Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]5[CH2:27][CH2:26][CH2:25][C:24]5=[O:28])[CH:20]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=C[CH:33]=1.ClC(OC1C=CC=CC=1)=[O:40].C1(N)CC1>CN(C=O)C>[CH:37]1([NH:32][C:33]([NH:1][C:2]2[CH:30]=[CH:29][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]6[CH2:27][CH2:26][CH2:25][C:24]6=[O:28])[CH:20]=5)[S:15][C:8]=34)=[C:4]([F:31])[CH:3]=2)=[O:40])[CH2:35][CH2:36]1
Reactant: c1ccncc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cnn(CCN5CCCC5=O)c4)sc23)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4cnn(CCN5CCCC5=O)c4)sc23)c(F)c1)NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a stirred solution of 165 (400 mg, 0.914 mmol) and pyridine (0.222 mL, 2.74 mmol) in DMF (10 mL) at 0° C. under nitrogen was added phenyl chloroformate (0.287 mg, 2.286 mmol) and the reaction mixture was stirred at 0° C. for 2 hrs. Cyclopropylamine (0.322 mL, 4.57 mmol) was added and the reaction mixture was heated at 55° C. for 5 hrs. The reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate solution, then washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent EtOAc to 20% MeOH in EtOAc) to afford title compound 166 (250 mg, 53% yield) as a white solid. 1H NMR (400 MHz. DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.44 (d, J=5.48 Hz, 1H), 8.35 (s, 1H), 8.035 (s, 1H), 7.74 (m, 1H), 7.70 (s, 1H), 7.35 (t, J=8.99 Hz, 1H), 7.19 (d, J=8.99 Hz, 1H), 6.55 (m, 2H), 4.28 (t, J=5.87 Hz, 2H), 3.59 (t, J=5.86 Hz, 2H), 3.17 (t, J=6.84 Hz, 2H), 2.55 (m, 1H), 2.15 (t, J=7.83 Hz, 2H), 1.86 (m, 2H), 0.64 (m, 2H), 0.42 (m, 2H). MS (m/z)=521.38 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][C@H:21]([OH:23])[CH3:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][C@H:21]([OH:23])[CH3:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:24][CH:25]=1
Reactant: C[C@@H](O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)COc1ccc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 73 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a suspension of (R)-1-((4-(4-nitrophenoxy)quinolin-7-yl)oxy)propan-2-ol (3.6 g, 10.6 mmol) and HCOOK (6.2 g, 74.1 mmol) in THF/H2O (33 mL/11 mL) was added a catalytic amount of 10% Pd/C (33 mg). After stirring at 73° C. for 5 hours, the reaction mixture was cooled to room temperature. The mixture was filtered through a celite pad and the filter cake was washed with DCM (50 mL). The organic phase was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by a column chromatography on silica gel (EtOAc/PE=1:1) to give the title compound as a yellow solid (2.5 g, 76.2%).
Reaction SMILES: C(S)C.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCC(CC(=O)O)CC(=O)O)cc1
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(O)CC(CCc1ccc(O)cc1)CC(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a suspension of 57% sodium hydride-paraffin (2.2 g) in dry dimethylformamide (70 ml) in an atmosphere of nitrogen is slowly added ethanethiol (4.0 ml). The mixture is stirred at room temperature until a clear solution results. To this solution is added a solution of 3-[2-(4-methoxyphenyl)ethyl]glutaric acid (1.2 g) in dry dimethylformamide (10 ml) and the mixture is heated with stirring in a bath at 165° C. for 6.0 hours. The mixture is then evaporated to dryness in vacuo and the resulting residue is dissolved in water (50 ml), extracted with ether (two 50 ml portions) and the ether extract is discarded. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried with anhydrous magnesium sulfate, and evaporated to a residue. Crystallization of this from chloroform-hexane affords 1.0 g of the title compound, melting point 142°-144° C.
Reaction SMILES: [CH2:1]1[CH:7]([OH:8])[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:22])[NH:20]O)[CH3:17].ClC(Cl)(Cl)C(O)=O>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:22])[NH:20][O:8][CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[CH3:17]
Reactant: CCOC(=O)NO
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)NOC1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 72 h

