Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2.[OH-].[K+].I[CH3:20]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:20])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2
Reactant: CCCCCCc1cc2cc(Cl)ccc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCc1cc2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution 5-Chloro-2-hexyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, iodomethane was added and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-Chloro-2-hexyl-1-methyl-1H-indole was purified by column chromatography.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CN(C=O)C>[C:1]1([S:7][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Sc2ccccc2)c1
Temperature: 100 °C

Procedure:
A mixture of thiophenol (1.0 g, 9.1 mmol), 3-iodonitrobenzene (1.9 g, 7.6 mmol), CuI (0.14 g, 0.76 mmol), K2CO3 (1.67 g, 12.1 mmol), and DMF (10 mL) was heated to 100° C. in a flame-dried sealed tube for 16 h. The mixture was allowed to cool and was poured over ice. The resulting mixture was extracted with EtOAc (2×), and the organic extracts were combined and washed sequentially with equal volumes of aqueous 1M HCl, water, and aqueous 1M NaOH. The solution was dried, concentrated, and the residue was purified by FCC (100:0 to 95:5 hexanes/EtOAc) to provide the titled compound, which was contaminated with ca. 10% thiophenol (1.43 g), and was taken on to subsequent steps without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12]>CO.Cl>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: O=Cc1ccccc1Br
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Product: COC(OC)c1ccccc1Br
Yield: 84.1 %

Procedure:
A solution of 2-bromobenzaldehyde (451.9 g, 2.44 mol), trimethyl orthoformate (324 g, 3.05 mol) and concentrated hydrochloric acid (4.0 ml, 0.05 mol) in methanol (2 L) was refluxed for four hours. The volatile components were evaporated on the rotary evaporator and the residue dried over anhydrous potassium carbonate, filtered, and distilled (66°-72° C. at 0.1-0.2 mm) to give 474.1 g (84%) of the 2-Bromobenzaldehyde Dimethyl Acetal compound as a colorless oil. 'H NMR (CDCl3): 3.35 (s, 6, OCH3), 5.50 (s, 1, CH), 7.5 (m, 4, Ar--H).
Reaction SMILES: [CH3:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH:4](OCC)[O:5]CC.Cl>O.CC(C)=O>[CH3:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH:4]=[O:5]
Reactant: CCOC(CC(C)P(=O)(OCC)OCC)OCC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(C)CC=O
Temperature: 62 °C

Procedure:
A solution of 400 grams (1.42 moles) of diethyl 1-methyl-3,3-diethoxypropylphosphonate in 1 liter of water and 4 liters of acetone containing 30 ml of concentrated hydrochloric acid was stirred and refluxed under nitrogen at 62° C for 1.5 hours. Low boiling materials were removed at 80° C/16 mm to give the diethyl 1-methyl-3-oxopropylphosphonate in a 296 grams (quantitative) yield as a pale yellow liquid. The structure was confirmed by NMR.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)[CH2:4]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of methyl (2-aminoindan-5-yl)acetate hydrochloride (2.43 g), potassium carbonate (5.52 g), water (60 ml), ethyl acetate (60 ml) and 4-chlorophenylsulfonyl chloride (2.11 g) is stirred at room temperature for one hour. The ethyl acetate layer is separated from the reaction mixture, washed with aqueous saline solution, dried, and distilled under reduced pressure to remove the solvent. The resulting crude product is recrystallized from a mixture of ethyl acetate and n-hexane to give methyl [2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (3.02 g).
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)C.[C:20]([O:23]CC)(=[O:22])[CH3:21].C(OO)(=O)C>O>[C:20]([O:23][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCCCOc1ccc(OCCCC)c(C(C)=O)c1
Agent: CC(=O)OO
Solvent: O
Product: CCCCOc1ccc(OCCCC)c(OC(C)=O)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Next, 67.1 [g] of 2-acetyl-1,4-di-n-butoxybenzene was added to 54 [ml] of ethyl acetate, 83 [ml] of 40 [wt %] peracetic acid was dripped in at 40° C., and the reaction was carried out while stirring at 40° C. for 18 hours. The reaction liquor was poured into 700 [ml] of water at room temperature, and extracted twice with 300 [ml] of ethyl acetate. The extraction solvent (i.e. the ethyl acetate solution) was washed with water, and concentrated by evaporating off the ethyl acetate solvent under reduced pressure. Concentration of the extraction solution was continued until there was almost no further evaporation of ethyl acetate (i.e., almost no further ethyl acetate remained in the extraction solution). Subsequently, the separated crystals were filtered off using filter paper, washed with a small amount of ethyl acetate, and dried to obtain 53.0 [g] of 2-acetoxy-1,4-di-n-butoxybenzene.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH:34]=[O:35])=[C:18]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]([NH2:33])=[O:32])=[CH:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(C1C=C2C(=CC=1)C(=O)N(C1C(C=O)=C(N3C4C(=CC=CC=4)C(C#N)=C3)C=CC=1)N=C2)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:34][OH:35])=[C:18]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]([NH2:33])=[O:32])=[CH:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3C=O)ncc2c1
Agent: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c5ccccc54)c3C=O)ncc2c1
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3CO)ncc2c1
Yield: 63 %

