Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[CH:6]=[C:5](Cl)[CH:4]=[C:3]([C:8]([O:10]O)=O)C=1.[C:12]([O:17]C(CC=C)C)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:12]([O:17][CH:5]([CH2:4][CH:3]1[O:10][CH2:8]1)[CH3:6])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=CCC(C)OC(=O)C(=C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)OC(C)CC1CO1
Temperature: 23 °C
Reaction time: 6 h
Yield: 61.5 %

Procedure:
A solution of m-CPBA (32 g) in chloroform (150 ml) was cooled in cold water and then 4-penten-2-yl methacrylate (14 g) was added. The mixture was stirred at 23° C. for 6 hours. The post-reaction mixture was then poured into dilute potassium carbonate (300 ml) and the organic layer was separated. The organic layer was washed with three more portions of carbonate, finally with water and then dried. Remaining solvents were then removed and the residue was subjected to chromatography on silica gel. As a result pure 4,5-epoxypent-2-yl methacrylate (9.5 g) was isolated.
Reaction SMILES: ClC1C=C([C@H]2OC(=O)N([C@H](C)C[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)C2)C=CC=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:22]1[C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=2[O:23][C:26]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: C[C@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccccc2O1

Procedure:
More specifically, the chiral synthesis may be carried out by performing the synthetic reaction sequence outlined in Scheme III. L-DOPA 19 is treated with di-t-butyl-dicarbonate in dimethylformamide, giving (S)-N-(1-(1,1-dimethylethoxy)carbonyl)-3-hydroxy-L-tyrosine 20 which is reacted with methyl iodide and anhydrous potassium carbonate in acetone, giving (S)-N-(1,1-dimethylethoxy)carbonyl)-3,4-dimethoxy-L-phenylalanine methyl ester 21 which is reduced with lithium borohydride giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1-(hydroxymethyl)ethyl)carbonate 22, which is reacted with methane sulfonyl chloride and triethylamine in methylene chloride, giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1(((methylsulfonyl) oxy)methyl)ethyl)carbamate 23. Compound 23 is treated with trifluoroacetic acid and then is reduced using 10% Pd/C and hydrogen giving (R)-3,4-dimethoxy- -methylbenzeneethanamine 24. The compound 24 is treated with 3-chlorostyrene oxide 25 and N-(trimethylsilyl) acetamide giving a mixture of (R,S)- and (S,S)-3-chloro-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 26. Reaction of 26 with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by chromatographic separation of the diastereomers gives cyclized derivative 27, which is reacted with boron tribromide in dichloromethane, giving (R,R)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone 28. Compound 28 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R,R)-5-(2-5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3benzodioxole-2,2-dicarboxylic acid, diethyl ester 29. Compound 29 is reacted with 5N sodium hydroxide in ethanol and then isolated by reverse phase chromatography to give (R,R)-1,3-benzodioxole-2,2-dicarboxylic acid, 5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-, disodium salt 15.
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C[Si]([C:21]#[N:22])(C)C.CCCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[N:12]1([C:4]2([C:21]#[N:22])[CH2:5][CH2:6]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C[Si](C)(C)C#N
Reactant: C1CCNC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: N#CC1(N2CCCC2)CC1

Procedure:
The reaction of (1-ethoxycyclopropoxy)trimethylsilane 13 and pyrrolidine 14D with trimethylsilylcyanide yielded after column chromatography with a gradient of heptane/ethyl acetate (v:v 4:1) to ethyl acetate as solvent 1-(pyrrolidin-1-yl)cyclopropanecarbonitrile as a yellow oil (quant.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[CH:5]=[C:6]([OH:8])[CH:7]=1.[ClH:21].O1CCOCC1>C(Cl)Cl>[ClH:21].[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(O)cc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Oc1cc(F)cc([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
To a solution of (R)-tert-butyl 2-(3-fluoro-5-hydroxyphenyl)pyrrolidine-1-carboxylate (10.3 g, 36.5 mmol) in DCM (20 mL) was added 4N HCl in dioxane (36.5 mL, 146 mmol) and the mixture was stirred at ambient temperature for 15 hours. The resulting precipitate was filtered and washed with DCM to afford (R)-3-fluoro-5-(pyrrolidin-2-yl)phenol hydrochloride (5.81 g, 73.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.C1COCC1.[Cl:21]N1C(=O)CCC1=O>O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[C:11]([Cl:21])[C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a mixture of methyl((3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (10.4 g) and THF (20 mL) was added N-chlorosuccinimide (6.67 g). The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (8.8 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:25]([OH:27])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:32]1([NH:34][C:25]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:27])[CH2:33][CH2:31]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 189.2 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(2-phenylethyl)-1H-1,2,3-triazole-4-carboxylic acid (501 mg, 1.37 mmol) obtained in Example 98b), HOBt (93.8 mg, 0.687 mmol, 0.5 eq.) and cyclopropylamine (0.128 ml, 1.79 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 7.5 ml), WSC (323 mg, 1.65 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (40 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layer was each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (526 mg, 1.30 mmol, 95.2%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=[O:20]>>[N:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])=[CH:23][CH:24]=3)[CH2:29][CH2:30]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: ClCCCCCCn1ccc2ccccc21
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(6-chlorohexyl)-1H-indole and 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 446.3 (M+H)+.
Reaction SMILES: [C:1]1([CH:7](C)[C:8](O)=[O:9])C=CC=CC=1.Cl.C[O:14][C:15](=[O:33])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:32])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29].ON1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl.C(N(CC)CC)C>[C:38]1([CH2:1][CH2:7][C:8]([NH:29][C@H:28]([C:27]([N:23]2[CH2:24][CH2:25][CH2:26][C@H:22]2[C:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[C:15]([OH:14])=[O:33])=[O:32])=[O:31])[CH3:30])=[O:9])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: On1nnc2ccccc21
Reactant: CC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@H](NC(=O)CCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 538.9 %

