Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[O:6]([C:13]([NH:15][O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:6]([C:13]([N:15]([CH:3]([C:2]#[CH:1])[CH3:4])[O:16][C:17]([O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#CC(C)O
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a 0° C. solution in THF (200 mL) of 3-butyn-2-ol (3.00 g, 42.9 mmol), N,O-bis(phenoxycarbonyl)hydroxylamine (11.7 g, 42.9 mmol), prepared according to the method of Stewart and Brooks, J. Org. Chem. 1992, 57, 5020, and triphenylphosphine (11.7 g, 42.9 mmol), was added dropwise diethylazodicarboxylate (7.40 g, 42.8 mmol). The reaction mixture was stirred for 2 hours at 0°-5° C. and then was concentrated almost to dryness. The residue was diluted with ethyl acetate, the solids were filtered off, and the filtrate was concentrated in vacuo. Chromatography on silica gel (5% ethyl acetate, pentane) provided N,O-bis(phenoxycarbonyl)-N-(3-butyn-2-yl)hydroxylamine (12.3 g, 88%).
Reaction SMILES: [CH3:1]OC1C=CC(N2C(=O)C(C(C)C)NC2=O)=CC=1.N1C2C(=CC=CC=2)[CH:21]=[C:20]1[CH2:28][CH:29]1[NH:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:30]1=[O:43].COC1C=CC(N2C(=O)C(C3C=CC=CC=3)(C3C=CC=CC=3)NC2=O)=CC=1>>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([N:31]2[C:30](=[O:43])[CH:29]([CH2:28][CH:20]([CH3:21])[CH3:1])[NH:33][C:32]2=[O:34])=[CH:40][CH:39]=1
Reactant: COc1ccc(N2C(=O)NC(C(C)C)C2=O)cc1
Reactant: COc1ccc(N2C(=O)NC(Cc3cc4ccccc4[nH]3)C2=O)cc1
Agent: COc1ccc(N2C(=O)NC(c3ccccc3)(c3ccccc3)C2=O)cc1
Product: COc1ccc(N2C(=O)NC(CC(C)C)C2=O)cc1

Procedure:
3-(4-methoxyphenyl)-5-(1-methylethyl)-2,4-imidazolidinedione; 5-(1H-indol-2-ylmethyl)-3-(4-methoxyphenyl)-2,4-imidazolidinedione; 3-(4-methoxyphenyl)-5,5-diphenyl-2,4-imidazolidinedione; are set forth in Table 2.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][N:22]1[C:15](=[O:17])[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: c1ccc2c(c1)CCNC2
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCc3ccccc3C2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1,2,3,4-tetrahydro-isoquinoline via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C21H23NO5 [M+H]+: 370.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.[C-:14]#[N:15].[Na+]>CN(C)C=O>[C:14]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:15]
Reactant: [C-]#N
Reactant: ClCCCc1n[nH]c2ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCc1n[nH]c2ccccc12
Temperature: 90 °C
Yield: 449.8 %

Procedure:
A solution of (3-chloropropyl)indazole (Sasakura et al, Synth. Comm., 18, pg 259 (1988)) (750 mg, 3.75 mM) in dimethylformamide (25 ml) was stirred at room temperature and sodium cyanide (370 mg, 7.5 mM) added in one portion. The resulting mixture was heated at 90° C. for 4 hr. The dimethylformamide was removed in vacuo and the residue partitioned between water and ethyl acetate. The combined organics were dried over magnesium sulfate. Column chromatography (ethyl acetate/cyclohexane, 1:1) provided 3-(3-cyanopropyl)indazole as a clear oil (3.21 g, 83%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pd].[Pt](=O)=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][NH:12][CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cncc(-c2ccc(CCO)cc2)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(c2ccc(CCO)cc2)C1
Reaction time: 6 h

Procedure:
A solution of 5.40 g (19.6 mmol) of the compound from Example 55A in concentrated acetic acid (124 ml) was admixed with 1.00 g of palladium/carbon (10% palladium) and 1.00 g of platinum(IV) oxide. This was followed by hydrogenation under a hydrogen atmosphere at standard pressure for 6 h, then addition of another 1.00 g of palladium/carbon (10% palladium) and 1.00 g of platinum(IV) oxide, and hydrogenation under a hydrogen atmosphere at standard pressure overnight. This was followed by hydrogenation in a Pan apparatus under a 3 bar hydrogen atmosphere for a further 2 h. The reaction solution was filtered through Celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue was codistilled repeatedly with toluene and then dried under high vacuum. Yield: 6.63 g (56% of theory, purity 44%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[NH:8][CH2:7][C:6]=2[CH:12]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:10])(=[O:11])[N:8]([CH3:13])[CH2:7][C:6]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=S1(=O)NCc2cc(Br)ccc21
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CN1Cc2cc(Br)ccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 725.7 %