Procedure:
The preparation of 1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3-carboxamide, via nitrile hydrolysis of 1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3-carbonitrile (82 mg, 0.18 mmol) and use of catalyst hydrido(dimethylphosphinousacid-kp)[hydrogen bis-(dimethylphosphinito-kp)]platinum(II) catalyst (5 mg, 0.064 mmol) was carried out in a procedure analogous to that described in Example 18. Similar work up and purification provided desired product as a light yellow glassy solid (54 mg, 63% yield). LC/MS calcd for C28H24N4O3 (m/e) 464.5, obsd 465.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 7.21-7.37 (m, 3H) 7.48-7.59 (m, 2H) 7.67-7.76 (m, 2H) 7.85 (t, J=7.93, 1.00 Hz, 1H) 7.90 (s, 1H) 8.14-8.20 (m, 1H) 8.30 (s, 1H) 8.37 (d, J=8.31 Hz, 1H) 9.56 (s, 1H)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1([O:19][Si](C)(C)C)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)#[N:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:8][CH2:7][C:9]1([OH:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: C[Si](C)(C)OC1(C#N)CCCc2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(O)CCCc2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of lithium aluminum hydride (12 g, 0.32 mol, 2.25 equivalents) in refluxing THF (150 mL), under a nitrogen atmosphere, was added, dropwise over a period of 30 minutes, a solution of 1-cyano-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene, from Step 1, in 150 mL of THF. The resulting mixture was refluxed for 4 hours and then cooled to ambient temperature and diluted with THF. Sodium sulfate decahydrate was added to quench the excess lithium aluminum hydride. The solids were filtered over Celite® filter aid. The filtrate was then concentrated to give a light brown, waxy solid which was used in the next step without purification.
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10](=[O:21])[CH2:11][CH2:12][CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][CH:2]([NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)NC(=O)CCC(O)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)CCCC(C)NC(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 78 %

Procedure:
A mixture of N-(1,5-dimethyl-hexyl)-4-hydroxy-4-phenyl-butyramide (3.50 g, 12.0 mmol), prepared in the previous step, and pyridinium chlorochromate (3.89 g, 18.0 mmol) in 150 ml of methylene chloride was stirred at room temperature for 1.25 hours. The reaction was poured onto 400 g of silica gel (230-400 mesh) and the material eluted with methylene chloride-ethyl acetate. Isolation of the major component gave N-(1,5-dimethyl-hexyl)-4-oxo-4-phenyl-butyramide (2.71 g, 78%) as a light green solid, mp 84-87° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[NH2:40])[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[NH2:40][C:39]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[NH:29][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N)c(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (3.76 g, 19.9 mmol) and triethylamine (2.76 mL, 19.9 mmol) in THF (25 mL) was added 2-methylpropyl chlorocarbonate (2.58 mL, 19.9 mmol) under ice-cooling, and the mixture was stirred for 30 min. To this solution was added dropwise a solution of methyl 3,4-diaminobenzoate (3.00 g, 18.1 mmol) in THF (15 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was triturated with ethyl acetate to give the title compound (4.21 g, yield 69%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.Br.[O:20]=[C:21]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)[CH2:22][CH2:23][C@@H:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[C:30]([O:32][CH3:33])=[O:31].O>CN1CCCC1=O.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[S:13][CH2:12][CH2:11][N:27]1[CH2:28][CH2:29][C@@H:24]([CH2:23][CH2:22][C:21](=[O:20])[C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][CH:35]=2)[C@@H:25]([C:30]([O:32][CH3:33])=[O:31])[CH2:26]1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: BrCCSc1cccs1
Agent: Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 60 °C
Yield: 49.9 %