Procedure:
Phenylpropionic acid (3 g, 20 m mole) was dissolved in 1,2-dichloroethane (80 ml), and while maintaining the solution at an internal temperature between 5 and 8° C., L-alanyl-L-prolyl-L-proline methyl ester hydrochloride (6.69g), triethyl amine (2.02 g, 20 m mole), 1-hydroxybenzotriazole (0.35 g, 3 m mole), and dicyclohexylcarbod iimide (4.12 g, 20 m mole) were added, and the thus obtained mixture was stirred for 4 hours. After that, it was stirred at room temperature overnight, and the precipitated dicyclohexyl urea crystals and triethyl amine hydrochloride crystals were filtered off and were washed with 1,2-dichloroethane (20 ml). The filtrate and the washing were mixed together, and the obtained mixture was washed with 0.5N hydrochloric acid (50 ml), water (80 ml), 0.5N aqueous sodium hydroxide (60 ml) and water (80 ml) in order, and the 1,2-dichloroethane phase was concentrated under reduced pressure To the obtained syrupy residue, water (50 ml) and 5N aqueous sodium hydroxide (5 ml) were added and the obtained mixture was stirred at room temperature for 2 hours. After completion of the saponification, the precipitated dicyclohexyl urea crystals were filtered off and washed with water (5 ml). The filtrate and the washings were mixed together, and the thus obtained mixture was adjusted to pH 2.5 with 6N hydrochloric acid and was extracted with 1,2-dichloroethane (100 ml). The 1,2-dichloroethane phase was washed with water (30 ml), and the 1,2-dichloroethane was distilled off therefrom under reduced pressure To the concentrated residue, carbon tetrachloride (30 ml) was added, and the obtained solution was concentrated under reduced pressure and ethyl ether (100 ml) was added thereto. The solution was changed slowly to a solid material while stirring. A solid material was obtained by filtration, and dried to obtain N-(3-phenylpropionyl)-L-alanyl-L-prolyl-L-proline (5.8 g).
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].Cl[CH2:32][C:33]#[CH:34].CN(C)C=O.[H-].[Na+]>O>[F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:34][C:33]#[CH:32])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1O
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
239 mg of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (0.572 mmol), 128 mg (1.72 mmol) of 3-chloropropyne, 3 ml of anhydrous N,N-dimethylformamide and 20 mg (0.50 mmol) of 60% sodium hydride were mixed and stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 225 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1268).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(C)(C)C.FC(F)(F)C(O)=O.C([N:43](CC)CC)C.C[Si](N=C=O)(C)C>C(Cl)Cl.CCOC(C)=O>[NH:7]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[C:6]([NH2:43])=[O:5]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[Si](C)(C)N=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
{3-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (26 mg, 0.058 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 1 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (3 mL), triethylamine (0.080 mL, 0.58 mmol), and trimethylsilyl isocyanate (0.050 mL, 0.29 mmol), and the resulting mixture was stirred for 16 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 9.3 mg of the title compound. MS: (+) m/z 418.31 (M+Na).
Reaction SMILES: [SH2:1].[C:2](O)([CH3:5])([CH3:4])[CH3:3]>>[C:2]([S:1][C:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])([CH3:4])[CH3:3]
Reactant: S
Reactant: CC(C)(C)O
Product: CC(C)(C)SC(C)(C)C

