Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:32])[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:44][CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=O)(=O)C>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:32])[C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:44][CH2:45][O:46][CH2:47][C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCNCC4)cc2)CO3)CC1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(CCOCc5ccccc5)CC4)cc2)CO3)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl ]-4-(piperazin-1-yl)benzamide (500 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (5 mL) and potassium carbonate (170 mg, 1.3 mmol) was added. To the mixture was added a solution of 2-benzyloxyethyl mesylate (290 mg, 1.3 mmol) (described in: Beard, C; Edwards, J; Fried, J. U.S. Pat. No. 3,929,824, 1972) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 40° C. for 24 h. The solvent was evaporated in vacuo giving 950 mg of a crude product. Purification by column chromatography on silica gel using chloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent afforded 154 mg (24% yield) of the title compound as an oil: EIMS (70 eV) m/z (relative intensity) 569 (3, M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]1([NH2:34])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>FC(F)(F)CO>[C:24]1([NH:34][C:21]2[C:16]3[CH:15]=[C:14]([C:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=4)[NH:23][C:17]=3[N:18]=[CH:19][N:20]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CCNC1
Temperature: 80 °C

Procedure:
A sealed tube containing a solution of 4-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (250 mg, 0.75 mmol), 1-naphthylamine (160 mg, 1.12 mmol) and trifluoroacetic acid (287 μL, 3.73 mmol) in 2,2,2-trifluoroethanol (5 mL) was heated at 80° C. and maintained at this temperature overnight. The product was poured into saturated NaHCO3 solution (50 mL) and the precipitate was filtered off, giving the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ=9.48 (1H, s), 8.14-7.92 (3H, m), 7.82 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=7.2 Hz), 7.61-7.44 (3H, m), 6.40 (1H, s), 4.02 (2H, brs), 3.51 (2H, brs), 2.89 (2H, brs); MS (ES+): m/z 342.11 [MH+], HPLC: tR=1.71 min (MicromassZQ, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:32]2[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CCN1CCNCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CCN1CCN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-ethylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazine-1-carbonyl)benzamide. MS (Q1) 483 (M)+.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-])=O.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)(=O)C.CCCCCC.O>[F:11][C:12]([F:21])([F:22])[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:4]2[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: [O-][n+]1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 85.7 %

Procedure:
4-Nitropyridine-N-oxide (84.00 g), 4-Trifluoromethoxyphenol (107.8 g), K2CO3 (165.7 g) and DMF (420 mL) were placed in a vessel and stirred at 80-90° C. for 4.5 hr. The reaction mixture was then cooled to room temperature and water (2500 mL) and ethyl acetate (2500 mL) were added. The organic material was taken up in ethyl acetate and then the aqueous layer was extracted with ethyl acetate (1000 mL). The all organic extracts were washed three times with water (1000 mL×3). And then the organic extracts were condensed under reduced pressure to give the crude products (150.7 g). The crude products (150.7 g) and n-hexane (1500 mL) were placed in a vessel and stirred at 60° C. for 0.5 hr and then the mixture was allowed to cool to under 10° C. for 1 hr. The mixture was then filtered and the crystalline powder washed with n-hexane (168 mL) and dried at 50° C. for 17 hr to afford 139.4 g (85.73% yield) of a brown crystal target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[NH:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15]
Reactant: O=C1NCCN1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C1NCCN1Cc1cccc(Br)c1
Yield: 43.7 %

Procedure:
3-Bromobenzyl bromide (1.0 g, 4.0 mmol) was added to a solution of 2-imidazolidone (1.03 g, 12.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 2-propanol (10 mL), and the reaction stirred at reflux for 40 h. The cooled solution was partitioned between EtOAc and water. Organics were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) gave 446 mg (44%) of the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 7.40-7.48 (m, 2H), 7.21-7.28 (m, 2H), 4.30 (s, 2H), 3.29-3.41 (m, 4H). [M+H] calc'd for C10H11BrN2O, 255, 257; found, 255, 257.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1C=CC=CC=1>[OH-].[Na+]>[Cl:1][C:2]1[C:7]([CH:8]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cc(C=O)c(Cl)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cc(C=CC(=O)O)c(Cl)nc1C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g) piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and evaported to an oil. This oil was dissolved in sodium hydroxide solution and was extracted with chloroform (discarded). The aqueous phase was acidified with hydrochloric acid and was extracted with chloroform. The chloroform extracts were washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%) m.p. 150°-158°. This acid was esterified using ethanol and sulphuric acid to give the ethyl ester m.p. 85°-88°.
Reaction SMILES: [OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.Cl[C:23]1[S:24][C:25]2[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:26]=2[N:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C@H:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:23]2[S:24][C:25]3[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)[C:6](=[O:10])[CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCNC(=O)C2)ccc2c1COC2=O
Reactant: N#Cc1ccc2nc(Cl)sc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c([C@@H](O)CN2CCN(c3nc4ccc(C#N)cc4s3)C(=O)C2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
A mixture of 4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one [I-10] (30 mg, 0.10 mmol), 2-chloro-1,3-benzothiazole-6-carbonitrile (20 mg, 0.10 mmol), Pd2(dba)3 (19 mg, 0.021 mmol), Xantphos (24 mg, 0.041 mmol), and Cs2CO3 (50 mg, 0.16 mmol) in dioxane (2 mL) was sealed in a microwave tube and purged three times with nitrogen. It was heated to 120° C. for 10 minutes in a microwave reactor. LC showed formation of the title product, which was purified by silica gel flash chromatography. LC-MS (IE, m/z): 449 [M+1]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[CH:21]=2)=O)[CH2:3][CH2:2]1>C(O)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=3[N:13]=[C:14]2[C:16]2[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[CH:19]=[N:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)c1cncc(C(=O)Nc2cc(F)c(F)cc2NC2CC2)c1
Solvent: CC(=O)O
Product: CC(C)(O)c1cncc(-c2nc3cc(F)c(F)cc3n2C2CC2)c1
Temperature: 25 °C