Procedure:
550 mg (2 mmol) of 4-hydroxycyclophosphamide and 210 mg (2 mmol) of ethylhydroxycarbamate (hydroxyurethane) are dissolved in 5 ml of dry methylenechloride free of alcohol. A catalytic amount of trichloroacetic acid and molecular sieve 4 A are added thereto. The reaction mixture is allowed to stand at -25° C. for 3 days. Thereafter, the molecular sieve is separated and washed once with a diluted solution of NaHCO3. The methylenechloride phase is dried over sodium sulfate and part of the solvent is evaporated in a vacuum and thereafter diluted with ether. After standing for 20 hours at -25° C., the separated crystals are filtered off, washed and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:6]=[CH:5]2.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([S:36]C2C=C3C(=CC=2Cl)C=NC=C3)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].ClC1C=C2C(C=CNC2=O)=CC=1SC1CCNCC1>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([S:36][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[Cl:12])[C:8](=[O:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:6]=[CH:5]3)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(Cn2ccc3cc(Br)c(Cl)cc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2cc3ccncc3cc2Cl)CC1
Agent: O=c1[nH]ccc2cc(SC3CCNCC3)c(Cl)cc12
Product: COc1ccc(Cn2ccc3cc(SC4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1

Procedure:
Starting from 7-Chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (264) 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester could be obtained as described for compound (274). 7-Chloro-6-(piperidin-4-ylsulfanyl)-2H-isoquinolin-1-one.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[N:44]1([C:50](=[O:52])[CH3:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:50]([N:44]1[CH2:49][CH2:48][N:47]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:46][CH2:45]1)(=[O:52])[CH3:51]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 1-(piperazin-1-yl)ethanone (59 mg, 0.46 mmol, 3.00 equiv), potassium iodide (12.7 mg, 0.08 mmol, 0.50 equiv), and potassium carbonate (42.4 mg, 0.31 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 54.8 mg (34%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): 8.94-8.92 (d, J=4.2 Hz, 1H), 8.66-8.64 (d, J=6.6 Hz, 1H), 8.43 (s, 1H), 8.14-8.09 (m, 3H), 7.88-7.87 (m, 1H), 7.79-7.54 (m, 7H), 4.72 (s, 2H), 4.47 (s, 2H), 3.82 (s, 3H), 3.65-3.62 (t, J=4.2 Hz, 1H), 3.33-3.29 (m, 5H), 2.15 (s, 3H), 2.04-2.01 (1, J=5.2 Hz, 4H), 1.82-1.81 (d, J=5.2 Hz, 1H). MS (ES, m/z): 699 [M+H]+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18]COCC>>[CH2:18]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(Br)cc1C
Reactant: CCOCC
Reactant: c1ccccc1
Agent: [Mg]
Product: COc1ccc(Cc2ccccc2)cc1C
Reaction time: 3 h

Procedure:
Grignard reagent was prepared from 12.15 g of magnesium (turnings) and 50.23 g of 1-bromo-4-methoxy-3-methylbenzene in 200 ml of anhydrous ether by conventional process. To this Grignard reagent was added 200 ml of anhydrous benzene and ether was distilled off under normal pressure. To this solution was added dropwise a mixed solution comprising 47.25 g of benzyl chloride and 50 ml of anhydrous benzene under refluxing with heating, followed by stirring for 3 hours. After being left for cooling, the reaction mixture was filtered and the filtrate was washed with dilute hydrochloric acid, dilute aqueous sodium hydroxide solution and water in this order. The filtrate was dried over anhydrous magnesium sulfate and then was concentrated under reduced pressure and thereafter, distilled under reduced pressure to obtain 30.8 g of 4-benzyl-2-methyl-1-methoxybenzene.
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#N.[OH-:16].[Na+].[OH:18]S(O)(=O)=O>O>[C:10]1([C:4]2([C:2]([OH:18])=[O:16])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1(c2ccccc2)CCNCC1

