Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:16]2[C:19]3[C:13]([NH:14][N:15]=2)=[N:12]C(SC)=[N:10][C:9]1=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C(O)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+].[CH3:47][S:48]([CH3:50])=[O:49]>ClCCl>[CH2:1]([N:8]1[CH2:18][CH2:17][C:16]2[C:19]3[C:13]([NH:14][N:15]=2)=[N:12][C:47]([S:48]([CH3:50])(=[O:30])=[O:49])=[N:10][C:9]1=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc2c3c(n[nH]c3n1)CCN2Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(C)=O
Agent: O=C(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nc2c3c(n[nH]c3n1)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 6-benzyl-4-methylsulfanyl-2,6,7,8-tetrahydro-1,2,3,5,6-pentaazaacenaphthylene (2.08 g, 7.00 mmol) in anhydrous dichloromethane (100 ml) was added solid m-CPBA (4.69 g, 77% pure, 21.0 mmol) directly. The reaction became clear immediately. After stirring overnight at room temperature, a white precipitate crashed out (benzoic acid and product) from the reaction. The reaction was monitored by HPLC to ensure completion (>95%). It was noreworthy that extended reaction time led to over-oxidation and 12-15 hours seemed optimal in most cases. DMSO (50-70 ml) was added to quench the reaction and the reaction was stirred for 30 min at room temperature. aq. NaHCO3 (100 ml) was added in one shot while stirring. Some precipitates remained. The off-white precipitates were filtered washed with a lot of water to give the desired product. The dichloromethane layer was separated, washed with aq. NaCl twice and concentrated. More precipitate crashed out. The precipitates were filtered and washed with a lot of water to give the desired product as an off-white solid. Combining all products yield product in total (1.35 g, 58%). The product was further dried by high vacuum pump and was used without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 13.64 (s, 1H), 7.28-7.41 (m, 5H), 4.89 (s, 2H), 3.74 (t, J=6.4 Hz, 2H), 3.15 (t, J=6.4 Hz, 2H), 2.51 (s, 3H). LC-Mass (m/e): 330.54 (M+1).
Reaction SMILES: BrBr.C(O[C@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)OC=C1)(=O)C.BrN1C(=O)CCC1=O.[O:30]=[CH:31][C@@H:32]([C@H:34]([C@@H:36]([C@@H:38]([CH2:40][OH:41])[OH:39])[OH:37])[OH:35])O.C(S)C.C(Cl)(=O)C1C=CC=CC=1>>[CH2:32]([C@@H:34]([OH:35])[C@H:36]([OH:37])[C@H:38]([OH:39])[CH2:40][OH:41])[CH:31]=[O:30]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: BrBr
Agent: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C1CCC(=O)N1Br
Solvent: O=C(Cl)c1ccccc1
Solvent: CCS
Product: O=CC[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Production of 2DG can be carried out using any known method. For example, 2-DG can be prepared from various starting materials such as D-glucose, D-mannose, calcium D-gluconate, D-arabinose, D-glucosamine hydrochloride, N-acetyl glucosamine, chitin, and chitosan and carboxymethylchitosan. Preparation methods vary with various starting materials. For example, D-glucose can be methylated and brominated, followed by debromination and acid hydrolysis to yield β-2DG. Bergmann et. al. (1992) Berichte der Deutschen Chemischen Gesellschaft Jahrg. 55:158-72. D-glucose or D-mannose can be treated with bromine and acetyl, followed by a Fischer procedure (Fischer et al. (1914) (Berichte der Deutschen Chemischen Gesellschaft Jahrg. 47:196-210), to yield 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol, which is reacted with bromine, then reduced to remove the acetyl group, yielding 2DG (Arita et al. (1972) Bull. Chem. Soc. Japan 45:567-69). The 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol intermediate can be treated with N-bromosuccinimide, followed by hydrogenation and deacetylation to yield 2DG. Monneret and Choay (1981) Carbohydr. Res. 96:299-305. D-glucose can be reacted with ethanethiol and benzoyl chloride, followed by dehydrogenation, reduction, and deprotection to give 2-DG. Wong and Gray (1980) Carbohydr. Res. 80:87-98). Glucal can be deacetylated by reacting with sulfuric acid to give 2-DG with an overall yield of 35%. Overend et al. (1949) J. Chem. Soc., 1:2841-45. D-arabinose can be treated with nitromethane and an acetylating agent, followed by treatment with diluted sodium hydroxide, to yield a-2-DG. Sowden and Fischer (1947)J. Am. Chem. Soc. 69:1048-50. D-arabinose can be condensed, reduced with acetone, then reacted with trifluoromethanesulfonic anhydride, to yield a product that is then reacted with sodium cyanide, followed by hydrogenation, reduction, and hydrolysis, yielding 2-DG. Shiue et al. (1979) Carbohydr. Res. 74:323-26.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[C:3](=[O:8])[NH:4][CH2:5][CH:6]=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl.O>[O:8]1[CH:6]=[CH:5][N:4]=[C:3]1[C:2]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:1]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)NCC=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)c1ncco1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A solution of benzyl 2-methyl-1-oxo-1-(2-oxoethylamino)propan-2-ylcarbamate (2.23 g, 8 mmol) in methylene chloride (50 mL) was added to a freshly prepared solution of PPh3 (3.15 g, 12 mmol), I2 (3.05 g, 12 mmol) and Et3N (2.43 g, 24 mmol) in methylene chloride (100 mL). The resulting mixture was stirred at room temperature until TLC showed the reaction was completed. Then water (150 mL) was added. The organic layer was washed with 5% sodium bisulfite (150 mL×2), brine (150 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil which was purified by column chromatography (silica gel, 50 g, eluting with 25% ethyl acetate in petroleum ether) to yield the title compound (0.63 g, 30%) as colorless oil; MS: m/e 261.2 [M+H]+. 1H NMR (300 MHz, CDCl3): δ 7.57 (s, 1H), 7.37-7.33 (m, 5H), 7.05 (s, 1H), 5.06 (s, 2H), 1.74 (s, 6H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:14]=1)=[N:8][CH:9]=[C:10](Br)[C:11]=2[CH3:12])[CH2:2][CH3:3].C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>C1COCC1>[CH2:1]([C:4]1[N:5]=[C:6]2[CH:11]([CH3:12])[C:10]([CH:22]=[O:23])=[CH:9][N:8]=[C:7]2[N:14]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ncc(Br)c(C)c2[nH]1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC1=NC2=NC=C(C=O)C(C)C2=N1
Temperature: -78 °C

