Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=2[CH3:15])([OH:8])[CH3:7])=[CH:2]1.[H-].[Na+].CI.[C:20](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][O:8][C:6]([C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[CH3:15])([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH3:7]
Reactant: O=C([O-])O
Reactant: Cc1nc(C)c(C(C)(O)c2ccoc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(C)(c1ccoc1)c1oc(C)nc1C
Reaction time: 0.33 h

Procedure:
1-(3-Furyl)-1-(2,4-dimethyl-5-oxazolyl)ethanol (2 g) in dry N,N-dimethylformamide (15 ml) was added to a stirred suspension of sodium hydride (80%, 300 mg) in dry N,N-dimethylformamide (10 ml) at 0° C. After 20 minutes, methyl iodide (1.5 g) was added dropwise. The mixture was allowed to warm to room temperature and after 30 minutes aqueous sodium hydrogen carbonate was added.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[CH3:11][C:12]([O-])=[O:13].[Na+].CC(O)=O.CC(OC(C)=O)=O>C1(C)C=CC=CC=1>[CH3:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:1][C:12](=[O:13])[CH3:11])[N:7]=1
Reactant: Cc1nc(N)ncc1C#N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ncc(C#N)c(C)n1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A 250 ml 3-neck flask was equipped with an overhead stirrer, reflux condenser, and a thermocouple. The flask was charged with 2-amino-4-methyl-5-cyanopyrimidine (8.00 g, 59.64 mmol) and an anhydrous NaOAc ((0.035 g, 0.43 mmol) in a mixture of HOAc (16.00 g, 266.43 mmol) and Ac2O (16.00 g, 156.72 mmol). The resultant suspension was stirred and heated to 115° C. to yield a brown suspension, which was stirred at 115° C. for 2 h during which time all starting material dissolved to yield a solution. The resultant mixture was heated at 115° C. for 6.5 hours and then cooled to room temperature to afford a suspension. Toluene (69.70 g) was added to the suspension, and the resultant mixture was then heated to about 108-114° C. to distill about 70 ml of solvent atmospherically (solution was effected at 70° C.). The resultant solution was cooled, fresh toluene (69.70 g) was added, and about 90 ml of solvent was distilled atmospherically at about 110-115° C. The resultant solution was cooled to 90° C., whereupon the mixture began to solidify. Toluene (8.7 g) and heptane (61.2 g) were added and the resultant suspension was stirred and gradually cooled to room temperature. After stirring at room temperature for 1 h, the suspension was filtered and the solid was washed twice with heptane (27.2 g portions) and then dried in a vacuum oven at 70° C. overnight. The title compound—N-(4-Methyl-5-cyano-2-pyrimidinyl)-acetamide—was isolated as a solid.
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 of 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: [F:1][C:2]([F:25])([F:24])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:33][N:34]=[C:35]=[O:36]>C1COCC1>[CH3:33][NH:34][C:35]([N:10]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)[C:6]2=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[N:7]2[CH2:8][CH2:9]1)=[O:36]
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NCCn1c(C(F)(F)F)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To tert-butyl 6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (600 mg, 1.67 mmol), THF (3 mL) and Et3N (698 μL, 5.01 mmol) was added methyl isocyanate (199 μL, 3.34 mmol). The mixture was allowed to stir at room temperature for 2 h. The mixture was charged with additional Et3N (698 μL, 5.01 mmol) and methyl isocyanate (199 μL, 3.34 mmol), and the reaction was stirred at room temperature for 3 d. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (40 mL) and washed with water (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 2-(methylcarbamoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (680 mg, 97%). ESI-MS m/z calc. 416.2, found 417.4 (M+1)+; Retention time: 1.73 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.14 (q, J=4.3 Hz, 1H), 6.56 (d, J=3.4 Hz, 1H), 6.03 (d, J=3.9 Hz, 1H), 3.88 (t, J=5.4 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 3.69-3.55 (m, 2H), 3.23-3.03 (m, 2H), 2.78-2.62 (m, 2H), 2.56 (d, J=4.4 Hz, 3H), 1.76-1.60 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>>[CH2:14]([O:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:24](=[O:25])[CH2:23][C:22]([CH3:21])=[O:26])=[CH:5][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C1CC(=O)O1
Reactant: OCCc1ccc(OCCOCc2ccccc2)cc1
Product: CC(=O)CC(=O)OCCc1ccc(OCCOCc2ccccc2)cc1

