Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:35])[N:25]([CH3:34])[CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])=[CH:11][N:10]=1)(C)(C)C.[ClH:37]>CCOC(C)=O>[ClH:37].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:25]([CH3:34])[CH:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27])=[O:35])=[CH:11][N:10]=1
Reactant: COc1cc2c(CC(=O)N(C)C(C)c3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(CC(=O)N(C)C(C)c3ccccc3)cnc(CN)c2cc1OC
Yield: 99 %

Procedure:
As described in Example 1, 85 mg of (6,7-dimethoxy-4-{[methyl-(1-phenyl-ethyl)-carbamoyl]-methyl}-isoquinolin-1-ylmethyl)-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 67 mg (99%) of 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-N-methyl-N-(1-phenyl-ethyl)-acetamide hydrochloride. MS: APCI (M+H) calc'd for C23H27N3O3+H 394.5; found 394.1.
Reaction SMILES: [CH3:1][C@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11]C[O:9]1)C)[CH2:3][OH:4].[C:14](Cl)(=O)CCC.Cl>N1C=CC=CC=1>[C:8]([O:7][CH2:5][C@H:2]([CH3:1])[C@@H:3]([OH:4])[CH3:14])(=[O:9])[CH2:13][CH2:12][CH3:11]
Reactant: C[C@H](OC1CCCCO1)[C@@H](C)CO
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)OC[C@H](C)[C@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
3.76 g (0.02 tool) of (2S,3S)-2-methyl-3-tetrahydropyranyloxybutanol was dissolved in 30 ml of pyridine. Thereto was dropwise added 2.56 g (0.024 mol) of butyryl chloride at room temperature. The mixture was stirred for 30 minutes at room temperature. 2 N hydrochloric acid was added to the reaction mixture. The mixture was extracted with ether. The ether layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to purification by chromatography to obtain 3.70 g (yield: 71.7%) of a desired compound. 3.40 g (0.013 mol) of the compound was dissolved in 50 ml of methanol. Thereto was added 10 g of Amberlist 15. The mixture was stirred overnight at room temperature. The Amberlist 15 was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to purification by silica gel column chromatography (developing solvent: chloroform) to obtain 1.51 g (yield: 66.8%) of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:22])(=[O:3])[CH3:2].[N+](=[CH2:30])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.C(OCC)C>[C:1]([O:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:30])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:22])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O

Procedure:
to a solution of 8 parts of (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oic acid in 175 parts of diethyl ether is added an ethereal solution of diazomethane prepared from 30 parts of N-nitrosomethylurea, 90 parts of aqueous 40% potassium hydroxide, and 210 parts of diethyl ether as described in Org. Syn., 15, 4 (1935). The resultant mixture is allowed to stand at 5° for 30 minutes, whereupon 2 parts of acetic acid is introduced and the mixture thus obtained extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 30% ethyl acetate in benzene, on evaporation of solvent, methyl (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oate is obtained as a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1>CO.[Pd]>[CH:23]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][C:12]2[N:11]3[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)N1CCn2c(Cc3ccccc3C3=CCCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCn2c(Cc3ccccc3C3CCCCC3)nc(=O)c(O)c2C1=O
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a stirred solution of 9-benzyloxy-6-(2-cyclohex-1-enyl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (156) (170 mg, 0.352 mmol) in methanol (20 mL) was added Pd/C(10%) (170 mg) and hydrogenated under balloon pressure for 2 h at room temperature. After completion of the reaction, the mixture was filtered through a celite pad, washed with methanol (30 mL), evaporated under reduced pressure to get a crude product which was purified by preparative HPLC to get 6-(2-cyclohexyl-benzyl)-9hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (157) (115 mg, 82.72%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14]2)[CH:5]=[N:6][CH:7]=1
Reactant: ClCCCBr
Reactant: N#CCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2cncc(Br)c2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-pyridin-3-yl)-acetonitrile (Stage 220.1.3, 1.37 mmol) in dry DMF (10 ml) was added 55% sodium hydride in oil (1.507 mmol). After 30 min stirring at rt was added 1-bromo-3-chloropropane (1.507 mmol). The RM was stirred for 1 h at rt then was added 55% sodium hydride in oil (1.507 mmol). The RM was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a red oil. (HPLC: tR 2.86 min (Method A); M+H=237, 239 MS-ES)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][C@@H:14]2[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH2:20](O)[CH2:21][OH:22].CS(O)(=O)=O.N>O.C1C=CC=CC=1>[CH2:21]1[O:22][C:17]2([CH2:16][CH2:15][C@H:14]3[C@:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:18]2)[O:19][CH2:20]1
Reactant: COc1cccc([C@]23CCNC[C@H]2CCC(=O)C3)c1
Reactant: OCCO
Agent: CS(=O)(=O)O
Agent: N
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc([C@]23CCNC[C@H]2CCC2(C3)OCCO2)c1