Procedure:
To a suspension of 5-bromo-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (200 mg, 0.92 mmol) and potassium carbonate (128 mg, 0.92 mmol) in EtOH (2 mL) was added iodomethane (0.2 mL, 3.2 mmol) and the reaction was stirred at room temperature for 18 hours followed by heating to 50° C. for 2 hours. The reaction was cooled, concentrated in vacuo and diluted with DCM (20 mL). The solution was washed with water (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the title compound as a white solid (1.75 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[I-].[Na+].C(N(C(C)C)[CH:18]([CH3:20])[CH3:19])C.C(Br)C=C>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[CH:18]=[CH2:19]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C=CCBr
Product: C=CCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde and 44.8 g (299 mmol) sodium iodide in 400 ml acetone are added 51.2 ml (299 mmol) N-ethyldiisopropylamine and 25.3 ml (299 mmol) allyl bromide. After stirring for 18 h at r.t. the reaction mixture is filtered and the solvent is evaporated. Extraction of the residue with 1 M aqueous hydrochloric acid/dichloromethane followed by chromatography (hexane/ethyl acetate) yields 5-allyloxy-2-nitro-benzaldehyde.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@H:24]([C:33]([NH:35][C@H:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C(OCC)(=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:2][C:3]([NH:23][C@H:24]([C:33]([NH:35][C@H:36]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:5]
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 87 %

Procedure:
By coupling Z-Gly-OSu and H-Asp(OtBu)-Val-OtBu there is obtained Z-Gly-Asp(OtBu)-Val-OtBu, m.p.132° C. (ethyl acetate), yield: 87%.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([CH2:10][C:11]([OH:13])=[O:12])=[C:5]([F:14])[CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[C:8]([F:9])[C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:14]
Reactant: CO
Reactant: N#Cc1cc(F)c(CC(=O)O)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(F)c(C#N)cc1F
Temperature: 85 °C

Procedure:
(4-Cyano-2,5-difluorophenyl)acetic acid (0.5 g, 2.5 mmol) was dissolved in methanol (20 mL), and thionyl chloride (0.5 mL) was added drop wise to the solution. The reaction was heated to 85° C. for 4 hours. Then it was cooled and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the title compound after purification on silica gel (eluted with 5-20% ethyl acetate-hexanes) as an off white solid. 1H NMR (500 MHz, CDCl3): δ 7.31 (dd, J=5.2, J=5.2 Hz, 1H), 7.19 (dd, J=5.7, J=5.8 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 2H). LC-MS (IE, m/z): 212 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].[OH2:15]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][OH:15])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: C=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(CCO)cc([N+](=O)[O-])c1
Yield: 25 %

Procedure:
3,5-Dinitrostyrene (0.28 g, 1.43 mmol) was dissolved in acetonitrile (150 ml) and water (300 ml) was added. The mixture was poured into a photolysis apparatus and irradiated with an UV-lamp (HPK 125, Phillips) for 3 h. The organic solvent was evaporated and the aqueous phase extracted with methylene chloride (2×100 ml). The solvent was evaporated and the residue was purified by flash chromatography o n a column of silica using heptane/ethyl acetate (1/1) as eluent. Evaporation of solvent gave 76 mg (25%) of a crystalline product.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol (0.46 g, 1.5 mmol) and 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added water (100 ml), and the mixture was extracted with- ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the objective substance (0.55 g, 77%) as crystals.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OC(C)C)(C)C>C(O)(C)C>[C:19]1([C:17]2[N:18]=[C:14]([C@H:12]3[CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[NH:2][C:3]=4[C:35]4([CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)[NH:13]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H](c1nc(-c3ccccc3)c[nH]1)Cc1c2[nH]c2ccccc12
Yield: 79.8 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine hydrochloride (14 g, 35 mmol) in isopropanol (210 ml) was added 1-tert-butoxycarbonyl-4-piperidone (35 g, 170 mmol) and the mixture refluxed for about two hours. The solvent was evaporated under reduced pressure. Water (150 ml) was added to the residue followed by 10% NaHCO3 solution until neutral pH and extracted by ethyl acetate (4×50 ml). The combined organic extracts were washed with water (2×50 ml) and dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which solidified on addition of diisopropyl ether (150 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried to afford 13.5 g of the desired product. Melting point: 118-120° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:5].C(OC(=O)CCC)(=O)CCC.[N+:28]([O-])([OH:30])=[O:29].[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:16]([N+:28]([O-:30])=[O:29])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: COCC(=O)Nc1ccccc1C(=O)OC
Agent: CCCC(=O)OC(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51 %