Procedure:
Diketene (3-buteno-β-lactone, available, e.g., from Aldrich Chemical Co.) is then added to the hydroxyalkylbenzene derivative 4 under basic conditions, e.g., using triethylamine in dimethoxyethane (DME) to form a ω-phenylalkylacetoacetate derivative (5). For example, 1-(2-hydroxyethyl)-4-(2-benzyloxyethoxy)benzene is reacted with diketene to afford 2-[4-(2-benzyloxyethoxy)phenyl]ethylacetoacetate (5). (Step 5.)
Reaction SMILES: OC1NC2C(C=1)=CC=CC=2.CC1C(C)(C)C2C(=CC=C(CC(O)=O)C=2)N=1.Cl.[C:28]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]N)=[CH:34][CH:33]=1)([OH:30])=[O:29].[OH:40][CH2:41][CH:42]([CH2:46][OH:47])[C:43](=O)[CH3:44]>C(O)(=O)C>[OH:40][CH2:41][C:42]1([CH2:46][OH:47])[C:36]2[C:35](=[CH:34][CH:33]=[C:32]([CH2:31][C:28]([OH:30])=[O:29])[CH:37]=2)[N:38]=[C:43]1[CH3:44]
Reactant: NNc1ccc(CC(=O)O)cc1
Reactant: CC(=O)C(CO)CO
Agent: CC1=Nc2ccc(CC(=O)O)cc2C1(C)C
Agent: Cl
Agent: Oc1cc2ccccc2[nH]1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(CC(=O)O)cc2C1(CO)CO

Procedure:
The hydroxy-indole compound is readily prepared by a known method (P. L. Southwick et al., One pot Fischer synthesis of (2,3,3-trimethyl-3-H-indol-5-yl)-acetic acid derivatives as intermediates for fluorescent biolabels. Org. Prep. Proced. Int. Briefs, 1988, 20(3), 279-284). Reaction of p-carboxymethylphenylhydrazine hydrochloride (30 mmol, 1 equiv.) and 1,1-bis(hydroxymethyl)propanone (45 mmole, 1.5 equiv.) in acetic acid (50 mL) at room temperature for 30 minutes and at reflux for one minute gives (3,3-dihydroxymethyl-2-methyl-3-H-indol-5-yl)-acetic acid as a solid residue. The reaction of 3-bromopropyl-N,N-bis(carboxymethyl)amine, which was prepared as described in Example 5, with the intermediate indole and subsequent reaction of the indole intermediate with glutaconaldehyde dianil monohydrochloride (see Example 1) gives the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.N1C=CC=CC=1.[CH3:22][N:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1>O1CCCC1.O>[NH2:12][C:9]1[N:10]=[CH:11][C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:28]([C:27]3[N:23]([CH3:22])[N:24]=[C:25]([CH3:31])[CH:26]=3)=[O:29])[CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n(C)n1
Yield: 61.5 %

Procedure:
To a solution of 5-(3-aminophenoxy)pyridin-2-amine (975 mg, 4.85 mmol) and pyridine (410 μL, 5.09 mmol) in tetrahydrofuran (10 mL) was added dropwise with stirring under ice-cooling a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (807 mg, 5.09 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, extracted with ethyl acetate (×3), and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20→40/100) and recrystallized from ethyl acetate-hexane to give the title compound (964 mg, 61%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[Br:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Br:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C:14]([NH:13][C:4]2[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: NS(=O)(=O)c1ccc(OCCBr)cc1
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(OCCBr)cc1

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-(2-bromoethyloxy) benzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-[4-(2-bromoethyloxy)benzenesulfonyl]-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 760 mg (1.50 mmol) of N-[4-(2-bromoethyloxy)benzenesulfonyl]-N'-(2-carboxyl-5-chlorophenyl)urea 320 mg of the above-identified compound (yield 46.4%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):3.82 (2H,t), 4.46 (2H,t), 7.12 (1H,s), 7.12-7.23 (3H,m), 7.85 (1H,d), 8.11 (2H,d), 11.59 (1H,s).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=O.C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>O.O1CCCC1>[OH:4][CH2:5][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CO)OCc1ccccc1
Reaction time: 0.17 h
Yield: 105.3 %