Procedure:
A solution of the title compound from Step D (0.070 g, 0.20 mmol) in acetic acid (1.0 mL) was heated at 100° C. for 1 hour, and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed sequentially with aqueous 1 N sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (50-80% ethyl acetated in hexanes) provided the title compound: LCMS m/z 330.04 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1 H), 8.87 (s, 1 H), 8.44 (d, J=1.8 Hz, 1 H), 7.58 (dd, J=10.3, 7.3 Hz, 1 H), 7.40 (dd, J=9.7, 7.0 Hz, 1 H), 3.59-3.58 (m, 1 H), 2.89 (br s, 1 H), 1.69 (s, 6 H), 1.22-1.19 (m, 2 H), 0.79-0.78 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(OCC)(=O)C.[CH3:18][N:19](C)C=O>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:18]#[N:19])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)CCC2=O
Temperature: 140 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
5-Bromo-2,3-dihydro-1H-inden-1-one (21.1 g, 100 mmol) and cupric cyanide (17.9 g, 200 mmol) were mixed in 200 ml of dimethylformamide and stirred overnight at 140° C. After the solution was cooled down to room temperature, 500 ml of ethyl acetate was added and the precipitate was removed by filteration using kieselguhr. The solid was rinsed with ethyl acetate for several times. The pooled filtrates were washed with 1 N hydrochloric acid twice and then with brine for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified on silica gel, eluting with ethyl acetate/hexanes (1:2), to obtain 7.9 g of the desired compound (50% yield). MS (M+1)=158.05.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:39][C:40](C)([O-:42])C.[K+]>CCO>[CH2:40]([O:42][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1)[CH3:39]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: CCOc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 80 °C

Procedure:
In a 150 mL pressure vessel, to the stirred solution of 3-(2-Fluoro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 3BV (2.0 g, 4.0 mmole) in anhydrous EtOH (40 mL), solid potassium tert-butoxide (12 g, 10.0 mmole) was added under dry N2 gas. The pressure vessel was tightly sealed and heated at 80° C. for 24 hours. The pressure vessel was cooled to 0° C. in ice-bath before opening. The contents of the pressure vessel were transferred to 250 mL RBF and concentrated to a small volume. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated to dryness to give a crude solid 11BV (1.5 g, 71%).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].C(O)(=O)C.N1CCCCC1>ClCCl>[C:14]([C:13]([C:12](=[O:17])[CH3:11])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:16])[CH3:15]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O

Procedure:
2.3 g (17.5 mmol) of 4-formylbenzonitrile, 1.98 ml (19.29 mmol) of 2,4-pentanedione, 1 ml (26 mmol) of acetic acid and 0.34 ml (3.5 mmol) of piperidine in 40 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from diethyl ether. 3.18 g (85% of theory) of the title compound are obtained as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>CC(C)=O>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCC2CO2)cc1
Yield: 60.7 %