Procedure:
[step 1] Methyl 2-(2-methoxyacetamido)benzoate (U.S. Pat. No. 5,091,403; 3.0 g, 13.4 mmol) was suspended in butyric anhydride (12.7 mL, 134.0 mmol), fuming nitric acid (2.3 mL, 51.1 mmol) was added dropwise under ice-cooling, and the mixture was stirred at 0° C. for 40 min. Water was added to the mixture, 4 mol/L aqueous sodium hydroxide solution was added dropwise to neutralize the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-60/40 v/v) to give methyl 2-(2-methoxyacetamido)-3-nitrobenzoate (1.9 g, 51%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[CH:5]=1.[CH3:20][S-:21].[Na+].CO>O>[CH3:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:13](=[O:14])[C:4]([CH2:3][S:21][CH3:20])=[CH:5]1
Reactant: C[S-]
Reactant: Cn1cc(CCl)c(=O)c2ccc(C(F)(F)F)cc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSCc1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C

Procedure:
3-Chloromethyl-1-methyl-7-trifluoromethyl-4-quinolone hydrochloride (4.7 g.) was added to a stirred solution of sodium methanethiolate in methanol (16 ml. containing 0.039 mole NaSMe) at 0° during 5 minutes. The resulting mixture was allowed to warm to room temperature then poured into water (100 ml.). The resulting precipitate was collected, dried and crystallised from dichloromethane:petroleum ether (b.p. 60°-80°) to give the novel 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone, m.p. 182°-184°.
Reaction SMILES: [CH:1]([Si:4]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:7]2[CH:12]([CH2:13][OH:14])[CH2:11][O:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[O-:21]Cl=O.[Na+]>C(Cl)Cl.O>[CH:18]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:7]2[CH:12]([C:13]([OH:21])=[O:14])[CH2:11][O:10][C:8]=2[N:9]=1)([CH3:20])[CH3:19]
Reactant: CC(C)[Si](c1nc2c(s1)C(CO)CO2)(C(C)C)C(C)C
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](c1nc2c(s1)C(C(=O)O)CO2)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A soln. of (2-(triisopropylsilyl)-5,6-dihydrofuro[2,3-d]thiazol-6-yl)methanol (1.77 g, 5.64 mmol)) in DCM (56 mL) was treated at 0° C. with DMP (2.87 g, 6.77 mmol) portionwise over 1 h. The mixture was stirred at 0° C. for 2 h, then, it was allowed to warm to RT and stirred for 2 h. Subsequently, the mixture was quenched with aq. sat. Na2S2O3 and aq. sat. NaHCO3 and was extracted with DCM. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was dissolved in tert-BuOH (16 mL) and 2-methyl-2-butene (4 mL) and treated at 0° C. dropwise over 30 min with a soln. of NaH2PO4 (2.64 g, 16.9 mmol) and NaClO2 (0.96 g, 8.46 mmol) in H2O (5 mL). The mixture was stirred at RT for 45 min, then, the volatiles were removed in vacuo, the residue was diluted with H2O and extracted with EtOAc. The comb. org. layers were dried over MgSO4 and conc. in vacuo.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][NH2:37]>>[CH3:28][N:4]1[C:3]([CH2:2][NH:37][CH2:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][N:30]2[CH3:29])=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN1CCCCC1CN
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC3CCCCN3C)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (1-methylpiperidin-2-yl)methanamine via General Procedure E to give 4.1 mg of 282 following reverse phase purification. MS (Q1) 490.2 (M)+
Reaction SMILES: [B]=O.[CH:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=O>N1CCCCC1.C1C=CC=CC=1>[CH:13](=[C:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:11]1=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Cc2ccccc2C1=O
Reactant: O=Cc1ccccc1
Agent: [B]=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
(8) (Chem. Pharm. Bull. 1974, 22(2), 448-451). Boron oxide (720 mg, 10.26 mmol) and benzaldehyde (800 mg, 7.53 mmol) were added to a stirred solution of the indandione (1.00 g, 6.84 mmol) and piperidine (3 drops) in 10.2 ml of benzene. The solution was refluxed with stirring for 30 minutes. After filtration of the solution, the filtrate was concentrated under reduced pressure. The resulting crystalline solid was recrystallized from ethanol to afford 1.00 g (62.4%) of yellowish-green platelets: mp 149.5-150.0° C. (lit. mp 150° C., Okukawa, et al., Chem. Pharm. Bull., 1974, 22(2), 448-451). 1H NMR (250 MHz) δ 8.47-8.45 (m, 2 H), 8.06-7.99 (m, 2 H), 7.90 (s, 1 H), 7.84-7.79 (m, 2H), 7.58-7.50 (m, 3 H); 13C NMR (62.7 MHz) 190.5, 189.2, 147.2, 142.7, 140.2, 135.6, 135.4, 134.3, 133.4, 133.2, 129.3, 129.0, 123.5, 123.5 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([C:19]#[C:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1.[H][H]>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([CH2:19][CH2:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1
Reactant: COc1ccc(CNc2nnc(C#CC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(CCC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Yield: 57.4 %