Procedure:
25.93 g (0.1 mol) of octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone (see Example 1), 100 ml of benzene, 11.2 ml (0.2 mol) of ethylene glycol and 8.1 ml (125 mmol) of methanesulphonic acid are boiled for 3 hours in a water separator. The mixture is cooled, made basic with aqueous ammonia and extracted with methylene chloride. The organic phase is evaporated to dryness to yield octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone ethylene ketal. The ketal is dissolved in 50 ml of absolute methanol, cooled to 0° C., and 13.91 ml (0.1 mol) of triethylamine and 7.46 ml (0.12 mol) of methyl iodide are added thereto. The mixture is kept at 22° for 1 hour. The mixture, containing octahydro-4a-(3-methoxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone ethylene ketal, is mixed with 20 ml of dioxane and concentrated by evaporation. 100 ml of dioxane and 100 ml of 2 N aqueous hydrochloric acid are added to the residual oil. The resultant mixture is stirred for 2 hours at 40°, made basic with aqueous ammonia, and extracted with toluene. The extracts are concentrated by evaporation to yield the title compound as an oil, which is crystallized as the hydrogen fumarate from ethanol.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([Si:20]2(C3C=CC=CC=3)[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([Si@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)=[CH:7][CH:8]=1
Reactant: COCCCCCC1CC[Si](c2ccccc2)([C@H]2CC[C@H](CBr)CC2)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: COCCCCC[C@H]1CC[Si@H]([C@H]2CC[C@H](COc3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 4-trifluoromethylphenol and 4-(trans-4-bromomethylcyclohexyl)-4-phenyl-1-(5-methoxypentyl)-4-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: C(=O)([O-])O.[K+].Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1.[CH3:20][C:21]1[N:22]=[CH:23][S:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C(C)C.C(P(C(C)(C)C)C1CCCCC1)(C)(C)C>C1(C)C=CC=CC=1.Cl[Pd]Cl.[Cu](Br)Br>[CH3:20][C:21]1[N:22]=[C:23]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=2)[S:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1scnc1C
Reactant: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Agent: Br[Cu]Br
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(C1CCCCC1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)C(=O)O
Product: CCOC(=O)c1sc(-c2ccc(OC(C)C)c([N+](=O)[O-])c2)nc1C
Temperature: 120 °C
Yield: 66.1 %

Procedure:
A reaction mixture solution prepared by suspending 2.18 g of 4-bromo-2-nitrophenol and 2.07 g of potassium carbonate in 40 mL of dimethylformamide and adding 2.04 g of isopropyl iodide was heated under stirring at 110° C. for 14 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 2.08 g of 4-bromo-2-nitro-1-(propan-2-yloxy)benzene. (2) A suspension was prepared by adding 1.05 g of potassium hydrogen carbonate, 22 mg of palladium chloride (II) and 102 mg of a copper bromide (I) dimethylsulfide complex to 2.08 g of 4-bromo-2-nitro-1-(propan-2-yloxy)benzene obtained above, followed by suspending the mixture in 15 mL of toluene. Subsequently, a reaction mixture solution prepared by adding 1.02 g of ethyl 4-methyl-1,3-thiazole-5-carboxylate, 46.2 μL of isobutyric acid and 114 mg of di-t-butylcyclohexylphosphine to the suspension was heated at 120° C. for 14 hours under a nitrogen atmosphere. The reaction mixture solution was celite-filtered to remove insoluble matter, water was added to the filtrate, extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure, followed by purifying by a conventional method to obtain 1.38 g of ethyl 4-methyl-2-[3-nitro-4-(propan-2-yloxy)phenyl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(OCC)=O)[N+:5]([O-:14])=[C:4]([NH:15]C(OCC)=O)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:15][C:4]1[CH:3]=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:7]=[C:6]([NH2:8])[N+:5]=1[O-:14]
Reactant: C1CCNCC1
Reactant: CCOC(=O)Nc1cc(Cl)cc(NC(=O)OCC)[n+]1[O-]
Product: Nc1cc(N2CCCCC2)cc(N)[n+]1[O-]
Yield: 8 %