Procedure:
3.8 cm3 of diisopropylethylamine and 1.54 g of 2-(2-bromoethylthio)thiophene are added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 2.23 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate hydrobromide in 350 cm3 of anhydrous N-methylpyrrolidone. After heating for 3 hours at a temperature in the region of 60° C., the reaction mixture is cooled to approximately 20° C., poured onto 50 cm3 of water; and 25 cm3 of ethyl acetate are added. The mixture obtained is extracted 3 times with 25 cm3 of ethyl acetate. The organic extracts are combined, washed twice with 50 cm3 of distilled water and then extracted successively with 25 cm3 of 1N aqueous HCl solution (the pH is brought to 2) and then with 25 cm3 of distilled water. The aqueous phases are combined and the pH is brought to 9 by addition of 25 cm3 of a 1N aqueous sodium hydroxide solution. The resulting aqueous phase is extracted with 50 cm3 of ethyl acetate and then 3 times with 25 cm3 of ethyl acetate. The organic phases are combined, washed with 50 cm3 of distilled water and then dried over sodium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is purified by chromatography under a pressure of 50 kPa of nitrogen on a column of silica gel (particle size 20-45μ; diameter 3.4 cm; weight of silica 47 g), elution being carried out with an ethyl acetate/cyclohexane (60/40 by volume) mixture and 40-cm3 fractions being collected. Fractions 8 to 42 are combined and then concentrated under the above conditions to afford 1.27 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in the form of a yellow oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[O:15][C:16]2[C:21]([C:22](=[O:24])[CH:23]=1)=[CH:20][CH:19]=[C:18]([O:25]C)[CH:17]=2>O>[OH:25][C:18]1[CH:17]=[C:16]2[C:21]([C:22](=[O:24])[CH:23]=[C:14]([O:13][CH3:12])[O:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c(=O)cc(OC)oc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(=O)c2ccc(O)cc2o1
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
Under nitrogen atmosphere, 170 mg of aluminium trichloride was added to 5 ml solution of toluene with 103 mg of 2,7-dimethoxy-4H-chromen-4-one, and the mixture was stirred at 90° C. for 4 hours. Water was added to the reaction solution, the deposited white solid was filtered, separated and purified by preparative thin-layer chromatography (chloroform/methanol=9/1), to obtain 62 mg of the above compound as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2C=C(N2CCN(C)CC2)[C:9]2[CH:25]=[CH:26][CH:27]=[CH:28][C:8]1=2>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC.CCCCCC.C1COCC1>[CH:3](=[C:2]1[C:1]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:13][C:7](=[O:6])[C:8]2[CH:28]=[CH:27][CH:26]=[CH:25][C:9]1=2)[CH3:4]
Reactant: [Li]CCCC
Reactant: CN1CCN(c2cc3ccccc3c(=O)c3ccccc23)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC=C1c2ccccc2CC(=O)c2ccccc21
Yield: 98 %

Procedure:
To a stirred slurry of ethyltriphenylphosphonium bromide (21 g, 0.057 mole) in ether (400 ml) was added dropwise butyllithium in hexane (48 ml, 1.3 M). To the resulting solution was added a solution of 1-(5-keto-5H-dibenzo[a,d]cyclohepten-10-yl)-4-methylpiperazine (13.5 g, 0.044 mole) in THF (100 ml). The resulting mixture was stirred and heated under reflux for 3.5 hours, cooled and poured into ice H2O (300 ml). The organic phase was separated and the aqueous phase extracted with ether (2×150 ml). The combined organic solutions were concentrated under reduced pressure. The concentrate was stirred with a mixture of 1 N aqueous hydrochloric acid (300 ml) and ether (300 ml). The ether phase was separated, the aqueous phase extracted with ether, and the combined ether solutions dried over Na2SO4, filtered and the filtrate concentrated to 100 ml. Triphenylphosphine oxide was removed by filtration and the filtrate was chromatographed on silica-gel which was eluted with chloroform to yield 10.1 g (98%) of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, m.p. 93°-95° C.
Reaction SMILES: C([O:9][CH:10]([C@@H:16]1[CH2:20][C@@H:19]([O:21]C(=O)C)[C@H:18]([N:25]2[C:29]3[N:30]=[C:31]([NH2:35])[NH:32][C:33](=[O:34])[C:28]=3[S:27][C:26]2=[O:36])[O:17]1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:35][C:31]1[NH:32][C:33](=[O:34])[C:28]2[S:27][C:26](=[O:36])[N:25]([C@H:18]3[C@H:19]([OH:21])[CH2:20][C@@H:16]([CH:10]([CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[OH:9])[O:17]3)[C:29]=2[N:30]=1
Reactant: CC(=O)O[C@@H]1C[C@@H](C(OC(=O)c2ccccc2)C2CCCC2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](C(O)C3CCCC3)C[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.1 %