Procedure:
To a cooled (-78° C.) stirred solution of 2-propyl-6-bromo-7-methylimidazo[4,5-b]pyridine (540 mg, 2.15 mmol) in THF (20 mL) was added tert-butyl-lithium (4.40 mL, 1.7M/pentane) over 30 seconds After 45 minutes, dimethylformamide (0.665 mL) was added and after 10 additional minutes the reaction was warmed to RT and quenched with 20% aqueous 4 NH4Cl. Extractive workup EtOAc (4×10 mL) and purification (SiO2, 4% MeOH/EtOAc) gave 2-propyl-7-methylimidazo[4,5-b]pyridine-6-carboxaldehyde (350 mg). To a stirred, cooled (0° C.) methanolic (15 mL) solution of the aldehyde (300 mg) was added NaBH4 (84 mg). After 30 minutes HOAc (0.1 mL) was added, the mixture was warmed (RT), concentrated, and purified (SiO2, 10% MeOH/CH2Cl2) to give 190 mg of 6-hydroxymethyl-7-methyl-2-propylimidazo[4,5-b]pyridineas an oil. The title compound was prepared by using a similar method to that described in Example 7, Part B.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:37])[CH3:11])=[CH:6][CH:5]=1.CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][CH2:26][CH2:25][CH2:24][C@@:15]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13](=[O:37])[N:12]([C@H:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([OH:40])=[O:1])=[CH:5][CH:6]=3)[CH3:11])[CH2:17][CH2:16]2)=[CH:34][CH:33]=1
Reactant: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CCO)cc3)C(=O)O2)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(=O)O)cc3)C(=O)O2)cc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(2-hydroxyethyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (260 mg, 0.517 mmol) in acetone (2 mL) was added Jones reagent (0.25 mL, 2.5 mol/L), and the formed mixture was stirred for 30 min. The mixture was extracted with EtOAc. The combined organic layer was concentrated to give crude 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetic acid (260 mg, 97%), which was used for the next step without purification.
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[C:23](Cl)=[C:24]([C:30](=[O:37])[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:25]([CH3:29])=[N:26][C:27]=1[CH3:28]>CC#N.CCOCC>[Br:21][C:22]1[C:23]([N:7]2[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]2)=[C:24]([C:30](=[O:37])[C:31]([O:33][CH:34]([CH3:35])[CH3:36])=[O:32])[C:25]([CH3:29])=[N:26][C:27]=1[CH3:28]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.6 %