Procedure:
A mixture of 4-chloro-2,6-bis-(ethoxycarbonylamino)pyridine 1-oxide (10.0 g., 0.03 mole) obtained according to the procedure of Example 1(a) and 60 ml. of piperidine is heated in a sealed tube at 135° C. for a period of 48 hr. The reaction mixture is concentrated to dryness and the residual material taken up in a mixture of chloroform and 10% aqueous sodium carbonate. After separating the organic and aqueous fractions, the aqueous layer is washed with chloroform, the chloroform fractions combined and dried over magnesium sulfate. The dried chloroform extract is concentrated to a volume of approximately 100 ml., cooled and filtered to afford 0.52 g., (8% yield) of 2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide, m.p. 249°-265° C. (dec.).
Reaction SMILES: [C:1]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].CO>[CH:1]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CCCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CCCC2)C1
Reaction time: 12 h
Yield: 92.2 %

Procedure:
A mixture of tert-butyl 9-(cyclopenta-1-en-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (140 mg, 0.444 mmol) and 10% palladium on carbon (100 mg) in methanol (5 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the desired product (130 mg, 92.2%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[CH2:8][Br:11]
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COc1ccc(CBr)cc1Br
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2-Bromo-4-methyl anisole 14 (2.2 mL, 14.9 mmol) was dissolved in dichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 16.4 mmol) was added followed by AIBN (26.0 mg). The reaction was heated to reflux for 19 hrs., then cooled to room temperature and the precipitate was filtered off. The filtrate was diluted with dichloromethane and washed with 0.5 M aqueous sodium bicarbonate, followed by water. The organic mixture was dried over sodium sulfate, filtered and concentrated under vacuum to yield 15 (4.16 g, 100%). The benzyl bromide was used as the crude material without further purification.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]([Br:11])(Br)[Br:9]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+]>[Br:9][C:8]1([Br:11])[CH2:3][C:2]1([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: C=C(C)C(=O)OC
Reactant: BrC(Br)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)C1(C)CC1(Br)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a stirred solution of methyl methacrylate (3.15 g, 31.5 mmol.) and benzyltriethylammonium chloride (0.72 g, 3.2 mmol.) in aqueous NaOH (12.6 ml of a 50% w/w solution, 0.16 mol.) was slowly added bromoform (15.95 g, 63 mmol.) and the deep brown solution stirred at room temperature for 18 hours. The mixture was partitioned between dichloromethane (50 ml) and water (50 ml), the layers separated and the aqueous layer extracted with further dichloromethane (50 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give the desired methyl 2,2-dibromo-1-methylcyclopropanecarboxylate (8.0 g, 93%). This was dissolved in a mixture of TBF (70 ml) and water (30 ml) and LiOH (1.05 g, 44 mmol.) added. The mixture was vigorously stirred at room temperature for 20 hours then the THF was evaporated and the aqueous residue washed with ether (2×25 ml), acidified with 5N HCl to pH1 and extracted with ethyl acetate (2×50 ml). The combined ethyl acetate layers were dried (MgSO4) and evaporated to give the desired 2,2-dibromo-1-methylcyclopropanecarboxylic acid as a tan solid (4.2 g, 55%) which was dissolved in 2,2,2-trifluoroethanol (200 ml). Silver trifluoroacetate (5.75 g, 26 mmol.) was added under nitrogen and the reaction refluxed in the dark for 16 hours after which time the mixture was filtered and evaporated. The residue was taken up in ether (100 ml), washed with water (100 ml), and with saturated aqueous NaHCO3 (100 ml), then dried (MgSO4) and evaporated to give an oil (1.1 g) which was purified by chromatography (SiO2; dichloromethane:hexane; 4:1 w/w) to afford the desired 4-bromo-3-methyl-2(5H)-furanone (520 mg).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11]([C:13]1[S:27][C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:24]([OH:26])=O)=[CH:21][C:22]=3[S:23][C:15]=2[C:14]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:9][O:10][C:11]([C:13]1[S:27][C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:24](=[O:26])[NH:8][CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:21][C:22]=3[S:23][C:15]=2[C:14]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:12]
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NCC3CCCCC3)ccc12
Reaction time: 48 h
Yield: 55.7 %