Procedure:
690 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)-1-ethynyl]-6-phthalazine carbonitrile was dissolved in 200 ml tetrahydrofuran, 50 mg of 10% Pd—C was added thereto, and the mixture was stirred for 0.5 hr in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography to give 400 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)ethyl]-6-phthalazine carbonitrile. This product was converted in a usual manner into the hydrochloride.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH2:11][C:12]([O:14][C@@H:15]([C@@H:54]([C:56]([OH:58])=[O:57])[CH3:55])[C@@H:16]([C@H:18]1[O:23][C@:22]2([O:27][C@@:26]([C@@H:29]3[O:33][C@@:32]([C@@H:35]4[O:39][C@@H:38]([C@H:40]5[O:45][C@@:44]([OH:48])([CH2:46][OH:47])[C@H:43]([CH3:49])[CH2:42][C@@H:41]5[CH3:50])[CH2:37][C@@H:36]4[CH3:51])([CH3:34])[CH2:31][CH2:30]3)([CH3:28])[CH2:25][CH2:24]2)[CH2:21][C@H:20]([OH:52])[C@H:19]1[CH3:53])[CH3:17])=[O:13]>N1C=CC=CC=1.ClCCl>[CH3:10][CH2:11][C:12]([O:14][CH:15]([CH:54]([C:56]([OH:58])=[O:57])[CH3:55])[CH:16]([CH:18]1[O:23][C:22]2([O:27][C:26]([CH:29]3[O:33][C:32]([CH:35]4[O:39][CH:38]([CH:40]5[O:45][C:44]([OH:48])([CH2:46][O:47][C:8]([NH:7][C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[O:9])[CH:43]([CH3:49])[CH2:42][CH:41]5[CH3:50])[CH2:37][CH:36]4[CH3:51])([CH3:34])[CH2:31][CH2:30]3)([CH3:28])[CH2:25][CH2:24]2)[CH2:21][CH:20]([OH:52])[CH:19]1[CH3:53])[CH3:17])=[O:13]
Reactant: O=C=Nc1ccccc1
Reactant: CCC(=O)O[C@H]([C@H](C)[C@H]1O[C@@]2(CC[C@@](C)([C@H]3CC[C@@](C)([C@@H]4O[C@@H]([C@H]5O[C@@](O)(CO)[C@H](C)C[C@@H]5C)C[C@@H]4C)O3)O2)C[C@H](O)[C@H]1C)[C@H](C)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)OC(C(C)C(=O)O)C(C)C1OC2(CCC(C)(C3CCC(C)(C4OC(C5OC(O)(COC(=O)Nc6ccccc6)C(C)CC5C)CC4C)O3)O2)CC(O)C1C
Yield: 61.1 %

Procedure:
Phenyl isocyanate (2.38 g, 20 mmol) was added to a solution of laidlomycin (14 g, 20 mmol) in 100 ml of pyridine. The mixture was heated in an oil bath at 70° for 30 min. The mixture was cooled, diluted with dichloromethane, washed with 5% aqueous hydrochloric acid and water, and evaporated. The residue was purified by silica gel chromatography (75% ether hexane, 0.01% formic acid eluent) to afford 10 g of laidlomycin phenylcarbamate as an amorphous solid which melted at 88°-90° C. Carbon-13 NMR spectroscopy confirmed the structure.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:30])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH:17]([F:30])[F:16])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)F
Yield: 48 %

Procedure:
The title compound is prepared in 48% yield (178 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (253 mg, 1.0 mmol, Amine-5, single enantiomer) in a similar manner to Step-2 of Intermediate-1.