Procedure:
To a solution of 4-(trifluoromethyl)piperidine HCl (1.7 g, 8.97 mmol) and DIEA (3.13 mL, 17.9 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.97 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.9 g (71%). 1H NMR (500 MHz, CDCl3) δ 5.25-5.20 (m, 1H), 3.54-3.51 (m, 2H), 3.15 (dt, J=12.5, 2.0 Hz, 2H), 2.87 (s, 3H), 2.57 (s, 3H), 2.30-2.23 (m, 1H), 2.02-1.99 (m, 2H), 1.79 (dq, J=12.4, 4.1 Hz, 2H) 1.43 (d, J=6.2 Hz, 6H). UPLC (M+H)=453.2.
Reaction SMILES: [CH2:1]([O:6][C@@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][C@H:8]1[N:15]1[C:25]2[N:24]=[C:22]([NH2:23])[NH:21][C:19](=[O:20])[C:18]=2[N:17]=[CH:16]1)[CH2:2][CH2:3][CH2:4][CH3:5].C[Si](Cl)(C)C.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>N1C=CC=CC=1>[C:31]([NH:23][C:22]1[NH:21][C:19](=[O:20])[C:18]2[N:17]=[CH:16][N:15]([C:25]=2[N:24]=1)[C@@H:8]1[O:9][C@H:10]([CH2:13][OH:14])[C@@H:11]([OH:12])[C@H:7]1[O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21

Procedure:
2'-O-pentylguanosine (2.3 g) in pyridine (35 ml) was treated with trimethylsilyl chloride (4.15 ml, 5 eq) and isobutyryl chloride (3.4 ml, 5 eq) as per the procedure of Example 4 to yield the product as a foam (2.3 g). An analytical sample was crystallized from EtOAc/Hex. m.p. 178-180° C. 1H NMR (DMSO-d6) δ 0.75 (t, 3, CH3), 1.1 [m, 10, 2×CH2, CH(CH3)2 ], 1.4 (m, 2, CH2), 2.74 [m, 1, CH(CH3)2 ], 3.56 (m, 4, OCH2, H-5'), 3.93 (m, 1, H-4'), 4.25 (m, 1), 4.34 (m, 1), 5.0 (t, 1, 5'-OH), 5.17 (d, 1, 3'-OH), 5.88 (d, 1, H-1'), 8.27 (s, 1, H-8), 11.65 (br s, 1, NH) and 12.05 (br s, 1, NH). Anal. Calcd. for C19H29N5O6 : C, 53.89; H, 6.90; N, 16.54. Found: 53.75; H, 6.92; N, 16.40
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]1[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:13]2=[N:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Br:8][C:4]1[N:3]=[C:2]([N:17]2[CH2:16][CH2:15][N:14]3[C:10]([CH3:9])=[N:11][N:12]=[C:13]3[CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1nnc2n1CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1CCN(c1cccc(Br)n1)C2
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 2,6-dibromopyridine (434 mg, 1.832 mmol, Aldrich), 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (380 mg, 2.75 mmol, MolBridge) and potassium carbonate (253 mg, 1.832 mmol) in dioxane (1.8 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 4 h. The reaction was cooled to RT, H2O was added and the resulting precipitate was collected by filtration, washed with H2O and dried to give the crude product. MS (ESI, pos. ion) m/z: 294 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14]CC)=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][CH2:21][CH2:22][N:23]=1>>[ClH:1].[S:20]1[CH2:21][CH2:22][N:23]=[C:19]1[NH:18][C:12]([C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:17])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:14]
Reactant: NC1=NCCS1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1O
Product: Cl
Product: O=C(NC1=NCCS1)c1cnc2cc(Cl)ccc2c1O

Procedure:
Using the procedure of Example 2, ethyl 7-chloro-4-hydroxy-3-quinoline-carboxylate and 2-amino-thiazoline were reacted at reflux for 48 hours and the product was crystallized from acetic acid to obtain N-(4,5-dihydro-thiazol-2-yl)-7-chloro-4-hydroxy-3-quinoline-carboxamide hydrochloride melting at >260° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)([I:11])[CH2:8][C:6]=2[N:7]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([C:12]3[CH:13]=[C:14]([N:18]([CH3:28])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)([I:11])[CH2:8][C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(=O)N(C)c1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 60 mg of N-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)acetamide and 78 mg of cesium carbonate in DMF was added 12 μL of iodomethane. The reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate, washed with H2O. The organic layer was dried over (MgSO4) and evaporated to yield N-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)-N-methylacetamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=3[C:21]([OH:23])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:14]4[C:13]=3[C:21](=[O:23])[N:25]([CH:26]3[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]3=[O:28])[C:15]4=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cccc(OCc2ccc3c(c2)OCO3)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Yield: 29 %