Procedure:
A mixture of 16.7 gm (0.10 mole) of ethyl 4-hydroxybenzoate, 20.7 gm (0.15 mole) of potassium carbonate and 24 mL (0.30 mole) of epichlorohydrin in 250 mL acetone was heated to reflux for 12 hours. The reaction medium was then filtered and evaporated. The resulting oil was taken up in 100 mL toluene and washed with 100 mL 1.0N sodium hydroxide and 2×100 mL water. The toluene phase was then dried over magnesium sulfate and evaporated to give 13.5 gm (61%) of a clear oil. The NMR spectrum of this oil was consistent with the assigned structure and the oil was used in the next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:3]=1[C:4]([O:6][CH2:7][C:8](=[O:33])[C@@H:9]([NH:18][C:19]([C:21]1([CH3:32])[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22]1)=[O:20])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:2]([Cl:1])[C:3]=1[C:4]([O:6][CH2:7][C:8](=[O:33])[C@@H:9]([NH:18][C:19]([C:21]1([CH3:32])[O:25][N:24]=[C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:22]1)=[O:20])[CH2:10][C:11]([OH:13])=[O:12])=[O:5]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)C1(C)CC(c2ccccc2)=NO1)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(=O)N[C@@H](CC(=O)O)C(=O)COC(=O)c2c(Cl)cccc2Cl)CC(c2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound prepared in Example 1 (44 mg) was dissolved in dichloromethane (2 ml), and trifluoroacetic acid (1 ml) was added at 0□. The mixture was stirred for two hours while it was slowly warmed to room temperature, and then concentrated under reduced pressure to give the title compound (Iaa) in a stoichiometric amount.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:39])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH2:35][C:36](=[O:38])[CH3:37])[O:27]1>C(OCC)(=O)C>[CH3:39][C:26]1([CH3:25])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH2:35][CH:36]([OH:38])[CH3:37])[O:27]1
Reactant: CC(=O)CCCC1=CC(=O)OC(C)(C)O1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)CCCC1=CC(=O)OC(C)(C)O1
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 300 mg of 2,2-dimethyl-6-(4-oxopentyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the resultant residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the resultant residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 148 mg (yield 50%) of (-)-2,2-dimethyl-6-(4-hydroxypentyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 3, X is a hydrogen atom, Y is a hydrogen atom, and a subtituent is present at the 6-position].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.CC(C)(C)[CH2:25][OH:26].C1OCCOCCOCCOCCOCCOC1.[OH-].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:26][CH3:25])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: CC(C)(C)CO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Reaction time: 24 h
Yield: 52.9 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (1.2557 g, 3.30 mmol), 2,2-dimethylpropan-1-ol (0.914 g, 10.37 mmol), 18-crown-6 (0.087 g, 0.330 mmol), and potassium hydroxide (0.925 g, 16.50 mmol) (freshly ground). The vial was flushed with Ar (g), then dioxane (6.60 mL) was added. The vial was sealed and placed in a 120° C. oil bath and stirred for 24 hours. The reaction mixture was diluted with water and a small amount of brine. The aq. mixture was then extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-100% EtOAc/hexanes) to afford 0.657 g of (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a yellow solid. Step 2: A microwave vial was charged with (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.065 g, 0.173 mmol), 2-fluoropyridin-3-ylboronic acid (0.049 g, 0.346 mmol), potassium phosphate (0.110 g, 0.518 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.12 mg, 8.64 μmol). The vial was flushed with Ar (g), dioxane (0.648 mL) and water (0.216 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/EtOAc) to afford 65 mg of (S)-7-(2-fluoropyridin-3-yl)-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light yellow solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CO>C1COCC1>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH:17]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CN1CC=C(C2c3ccccc3CCc3ccccc32)CC1
Temperature: -78 °C
Yield: 93 %

Procedure:
Dissolved 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine (12 g, 0.042 mol) in 250 mL of dry THF. Cooled to -78° C. under a nitrogen atmosphere. Added n-butyl lithium (18 mL of 2.5M in hexane) dropwise via addition funnel. Maintain temperature at 0° C. for 1 hour then recooled to -78° C. Added 21 mL of dry methanol, and let warm to room temperature. Added saturated NH4Cl, and extracted with THF. Dried combined organic extracts with MgSO4, filtered, and evaporated to give 11.3 g (94% yield) of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-methyl-1,2,5,6-tetrahydropyridine as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9](OS(C)(=O)=O)[C@H:8]([N:22]=[N+]=[N-])[CH:7]=1)=[O:5])[CH3:2].[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9]2[C@@H:8]([N:22]2[P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:32])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](N=[N+]=[N-])[C@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C[C@H]2[C@@H]([C@H](OS(C)(=O)=O)C1)N2P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 383.4 mg of 14 and 4.0 mL toluene in a 10 mL round-bottom flask equipped with a magnetic stirrer, a reflux condenser maintained under an argon atmosphere at RT was added, 191 μl of triethyl phosphite. Nitrogen evolution began in about 5 min and after 30 min at RT the light yellow reaction mixture was heated to reflux for 5 h, then an additional 191 μl of triethyl phosphite were added and refluxing continued for another 2 h. The reaction mixture was cooled and evaporated at 40° C./60-10 mbar to yield 470 mg of the crude product as a yellow oil. The crude product was purified by SiO2 column chromatography using a 2/1 mixture of toluene and acetone. The combined fractions were evaporated and dried on a rotary evaporator 40° C./250-10 mbar to afford 87 mg of 16 as a yellow oil.