Procedure:
A solution of 1.63 g of sodium borohydride in 25 ml of water is added dropwise to a well stirred solution of 3.0 g of cis-(±)-4-(methoxycarbonyl)-3-[((phenylmethoxy)carbonyl)amino]-2-azetidinone in 190 ml of tetrahydrofuran. The addition is made over a period of 10 minutes while stirring in an ice bath. The reaction is stirred for 3 hours. Methylene chloride (250 ml) is added followed by anhydrous sodium sulfate. A clear solution is obtained by filtration. The solvent is removed and the residue is dissolved in acetone. The solution is clarified by filtration and concentrated to give 2.84 g of the title compound. Physical characteristics are as follows:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH2:22]>C(O)CCC.O.C(OCC)(=O)C>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:22][CH2:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccccn1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCCNC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: OC(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccccn2)C1
Yield: 21.5 %

Procedure:
A mixture of 3-(diphenylhydroxymethyl)piperidine (267 mg, 1.0 mmol), 2-vinylpyridine (0.32 g, 3.0 mol) and Triton B (3 drops) in 1-butanol (10 ml) was heated under reflux for 18 hours, diluted with water and ethyl acetate and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was twice taken up in toluene and evaporated and it was then purified by chromatography on SiO2 using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (80 mg) as a pale brown oil which was characterised containing 0.25 equivalents of water.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:12][C@@H](C)CSC)[O:5][C:6]2=[O:11].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CC1C=CC([NH2:28])=C(C)C=1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:6]([NH2:28])(=[O:11])[C:7]1[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:12])=[O:5]
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Reactant: CSC[C@H](C)N=C1OC(=O)c2cccc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
4-Chloro-3-[(S)-1-methyl-2-methylthioethylimino]-3-H-isobenzofuran-1-one (0.2 g) and 4-(3,5-bis-trifluoromethyl-benzyl)-2-methylaniline (0.22 g) were dissolved in acetonitrile (10 ml), to which p-toluenesulfonic acid hydrate (0.01 g) was added, and then stirred at room temperature for three hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bis-trifluoromethyl-benzyl)-2-methylphenyl]-3-chloro-N2-(S)-1-methyl-2-methylthioethyl)phthalamide (0.10 g).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:23]([S:31](Cl)(=[O:33])=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl.C(OCC)(=O)C>[CH2:23]([S:31]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])(=[O:33])=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCCCCCCCS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCS(=O)(=O)N[C@@H](CO)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of (2R)-2-amino-2-phenylethanol (960 mg) in methylene chloride (30 ml) was added triethylamine (2.0 ml) and the mixture was cooled to −78° C. To the mixture was added dropwise chlorotrimethylsilane (0.90 ml), the mixture was stirred for 3 hours at −78° C. and then stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C. again. To the mixture was added dropwise 1-octanesulfonyl chloride (1.4 ml) and the mixture was stirred for 2 hours at −78° C. and then stirred for 15 hours at 0° C. The reaction mixture was diluted with ethyl acetate and then washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→3:2) to give the title compound (1.70 g) having the following physical data.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH2:25][OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH:25]=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCC1CCCCN1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCC1CCCCN1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of DMSO (5.84 mL, 82.2 mmol) in dry DCM (220 mL) was added (COCl)2 (3.55 mL, 41.1 mmol) at −78° C. and the mixture stirred at same temperature for 20 minutes. A solution of compound 49 (6 g, 27.4 mmol) in DCM (30 mL) was then added slowly and the reaction mixture was stirred at −78° C. for 1 hour. TEA (13.8 mL, 137 mmol) was added at −78° C. and the reaction mixture was stirred and allowed to come to rt. The reaction mixture was diluted with DCM and the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to provide sticky compound 50.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])[CH2:16][CH2:15]3)=[C:7]([CH3:28])[C:6]=2[CH:29]=1.[OH-].[Na+].[CH2:34]([S:36](O)(=[O:38])=[O:37])[CH3:35]>O.C(O)C.C(Cl)(Cl)Cl>[CH2:34]([S:36]([O:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])[CH2:16][CH2:15]3)=[C:7]([CH3:28])[C:6]=2[CH:29]=1)(=[O:38])=[O:37])[CH3:35]
Reactant: COc1cc2oc(=O)c(CCN3CCN(c4ccccc4OC)CC3)c(C)c2cc1O
Reactant: CCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCS(=O)(=O)Oc1cc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2cc1OC
Temperature: 25 °C
Reaction time: 60 h
Yield: 59 %

