Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)(=O)=O.C(SSC(C)C)(C)C.[CH:14]([S:17]Cl)([CH3:16])[CH3:15].[C:19]1([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@H:37]([NH:43][C:44]3[C:47]4([CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[C:46](=[O:53])[CH:45]=3)[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=2)[C:28]2[C:23](=[CH:24][CH:25]=[N:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>O1CCCC1>[CH:14]([S:17][C:45]1[C:46](=[O:53])[C:47]2([CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:44]=1[NH:43][C@@H:37]([CH2:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[N:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[CH:35][CH:34]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:16])[CH3:15]
Reactant: CC(C)SCl
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC1=CC(=O)C12CCOCC2
Agent: CC(C)SSC(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC1=C(SC(C)C)C(=O)C12CCOCC2
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Sulphuryl chloride (13.6 g) was added drop-wise to diisopropyl disulphide (25.0 g) in tetrahydrofuran (THF, 150 mL) at 0-5° C. under nitrogen. After stirring out for 30 minutes, the resulting isopropyl sulphenyl chloride preparation was introduced slowly, from a graduated dropping funnel, to a solution of Example 9 (30.0 g) in THF (500 mL), held at the same temperature. Conversion to product was complete after 85 mL of the stock solution had been charged. The reaction was quenched with 10% sodium bicarbonate solution (175 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic solutions then washed with saturated brine (100 mL). The isolated organic phase was solvent swapped to ethanol (650 mL), by distillation at atmospheric pressure, from which the product crystallised on cooling. This suspension was filtered at 20° C. and the title compound washed with ethanol (2×30 mL) prior to drying in vacuo at 50-60° C. (26.9 g; 77.5% yield, off-white powder m.p. 221° C.). δH (DMSO d6, 390K) 9.83 (1H, s), 9.52 (1H, s), 8.94 (1H, d, J 9.5 Hz), 8.65 (1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.78 (2H, d, J 8.5 Hz), 7.68 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8.5 Hz), 7.12 (1H, d, J 5.7 Hz), 5.26 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.81-3.76 (2H, m), 3.64-3.55 (2H, m), 3.20 (1H, dd, J 13.8, 4.3 Hz), 2.96 (1H, dd, J 13.8, 10.3 Hz), 2.81-2.74 (1H, m), 2.06-1.93 (2H, m), 1.50-1.47 (1H, m), 1.32-1.28 (1H, m), 1.23 (3H, t, J 7.1 Hz), 1.07 (3H, d, J 6.6 Hz), 1.05 (3H, d, J 6.6 Hz); m/z (ES+, 70V) 547.2 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:37])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([Cl:36])[CH:27]=2)[C@@H:20]([CH3:38])[C:19]1=[O:39])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[Li+].[BH4-]>CO>[Cl:36][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C@@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][C:7]([N:9]3[CH2:16][CH2:15][C:12]4([CH2:13][CH2:14]4)[C@H:11]([OH:17])[CH2:10]3)=[O:8])[C:19](=[O:39])[C@@H:20]2[CH3:38])=[O:37])[CH:31]=[CH:30][C:29]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)[C@@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: C[C@H]1C(=O)N([C@@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 66 %

Procedure:
In analogy to the procedure described in example 53, (R)-2-[(S)-4-(3-chloro-4-trifluoromethyl-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester (example 145) and LiBH4 (2 M in THF)/MeOH gave the titled compound in 66% yield as amorphous white solid. MS: 561.20 (MH+, 1Cl).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])C)=O)C1C=CC=CC=1.C(N1CCOCC1)C.ClC(O[CH2:32][CH:33]([CH3:35])[CH3:34])=O>O1CCCC1>[C:33]([O:19][C:17](=[O:18])[C@@H:12]1[CH2:13][CH2:14][CH2:16][NH:11]1)([CH3:35])([CH3:34])[CH3:32]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1
Temperature: -15 °C
Reaction time: 10 h