Procedure:
In a similar manner, ethanol and H2S may be reacted to produce diethyl sulfide, isopropanol and H2S may be reacted to produce di-isopropyl sulfide; tertiary-butanol may be reacted with H2S to produce di-tertiary-butyl sulfide; and octanol-1 may be reacted with H2S to produce di-n-octyl sulfide.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35]Br.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([F:40])=[C:32]([F:31])[CH:33]=3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(F)c(F)c2)c1=O
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 3,4-difluorobenzyl bromide (256 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (138 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s, 1 H), 10.12 (br. s., 1 H), 7.28-7.52 (m, 2 H), 7.05-7.23 (m, J=5.43, 3.16 Hz, 1 H), 4.96 (s, 2 H), 4.63 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.25 (q, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.63 (s, 3 H), 1.28 (q, J=12.97 Hz, 2 H), 1.11 (q, 1 H)
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].C(O)C.[Na].[CH3:16][SH:17]>CCOCC.O>[CH3:16][S:17][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11]
Reactant: O=C1c2ccccc2CC1Br
Reactant: CS
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CSC1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
After 10 g of 2-bromo-1-indanone was dissolved into 50 ml of ethanol, 25 ml of a 15% aqueous solution of a sodium salt of methylmercaptan was added dropwise thereto. After stirring for 3 hours at room temperature, the reaction mixture was poured into 300 ml of cold water. After 200 ml of ether was added thereto for extracting an organic phase, the ether layer was sequentially washed with an aqueous sodium chloride solution and water. After the ether layer was dried with magnesium sulfate, the ether was evaporated under vacuum. The residue was isolated and purified through a silica gel column (elute: hexane/ethyl acetate=7/1) to provide 3.2 g of 2-(methylthio)-1-indanone (yield: 38%).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH2:14])[CH3:13])=[CH:4][CH:3]=1.[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]([CH2:26][CH:27]=O)[CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][CH2:27][CH2:26][C@@H:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16](=[O:15])[CH2:17]2)[CH3:13])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(F)c2ccccc12
Reactant: O=CC[C@H]1CC(=O)c2ccccc2C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](NCC[C@H]1CC(=O)c2ccccc2C1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a stirred solution of (R)-1-(4-fluoronaphthalen-1-yl)ethanamine (1.206 g, 6.38 mmol) in methanol (5 mL) was added (S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetaldehyde (1.2 g, 6.38 mmol) at 0° C. Acetic acid (0.365 mL, 6.38 mmol) was added and reaction was stirred for 5 min. Reaction was warmed to RT and stirred for 20 min. Again reaction was cooled to 0° C. Sodium cyanoborohydride (0.401 g, 6.38 mmol) was added to the reaction mixture and stirred for overnight (16 h). To the reaction solution were added NaHCO3 solution (5 mL) and water (10 mL) and the mixture was extracted with ethyl acetate (20 mL×2). The extract was washed with saturated brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude title compound (2.0 g, 5.53 mmol, 87% yield).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])[CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 590.1 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (9.69 g, 41 mmol) in CH2Cl2 (40 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-3-((E)-2-nitro-vinyl)-benzene (0.68 g, 3.37 mmol) and trifluoroacetic acid (0.21 ml) in CH2Cl2 (40 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.30 g (73%) of the title compound as a colorless oil. ES-MS m/e: 317.1 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:30])(=[O:29])[C:14]=2[CH:31]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:32])[C:13]2[O:19][C:18]3[C:20]([Cl:28])=[CH:21][C:22]([NH:24][CH2:25][CH2:26][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:29])(=[O:30])[C:14]=2[CH:31]=1)=[O:9]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCn3ccnc3)cc(Cl)c1O2
Temperature: 110 °C

Procedure:
Imidazole (0.118 g, 1.73 mmol) was added in an atmosphere of nitrogen, to a solution of Example 56k (1.3 g, 2.63 mmol) in dry DMF (10 mL) with stirring. The reaction mixture was then maintained at 110° C. for 18 h. It was cooled, concentrated and the solid obtained was filtered washed with water, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.120 g, (22.38%); 1H NMR (DMSO-d6): δ 2.7 (s, 3H, CH3), 3.2 (t, 2H, CH2), 3.9 (s, 3H, OCH3), 4.1 (t, 2H, CH2), 5.2 (s, 2H, CH2), 6.4 (s, 1H, NH), 6.6 (s, 1H, Ar), 6.75 (s, 1H, Ar), 6.9 (s, 1H, Ar), 7.2 (s, 1H, Ar), 7.6 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.2 (s, 1H, Ar); MS: m/e (ES+) 462 (M+).
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][C:9]1[O:13][N:12]=[C:11]([CH2:14][NH2:15])[CH:10]=1.[F:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30](O)=[O:31])[C:23]2=[O:36])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30]([NH:15][CH2:14][C:11]3[CH:10]=[C:9]([CH3:8])[O:13][N:12]=3)=[O:31])[C:23]2=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cc1cc(CN)no1
Agent: NCc1cocn1
Product: Cc1cc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)no1
Yield: 55 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (5-methylisoxazol-3-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methylisoxazol-3-yl)methyl)isonicotinamide was obtained as a colorless solid in 55% yield: mp 153-155° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.37-7.35 (m, 1H), 7.28-7.23 (m, 2H), 7.07-6.99 (m, 3H), 6.01 (s, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.36 (t, J=8.1 Hz, 2H), 2.37 (s, 3H); MS (ES+) m/z 409.9 (M+1).