Procedure:
A mixture of 3-(benzo[1,3]dioxol-5-ylmethoxy)-phthalic acid (1.2 g, 3.8 mmol), alpha-amino-glutarimide hydrochloride (0.66 g, 4.0 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(benzo[1,3]dioxol-5-ylmethoxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.45 g, 29% yield); HPLC: Waters Symmetry C18, 5 μm. 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.06 min (98.6%); mp, 229-231° C.; 1H NMR (DMSO-d6) δ 2.02-2.05 (m, 1H, CHH), 2.55-2.62 (m, 2H, CH2), 2.82-2.94 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.26 (s, 2H, CH2), 6.03 (s, 2H, CH2), 6.93-7.85 (m, 6H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.95, 30.91, 48.74, 70.00, 101.05, 108.10, 108.18, 115.49, 116.61, 120.28, 121.25, 129.78, 133.24, 136.95, 147.04, 147.38, 155.44, 165.30, 166.76, 169.89, 172.74. Anal Calcd For C21H16N2O7: C, 61.77; H, 3.95; N, 6.86. Found: C, 61.44; H, 3.72; N, 6.79.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:42][O:43][CH:44]([O:48][CH3:49])CNC.[CH3:50][N:51]([CH:53]=[O:54])[CH3:52]>C(Cl)Cl.O>[CH3:42][O:43][CH:44]([O:48][CH3:49])[CH2:50][N:51]([CH3:52])[C:53]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:54]
Reactant: CNCC(OC)OC
Reactant: CN(C)C=O
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(C)C(=O)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (30.4 mg, 0.1 mmol) obtained in step C of Example 1-1 was dissolved in a mixed solvent (0.5 ml) of methylene chloride and DMF (1:1). Thereafter, pyridine (16.2 μl, 0.2 mmol) and 4-nitrophenyl chloroformate (24.2 mg, 0.12 mmol) were added thereto under cooling on ice. The obtained mixture was then stirred at a room temperature for 2 hours. Thereafter, 2,2-dimethoxy-N-methylethylamine (15.4 μl, 0.12 mmol) was added to the reaction solution, and the obtained mixture was then stirred at a room temperature overnight. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate, followed by concentration. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:1), so as to obtain 1-(2,2-dimethoxyethyl)-1-methyl-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]urea (17.5 mg; yield: 39%) in the form of a colorless amorphous substance.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH2:52])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:33]([Si:37]([CH3:54])([CH3:53])[O:38][CH:39]([C:41]1[O:42][C:43]([CH2:46][N:47]2[N:51]=[C:50]([NH:52][C:16]([C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)=[O:18])[CH:49]=[N:48]2)=[CH:44][N:45]=1)[CH3:40])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(Cl)c2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid (37 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.24 min, [M+H]+=542.92.
Reaction SMILES: CO[C:3](=[O:28])[CH:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][OH:7].ClC1C=C(/C=C/[C:39]([N:41]2CCC(=O)N(C3CCOC3=O)C[CH2:42]2)=O)C=CC=1Cl.N1CCCCC1>CCO>[Cl:26][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[C:16]([N:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:8]([CH:4]([CH2:5][CH2:6][OH:7])[C:3]([N:41]([CH3:42])[CH3:39])=[O:28])[CH2:9][CH2:10]2)=[O:27])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)C(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Yield: 43 %

Procedure:
In analogy to the procedure described in example 3, treatment of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) in EtOH with piperidine for 1.5 days at 60° C. and 2 days at RT gave 43% of the titled compound as light yellow foam. MS: 482.2 (MH+, 2Cl).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[CH:11]=1.C=O.Cl>C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:17][CH:18]=1)[C:14](=[O:16])[O:15][CH2:2][CH2:19]2
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: C=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OCCc2cc(Br)ccc21
Reaction time: 0.17 h

Procedure:
LDA (12 ml, 17 mmol) was dissolved in THF (50 ml) at −78° C. then 4-Bromo-2-methylbenzoic acid (1.0 g, 4.6 mmol) in 10 ml THF was added. The mixture was stirred for 10 minutes then paraformaldehyde (0.56 g, 18.6 mmol) was added. The reaction was stirred at RT for 4 hours. When LC-MS showed the product M+1=229, the reaction was poured into 1N HCl and extracted with ether. The organic layer was washed with brine, dried and evaporated to dryness. The residue was flashed through an Analogix 115 g column and eluted with 0-100% ethyl acetate/hexane to yield 6-bromo-3,4-dihydro-1H-isochromen-1-one.