Procedure:
0.566 g (2.134 mmol) of N-(benzyloxycarbonyl)-L-leucine was taken up in 15 ml of tetrahydrofuran and cooled to -15° C. 0.245 g (2.134 mmol) of N-ethylmorpholine and 0.291 g (2.134 mmol) of isobutyl chloroformate were added. After 5 minutes the tetrahydrofuran solution prepared as described in the previous paragraph was added, followed by 0.451 g (4.27 mmol) of N-ethylmorpholine. The mixture was stirred at room temperature for 10 hours, the solvent was then removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution and then dried over anhydrous sodium sulphate. The solvent was removed under a vacuum to give 1.5 g of crude N-[3(S)-[[N-(benzyloxycarbonyl)-L-leucyl]amino]-2-(R and S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as an oil. The two isomers were separated by chromatography on silica gel using 50% n-hexane in ethyl acetate for the elution. There were obtained 180 mg of isomer 1 of N-[3(S)-[[N-(benzyloxycarbonyl)-L-leucyl]amino]-2(R or S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a crystalline material: Rf (System A): 0.34; MS: m/e 582 [M+H]+, and 70 mg of isomer 2 as a crystalline material: Rf (System A): 0.28: MS: m/e 582 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH3:23].C[Si](C)(C)[O-].[K+]>O1CCCC1>[F:1][C:2]1[C:10]2[O:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH3:23]
Reactant: COC(=O)c1cc2ncoc2c(F)c1Nc1ccc(I)cc1C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2ncoc2c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution comprised of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylate (0.024 M) in tetrahydrofuran is added solid potassium trimethylsilanolate (5.14 equiv.). The reaction mixture is stirred at ambient temperature under argon for 16 hours. An additional equivalent of potassium trimethylsilanolate is added and the mixture stirred 30 minutes. The reaction mixture is concentrated in vacuo to give a residue that is then taken up into 1:1 (v/v)ethyl acetate-diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, water, and brine, is dried (MgSO4), is concentrated in vacuo, and chased with chloroform to give a crude product. Recrystallization from an appropriate solvent like ethanol gives the purified desired product. cl Example 6
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: CN
Product: CNC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 78 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using methylamine (2 M solution in THF) instead of isopropylamine, to the title compound (81 mg, 78%), which was obtained as a white solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Br[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of pyridin-2-amine, 9, (0.5 g; 2.5 mmol), 2-bromo-5-nitropyridine, 10, (0.28 g; 2.9 mmol), 1,3-Bis(diphenylphosphino)propane (0.04 g; 0.08 mmol) in toluene was added to a mixture of sodium tert butoxide (0.33 g; 3.5 mmol) and Pd(dba)3 (0.05 g; 0.05 mmol) in toluene and allowed to stir at ambient temperature for 18 hours. The mixture was filtered through a bed of celite and the solvent removed under reduced pressure. The crude mixture was purified on a flash silica gel column (hexane/ethyl acetate) to afford 5-nitro-N-(pyridin-2-yl)pyridin-2-amine, 11, (0.25 g; 47%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][C:17]=3[N+:26]([O-:28])=[O:27])=[N:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=3[N+:26]([O-:28])=[O:27])=[N:13][N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nnc(-c3ccc(C(=O)O)cc3[N+](=O)[O-])o2)cc1
Yield: 41.5 %

Procedure:
A mixture of methyl 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]-3-nitrobenzoate (1.50 g), 1 M aqueous sodium hydroxide solution (7.8 ml) and tetrahydrofuran (10 ml) was heated under reflux for 30 min. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1-10:1, volume ratio) to give 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]-3-nitrobenzoic acid (0.600 g, yield 42%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 233–235° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10](Br)([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1
Temperature: 58 °C
Reaction time: 8 h