Procedure:
To a solution of [[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]-cyclopentyl-methyl] benzoate (compound 11d, 70 mg, 0.14 mmol) in methanol (10 mL) was added K2CO3 (136 mg, 1 mmol). After being stirred at room temperature for 12 hours, the reaction mixture was adjusted to pH 7.0 by addition of HOAc (120 mg, 2 mmol), concentrated in vacuo and the residue was purified by preparative HPLC to afford 4.7 mg of 5-amino-3-[(2R,3R,5S)-5-[cyclopentyl(hydroxy)methyl]-3-hydroxy-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 11) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:5]=C[C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1[N:23]=CC(N)=CC=1>>[F:9][C:8]([F:11])([F:10])[C:7]1[N:23]=[CH:5][C:4]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: Nc1ccc(C(F)(F)F)nc1
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a method analogous to the method used to prepare Intermediate 39 using 6-(trifluoromethyl)pyridin-3-amine as the starting material. LCMS (R—SO3−)=226.2.
Reaction SMILES: [N+:1]([C:4]1[CH:52]=[CH:51][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[C:40]5[C:35](=[C:36]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[CH:38][CH:39]=5)[C:22]5([CH2:27][CH2:26][N:25](CC6C=CC=CC=6)[CH2:24][CH2:23]5)[CH2:21]4)[C:14]=3[C@H:13]([CH3:50])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)OC(Cl)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[C:40]5[C:35](=[C:36]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH:37]=[CH:38][CH:39]=5)[C:22]5([CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)[CH2:21]4)[C:14]=3[C@H:13]([CH3:50])[CH2:12]2)=[O:9])=[CH:51][CH:52]=1)([O-:3])=[O:2]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCNCC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21

Procedure:
To a stirred solution of (5R,7R)-4-(1′-benzyl-4-((tert-butoxycarbonylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (30 mg, 0.043 mmol) in toluene (1 mL) was added 1-chloroethyl carbonochloridate (0.009 mL, 0.08 mmol) at about 0° C. The reaction mixture was heated at reflux for 1 h and then evaporated in vacuo. The residue was dissolved in MeOH (1 mL) and the mixture was heated at reflux for 1 h. After cooling, the solvent was evaporated in vacuo to give crude (5R,7R)-4-(4-((tert-butoxycarbonylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate, which was used in the next step without further purification. LCMS (APCI+) m/z 615 [M+H]+; Rt=3.31 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH:11]2[CH2:14][C:15]3[C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=3[CH:10]2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26].O>O1CCCC1>[ClH:26].[CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:14][C:15]3[C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=3[CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1OC)CC1C(=O)N(Cc3ccccc3)C(=O)C21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)CC1CN(Cc3ccccc3)CC21

Procedure:
6.19 g. of the resultant compound of Example 4 suspended in 15 ml. tetrahydrofuran (THF) was treated with 110 ml. 1M BH3 in THF under nitrogen atmosphere. The solution was refluxed 4 hours, then cooled and a solution of 35 ml. concentrated hydrochloric acid and 35 ml. water was added slowly. The solution was refluxed for 20 minutes and then concentrated in vacuum. The residue was made basic with potassium hydroxide solution and extracted with chloroform. The chloroform extracts were dried (K2CO3) and concentrated. The residue was acidified with HCl in isopropyl alochol and this solution was concentrated. Acetonitrile was added to give the product 5.78 g., m.p. 176°-178° C.
Reaction SMILES: [O:1]([CH:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>ClCCl.O1CCOCC1>[ClH:20].[O:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of tert-butyl 3-phenoxypyrrolidine-1-carboxylate (172 mg, 0.65 mmol; which may be prepared as described in Step 2) in dichloromethane (4.3 mL) was added dropwise HCl 4N in dioxane (3.2 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (135 mg, quantitative) as an orange oil.