Procedure:
4-Cyano-4-phenylpiperidine hydrochloride (2.0 g, 0.11 mol) was dissolved in 8 mL of conc. H2SO4 and 4mL of H2O, then the solution was heated at reflux for 4 hours. The solution was cooled and then NaOH was added to precipitate a white solid. The solid was collected, then dissolved in methanol, and the solution was filtered and concentrated to obtain a white solid. This dried solid was used without purification for Example 385B.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:3][CH:2]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[N:3][CH:2]=1
Reactant: O=C1CCC(Oc2ccncn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ccncn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(pyrimidin-4-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:37])[CH:21]([NH:25][CH2:26]C(OCC2C=CC=CC=2)=O)[CH:22]([CH3:24])[CH3:23])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H][H].[NH:40]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[C@H:41]([C:50]([OH:52])=O)[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1.O>CO.C1COCC1.[C].[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:37])[CH:21]([N:25]([C:50](=[O:52])[CH:41]([NH:40][C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[CH3:26])[CH:22]([CH3:23])[CH3:24])[CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C(NCC(=O)OCc1ccccc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)CS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)CS(C)(=O)=O)N(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 2-(benzyloxycarbonyl)methylamino-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-methanesulfonylmethylethylamide (0.65 g, 1.22 mmol) in methanol (10 ml), 10% palladium carbon (130 mg) was added and stirred in a hydrogen atmosphere at room temperature for 30 min. After filtration, the filtrate was concentrated under reduced pressure. To a solution of the thus obtained residue, Z-Phe(4-F)-OH (465 mg, 1.47 mmol) and CMPI (375 mg, 1.47 mmol) in THF (15 ml), TEA (0.41 ml, 2.93 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent:n-hexane:ethyl acetate=1:1) to give 2-((2-benzyloxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-methanesulfonylmethylethylamide (484 mg, 57%). A mixture of the above compound (424 mg, 0.609 mmol) and 10% palladium carbon (43 mg) in methanol (16 ml) was stirred at room temperature in a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (239 mg, 70%).
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].[C:7]([C:9]1[C:10]([NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11][CH:12]=[N:13][CH:14]=1)#[N:8].OO>CO.CS(C)=O.C(OCC)(=O)C>[C:21]1([CH2:20][CH2:19][CH2:18][CH2:17][C:16]2[NH:8][C:7](=[O:2])[C:9]3[C:10]([N:15]=2)=[N:11][CH:12]=[N:13][CH:14]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cncnc1NC(=O)CCCCc1ccccc1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c(CCCCc2ccccc2)nc2ncncc12
Yield: 1.8 %

Procedure:
Under an atmosphere of nitrogen, K2CO3 (3.057 g) was added to a solution of 5-phenyl-pentanoic acid (5-cyano-pyrimidin-4-yl)-amide (1.00 g) in MeOH (5 ml) and DMSO (1.2 ml). The mixture was cooled (ice bath) and hydrogen peroxide (35% in H2O, 1.5 ml) was added dropwise. The mixture was taken up in ethyl acetate and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. 2-(4-Phenyl-butyl)-3H-pyrimido[4,5-d]pyrimidin-4-one (18 mg, 1.8%) was obtained from the residue by subsequent column chromatography (silica gel, eluent gradient n-heptan/ethyl acetate=100:0-60:40) and preparative, reverse-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min). MS: m/e=279.3 [M−H−]. 1H NMR (d6-DMSO): δ 1.62-2.00 (m, 4H), 2.55-2.80 (m, 4H), 7.17-7.18 (m, 2H), 7.26-7.28 (m, 3H), 9.56 (d, 1H), 9.64 (d, 1H), 11.13 (bs, 1H).
Reaction SMILES: O[CH:2]1[CH:3]([CH3:56])[CH2:4][CH2:5][CH:6]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:7][C:8]([O:10][CH:11](/[C:16](/[CH3:47])=[CH:17]/[CH:18]=[CH:19]/[C:20]([CH3:46])([O:38][Si:39]([CH2:44][CH3:45])([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:21][CH:22]2[O:37][CH:23]2[CH:24]([CH3:36])[CH:25]([O:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:26][CH3:27])[CH:12]([CH3:15])[CH:13]=[CH:14]1)=[O:9].C(N(CC)CC)C.ClC([O:67][C:68]1[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=1)=O.[C:77]([O:80]CC)(=[O:79])C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:56][CH:3]1[CH:2]([C:77]([O:80][O:67][C:68]2[CH:69]=[CH:70][C:71]([N+:74]([O-:76])=[O:75])=[CH:72][CH:73]=2)=[O:79])[CH:14]=[CH:13][CH:12]([CH3:15])[CH:11](/[C:16](/[CH3:47])=[CH:17]/[CH:18]=[CH:19]/[C:20]([CH3:46])([O:38][Si:39]([CH2:40][CH3:41])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:21][CH:22]2[O:37][CH:23]2[CH:24]([CH3:36])[CH:25]([O:28][Si:29]([CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:26][CH3:27])[O:10][C:8](=[O:9])[CH2:7][CH:6]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(O)C=CC1C)O[Si](CC)(CC)CC
Reactant: CCOC(C)=O
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(C(=O)OOc2ccc([N+](=O)[O-])cc2)/C=C/C1C)O[Si](CC)(CC)CC
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(O)/C=C/C1C)O[Si](CC)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(C(=O)OOc2ccc([N+](=O)[O-])cc2)C=CC1C)O[Si](CC)(CC)CC
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of (8E,12E,14E)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (38.6 mg, 0.046 mmol), 4-dimethylaminopyridine (26 mg, 0.207 mmol) and triethylamine (28 mg, 0.276 mmol) in methylene chloride (2 mL) was cooled to 5° C. A solution of 4-nitrophenyl chloroformate (29 mg, 0.138 mmol) in methylene chloride (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at 5° C. for one hour. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with an aqueous solution of sodium hydrogencarbonate. The organic layer was sequentially washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogencarbonate and water, dried with anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:14) to obtain the title compound (46.1 mg, 100%) as a yellow pale oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:32][C:31]5(OCC[O:33]5)[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:37][CH3:38])[CH:6]=1.O>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:30][C:31](=[O:33])[CH2:32]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:37][CH3:38])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N4CC5(C4)OCCO5)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(Nc2nc3c(c(N4CC(=O)C4)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Temperature: 50 °C
Yield: 20.1 %