Procedure:
A solution of 30 g of 4-hydroxybenzaldehyde and 46 g of isopropyl bromide in 300 ml of N,N-dimethylformamide is treated with 104 g of finely powdered potassium carbonate and the mixture is stirred at 58° C. overnight. The suspension is suction filtered and the filtrate is concentrated in a vacuum. A solution of the residue in 100 ml of diethyl ether is washed twice with 100 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the crude product on silica gel with hexane/ethyl acetate (vol. 9:1) gives 40g of 4-(isopropyloxy)benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=2)=[CH:4][CH:3]=1.Cl.Cl.NC1C2CCN(CC2)C1.CCN(C(C)C)C(C)C.CS(C)=[O:49]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([OH:49])[N:18]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cnccn23)n1
Reactant: CS(C)=O
Agent: Cl
Agent: NC1CN2CCC1CC2
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nccc(-c2c(-c3ccc(F)cc3)nc3cnccn23)n1
Yield: 20 %

Procedure:
A solution of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine (Preparation #4, 0.050 g, 0.14 mmol), 3-aminoquinuclidine dihydrochloride (0.054 g, 0.27 mmol), DIEA (0.047 mL, 0.27 mmol), and DMSO (1 mL) were shaken at about 80° C. for about 24 h. Additional DIEA (0.100 mL) was added to the mixture. The mixture was concentrated in vacuo to remove DMSO. The material was treated with saturated solution of NaHCO3 (30 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was washed sequentially with EtOAc (3×50 mL) and DCM (50 mL). The combined organic layers were dried over MgSO4 and concentrated. The mixture was triturated in EtOAc and filtered to yield the title compound (0.007 g, 20%): LC/MS (Table 1, Method b) Rt=1.3 min; MS m/z: 308.2 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=3[N:23]([CH3:33])[S:24]([C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)(=[O:26])=[O:25])=[N:6][CH2:5]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.Cl.[NH:49]1[CH2:54][CH2:53][S:52](=[O:55])[CH2:51][CH2:50]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O.C(N(CC)CC)C>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([N:23]([CH3:33])[S:24]([C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:26])[CH:13]=1)[NH:10][C:9]([C:7]1[S:8][CH:4]([CH2:3][N:49]3[CH2:54][CH2:53][S:52](=[O:55])[CH2:51][CH2:50]3)[CH2:5][N:6]=1)=[CH:17]2
Reactant: O=S1CCNCC1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 18 %

Procedure:
To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (280 mg), trifluoroacetic acid (3.5 mL) and water (10.5 mL) was added concentrated sulfuric acid (3.5 mL), and the mixture was stirred at 60° C. for 3.5 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (10 mL), thiomorpholine 1-oxide hydrochloride (103 mg) and triethylamine (0.1 mL) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (233 mg) was added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography (methanol:ethyl acetate=0:100-10:90), and the obtained crude product was further purified by preparative HPLC to give the title compound (56 mg, yield 18%) as a white solid. MS: 581(MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C([Li])(C)(C)C.[C:38]1(=[O:42])[CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[NH2:15][C:6]1[C:5]2=[N:4][N:3]([CH2:30][CH2:31][CH3:32])[C:2]([CH2:1][C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1C
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 31.9 %

Procedure:
A solution of di(tert-butyl) 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (1.32 g, 3.00 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was cooled to −78° C. under an argon atmosphere. tert-Butyllithium (7.06 mL of a 1.7 M solution in pentane) was added over a period of eight minutes, and the resulting dark-colored solution was stirred at −78° C. for 40 minutes. Cyclobutanone (1.05 g, 15 mmol) was added over a period of two minutes, and the −78° C. bath was replaced with a 0° C. bath. The reaction mixture was stirred for 10 minutes, and then saturated aqueous ammonium chloride (30 mL) was added. The aqueous layer was separated and extracted three times with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.3 g) was purified by automated flash chromatography and then boiled in 2 M hydrochloric acid for 30 minutes. The solution was allowed to cool to room temperature overnight and then made basic with the addition of 2 M aqueous sodium carbonate. The resulting solution was extracted four times with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.2 g) was purified twice by automated flash chromatography and recrystallized from acetonitrile to provide 297 mg of 1-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclobutanol as a white solid, mp 191-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.[CH2:15]=[O:16].O>CO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:15][OH:16])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-n2oc(=O)[nH]c2=O)cc1
Reactant: C=O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Reaction time: 2 h

