc1)CC2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1[C@@H]2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% in oil, 67 mg, 1.67 mmol) was washed twice with THF and treated with a solution 1S,2S,5S)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 57; 116 mg, 0.47 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (430 mg, 1.4 mmol), 18-crown-6 (33 mg, 1.25 mmol) in THF (2 ml). The reaction mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C(#N)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CNCCN(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)CCN(C)CC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
A solution of N,N,N′-trimethylethylenediamine (899 mg, Tokyo Kasei Kogyo) in acetonitrile (31 ml) was cooled to 0° C., added with potassium carbonate (2.21 g, and then slowly added dropwise with tert-butyl bromoacetate (1.56 g, Wako Pure Chemical Industries), and the mixture was stirred at the same temperature for 12 hours. The reaction mixture was added with ethyl acetate, and the insoluble solids were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (methanol:chloroform=1:10) to obtain the title compound (1.25 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:24]=1.[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=5[F:25])=[CH:24][C:6]=4[N:7]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH3:23]
Reactant: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4o3)CC2)nc1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Product: CCc1cnc(N2CCC(c3nc4cc(-c5ccc(S(C)(=O)=O)cc5F)ccc4o3)CC2)nc1
Yield: 29.7 %

Procedure:
Following the General Procedure-1, the titled compound (30 mg) was prepared from Intermediate 6 (80 mg, 0.21 mmol) and Intermediate 3 (80 mg, 0.27 mmol) as an off-white solid. M.P.: 247-250° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.20 (s, 2H), 7.86 (s, 1H), 7.80 (m, 1H), 7.79-7.74 (m, 1H), 7.66 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.75 (d, J 13.4, 2H), 3.35-3.15 (m, 3H), 3.11 (s, 3H), 2.47 (q, J 7.6, 2H), 2.31-2.22 (m, 2H), 2.09-1.94 (m, 2H), 1.20 (t, J 7.6, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([OH:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>ClC1C=CC=CC=1>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:22]1[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:20]([F:19])[CH:21]=1)#[N:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Solvent: Clc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc([N+](=O)[O-])c(F)c3)c2cc1C#N
Yield: 62.5 %

Procedure:
4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline (1.7 g) and 3-fluoro-4-nitrophenol (2.0 g) were suspended in chlorobenzene (20 ml), and the suspension was heated to reflux for 6 hours. After completion of the reaction, the solvent was distilled off, ethyl acetate was added, and a solid precipitated. The solid was filtered out and washed with ether, washed with 1N sodium hydroxide water and with water, and then dried to obtain 1.55 g of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=[C:16](OC)[NH:17][C:18]=2[CH3:19])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[NH4+:39].[NH4+].C([O-])(=O)C.[NH4+]>C(O)C.C(OCC)(=O)C>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=[C:16]([NH2:39])[NH:17][C:18]=2[CH3:19])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC1=NC(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N=C(N)N1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
111 mg (0.234 mmol) of 4-(3-chlorophenyl)-2-methoxyl-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid (3,3-diphenylpropyl)amide was dissolved in 5 ml of ethanol. 67.4 mg (0.702 mmol) of ammonium carbonate and 11.8 mg (0.187 mmol) of ammonium acetate were added to the obtained solution, and they were stirred at 80° C. for 2 days. The reaction mixture was diluted with ethyl acetate. An insoluble matter thus formed was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (100% dichloromethane) to obtain the title compound.