Procedure:
The mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 184) (12 mg, 0.023 mmol) in Acetone (161 μL)/Water (32.3 μL)/HClO4, 70% (32.3 μL) was heated at 50° C. overnight. The crude product was purified by Prep-HPLC to get 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one (2.5 mg, 4.62 μmol, 20.5% yield). LC-MS (M+H)+=487.2 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (s, 1H) 7.42 (t, J=7.63 Hz, 3H) 7.26-7.38 (m, 3H) 7.12-7.26 (m, 2H) 7.00-7.12 (m, 1H) 5.23 (br. s., 4H) 4.43 (br. s., 1H) 3.68-3.79 (m, 3H) 3.10-3.27 (m, 1H) 2.93-3.08 (m, 1H) 2.71-2.84 (m, 1H) 2.37 (br. s., 1H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[C:9]([N:18]2[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]2)=[C:10]([F:17])[C:11]([F:16])=[C:12]([CH:15]=1)[CH:13]=O)([CH3:4])([CH3:3])[CH3:2].CCN([CH:44]([CH3:46])[CH3:45])C(C)C.Cl.[NH2:48][OH:49]>C1COCC1.C(Cl)Cl>[Si:5]([O:6][CH2:7][C:8]1[C:9]([N:18]2[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]2)=[C:10]([F:17])[C:11]([F:16])=[C:12]([CH:13]=[N:48][OH:49])[CH:15]=1)([C:1]([CH3:2])([CH3:4])[CH3:3])([C:45]1[CH:44]=[CH:46][CH:3]=[CH:1][CH:2]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:15]=1
Reactant: C[C@@H]1CN(c2c(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc(C=O)c(F)c2F)C[C@H](C)O1
Reactant: CCN(C(C)C)C(C)C
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C=NO)c(F)c2F)C[C@H](C)O1
Reaction time: 12 h

Procedure:
To an ice-bath cooled and stirred solution of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-benzaldehyde (Intermediate 4, 9.1 g, 17 mmol) in THF was added DIPEA (4.5 mL, 26 mmol) followed by hydroxylamine hydrochloride (1.3 g, 19 mmol) over a period of 15 min. The mixture was brought to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 and washed successively with 1 N HCl (1×250 mL), water and brine. The organic layer dried (Na2SO4), filtered and concentrated. The residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as white solid. Yield: 8.9 g, (86%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.[C:9](=[O:12])([O-])[O-].[K+].[K+].[CH3:15][N:16]([CH:18]=O)C>>[CH2:15]([NH:16][C:18]1[CH:4]=[CH:3][CH:2]=[CH:7][C:9]=1[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1O
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccccc1NCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a stirred mixture of 2-aminophenol (3.0 g, 27.5 mmol), potassium carbonate (6.0 g, 43.4 mmol) and DMF (25 mL) 1-(bromomethyl)benzene (3.75 mL, 31.3 mmol) was added. The mixture was stirred at 60° C. overnight. Purification by preparative HPLC (Kromasil C18; eluant:acetonitrile+0.1% TFA/water+0.1% TFA) gave the subtitled compound (1.82 g, 33%).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](=O)[CH3:5].Cl.[NH2:10][OH:11].C(=O)(O)[O-].[Na+]>O>[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](=[N:10][OH:11])[CH3:5]
Reactant: CC(=O)CC(C)(C)O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(CC(C)(C)O)=NO
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxy-4-methyl-2-pentanone (10.0 g, 85.7 mmole) and hydroxylamine hydrochloride (22.17 g, 343 mmole) in 90 ml of water was stirred vigorously at room temperature. To this solution was added slowly over a period of an hour solid sodium bicarbonate (26.8 g, 343 mmole). After 3 hours the reaction mixture was extracted with ethyl acetate (3×, 100 ml), dried (MgSO4) and evaporated under reduced pressure, to give the product as an oil. Yield 11.2 g