Procedure:
Alternative process: 1.3 g (3.1 mmol) of 6-hydroxy-7-methoxy-3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-4-methyl-2H-1-benzopyran-2-one (Example 2), two equivalents of sodium hydroxide and 2.5 equivalents of ethanesulphonic acid are dissolved in water/ethanol and stirred for 60 hours at room temperature. The reaction product is taken up in chloroform, washed with dilute sodium hydroxide and with water, dried over sodium sulphate, and the solvent is removed under reduced pressure. 0.94 g (59%) of pale yellow crystals with a melting point of 148°-150° C. (from ethanol/TBME) are obtained by column chromatography over silica gel (solvent: acetone/petroleum ether 1/1).
Reaction SMILES: CC1(C)OC2C3C(CCC)=CC(=O)OC=3C=C(O)C=2C=C1.[CH3:22][CH2:23][CH2:24][C:25]1[C:31]2[C:32]3[O:37][C:36]([CH3:39])([CH3:38])[CH:35]=[CH:34][C:33]=3[C:40]3[O:45][CH:44](C)[CH:43](C)[CH:42]([OH:48])[C:41]=3[C:30]=2[O:29][C:27](=[O:28])[CH:26]=1>>[CH3:39][C:36]1([CH3:38])[O:37][C:32]2[C:31]3[C:25]([CH2:24][CH2:23][CH3:22])=[CH:26][C:27](=[O:28])[O:29][C:30]=3[C:41]([C:42](=[O:48])[CH2:43][CH3:44])=[C:40]([OH:45])[C:33]=2[CH:34]=[CH:35]1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O
Agent: CCCc1cc(=O)oc2cc(O)c3c(c12)OC(C)(C)C=C3
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3

Procedure:
The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (−)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17])[CH2:5]2.CC(O)=O.[O:22]=[C:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][CH:33]=O)=[CH:31][C:26]=2[CH2:25][O:24]1.[BH3-]C#N.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:33][CH2:32][C:30]3[CH:29]=[CH:28][C:27]4[C:23](=[O:22])[O:24][CH2:25][C:26]=4[CH:31]=3)[CH2:13][C:12]1=[O:17])[CH2:5]2
Reactant: O=C1CNCCN1C1Cc2ccc(Br)cc2C1
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C1OCc2cc(CCN3CCN(C4Cc5ccc(Br)cc5C4)C(=O)C3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of product from Step C (0.39 mmol) in 20 mL of DCM/MeOH (3/1, v/v) was added HOAc (47 mg, 0.78 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (68 mg, 0.39 mmol) and NaBH3CN (49 mg, 0.78 mmol), and the mixture was stirred at RT for 2 hours. The reaction was diluted with DCM, washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the title product.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:9]2[C:4](=[C:5]([NH2:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=[C:10]3[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Cc1nc(Oc2cccc(C(F)(F)F)c2)c2cccc(N)c2n1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Oc2cccc(C(F)(F)F)c2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 13.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 2-methyl-4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-49, 150 mg, 0.47 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 200 mg, 0.71 mmol), oxalyl chloride (135 mg, 1.07 mmol), DMF (1 drop) and DIPEA (182 mg, 1.41 mmol) in CH2Cl2 (6 mL) to afford 38 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.99 (d, 1H), 8.12 (m, 2H), 7.84-7.74 (m, 4H), 7.41 (m, 2H), 4.32 (d, 2H), 2.50 (s, 3H), 1.14 (s, 9H); MS (m/z): 589.20 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:11][C:10]2=[O:29])=[CH:6][CH:5]=1)([OH:3])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[N:32]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13][N:12]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:11][C:10]3=[O:29])=[CH:30][CH:31]=2)=[O:3])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
23 mg (0.053 mmol) of 1-(4-carboxybenzyl)-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 6 mg (0.079 mmol) of pyrrolidine, 13 mg (0.079 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.022 ml (0.159 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.