Procedure:
Cyclohexanemethyamine (29 μl, 0.22 mmol) was added to a mixture of 1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2,6-dicarboxylic acid 2-methyl ester (42 mg, 0.11 mmol), HATU (49 mg, 0.13 mmol), and Et3N (50 1) in DMF (0.5 ml). The mixture was stirred for 2 days. Addition of EtOAc, washing with water, drying organic layers over MgSO4, filtration, and reoval of solvent in vacuo left crude material. Purification by column chromatography yielded 30 mg (58%) of 6-(cyclohexylmethylcarbamoyl)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].[CH3:19][N:20]=[C:21]=[O:22]>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][C:21](=[O:22])[NH:20][CH3:19])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: CN=C=O
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Solvent: c1ccncc1
Product: C=CCOC(=O)N1C[C@H](OC(=O)NC)C[C@H]1C=C(C)C(C)=O
Reaction time: 48 h

Procedure:
To a mixture of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (1.35 g) and methyl isocyanate (0.31 ml) was added a drop of pyridine. The resulting mixture was allowed to stand at ambient temperature for 2 days. Evaporation of the mixture gave a residue, which was chromatographed on silica gel (60 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-(methylcarbamoyloxy)-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (1.60 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)[O:4][N:3]=1.[CH3:15][N:16]1[C:20]([SH:21])=[N:19][N:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][N:16]1[C:20]([S:21][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)=[N:19][N:18]=[N:17]1
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(CCCCCCCSc2nnnn2C)on1
Yield: 101.6 %

Procedure:
7-(3-methylisoxazole-5-yl)heptylbromide (520 mg, 0.002 mol) was added to a mixture of 1-methyltetrazole thiol (232 mg, 0.002 mol) and potassium carbonate (276 mg, 0.002 mol) in anhydrous acetone (20 ml) while stirring.The mixture was heated under reflux for 3 hours. After cooling, the mixturewas filtered and the filtrate was concentrated under reduced pressure. The residual oil as dissolved in dichloromethane (50 ml), washed with water (50 ml×2), with 5% aqueous solution of potassium hydroxide (10 ml) and again with water (50 ml×2). The organic layer was dried over sodium sulfate. Removal of the solvent gave a yellow oil (600 mg) which was purified by elution from a silica gel column using methanol-dichloromethane (5:95) as an eluant to give 80% (472 mg) of a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[Cl:24][C:21]1[S:20][C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][N:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=[C:7]3[CH2:10][O:11][CH3:12])[CH:18]=2)=[CH:23][CH:22]=1
Reactant: COCc1ncc(C(=O)OC)n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ncc(C(=O)O)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 400 mg 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-methoxymethyl-3H-imidazole-4-carboxylic acid methyl ester in 5 ml THF and 1 ml water, 10.0 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT and concentrated under reduced pressure. The residue was acidified with half concentrated hydrochloric acid and filtered through a RP-18 cartridge eluting with H2O/MeCN gradient. The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][O:20][CH:21]([C:25]([NH:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:22](O)=[O:23]>>[CH3:19][O:20][CH:21]([C:25]([NH:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])=[O:26])[C:22]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:23]
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: COC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield 2-methoxy-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid. [α] 589=−71.8° (1% in CHCl3), MS m/e (%): 486.4 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28].C(N(CC)CC)C>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Yield: 70.1 %

Procedure:
0.51 g of 4-nitrophenethyl bromide, 0.5 g of 1,3-dimethyl-6-[1-piperazinyl]-2,4(1H,3H)-pyrimidinedione (Compound b) and 0.5 ml of triethylamine were suspended in 5 ml of isopropanol, and the resultant suspension was heated under reflux for 8 hours. The solvent was distilled off from the resultant reaction mixture under reduced pressure, and the residue was then dissolved in chloroform. After washing with water, the washed organic layer was dried over anhydrous sodium sulfate. In addition, the dried organic layer was treated under reduced pressure, and the solvent was then distilled off. Afterward, the residue was purified through a silica gel column chromatograph (chloroform/methanol=50/1 to 20/1 in volume ratio) to obtain 0.58 g of 1,3-dimethyl-6-[4-(2-[4-nitrophenyl]ethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.