Procedure:
2-(4-Methylphenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-methylphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin- 3,5-dione.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([OH:9])[CH:8]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:21]1[CH2:22][CH2:23][O:24][CH:20]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:9][C:7]1[CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=[CH:5][C:6]=1[CH3:10]
Reactant: BrCCCCCCCCC1OCCO1
Reactant: Cc1ccc(CO)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CO)cc1OCCCCCCCCC1OCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
To a stirred solution of 5-(hydroxymethyl)-2-methylphenol (0.57 g, 4.15 mmol) in dimethyl formamide (15 mL), was added 2-(8-bromooctyl)-1,3-dioxolane (1.00 g, 3.77 mmol) and potassium carbonate (0.63 g, 4.57 mmol), and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulphate), filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-7% ethyl acetate in iso-hexane to afford the title compound (0.5 g, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([N:14]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH3:31])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)C(F)(F)F)c2c(c(C)c1OC)COC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1N(C)C(=O)C(F)(F)F)C(=O)OC2
Reaction time: 24 h

Procedure:
To a solution of 0.35 g (0.82 mmol) of methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(trifluoroacetylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 4 ml of dimethylformamide was added 0.47 g (3.40 mmol) of potassium carbonate and 0.23 ml (3.69 mmol) of iodomethane. The mixture was stirred for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(N-trifluoroacetyl-N-methylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, an oil. NMR: δ 5.22-5.17 (multiplet ("m"), 2H); 5.10-5.04 (broad triplet, 1H); 3.81 (singlet ("s"), 3H); 3.62 (s, 3H); 3.42-3.27 (m, 5H); 2.45-2.25 (m, 5H); 1.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:30])[CH:12]2[CH2:29][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([O:27]C)=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[Li+].[OH-].CC(O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:30])[CH:12]2[CH2:29][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C1CCc2c(CC(=O)O)c3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of the product of Step 11 (0.38 g) in 10 mL of THF were added 5 mL of MeOH and 5 mL of 1N LiOH. After stirring for 2 h, 2 mL of AcOH was added and the mixture was partitioned between 50 mL of EtOAc and 20 mL of brine. The EtOAc extract was dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was swished from 3:1 EtOAc/hexane to give 0.18 g of the title compound. 1H NMR (500 MHz, acetone-d6) δ 8.11 (m, 2H), 7.53 (d, 1H), 7.47 (t, 2H), 7.28 (d, 1H), 7.10 (dd, 1H), 7.04 (dd, 1H), 4.53 (m, 1H), 4.20 (m, 1H), 3.90 (t, 1H), 3.67 (d, 1H, A of AB), 3.60 (d, 1H, B of AB), 3.15 (m, 1H), 2.97 (3H), 2.85-2.92 (m, 1H), 1.90-2.00 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].O>CN(C=O)C>[CH2:24]([O:26][C:27]([C:28]1[O:17][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][C:12]=2[CH:13]=1)=[O:30])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a solution of 4-benzyloxy-2-hydroxy-benzaldehyde (10.0 g, 44 mmol) in DMF (400 mL) is added K2CO3 (18.6 g, 131 mmol) followed by bromo-acetic acid ethyl ester (5.4 mL, 8.1 g, 48 mmol) and the resulting mixture was heated (80° C., 12 h). The reaction mixture was cooled (rt) and treated with H2O (200 mL). The solid was filtered to afforded the title compound as a beige solid (8.1 g, 62%). MS (ESI): mass calcd. for C18H16O4, 296.1; m/z found, 297.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.53 (d, J=8.7, 1H), 7.48-7.30 (m, 6H), 7.12 (d, J=2.0, 1H), 7.01 (dt, J=6.1, 3.1, 1H), 5.09 (d, J=28.6, 2H), 4.42 (q, J=7.1, 2H), 1.37 (dt, J=36.6, 9.6, 3H).