Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH2:24]2)=[CH:19][CH:18]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(Cl)Cl>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH2:24]3)=[CH:21][CH:22]=1)=[N:1]2
Reactant: CC(=O)N(C)C1CCN(c2ccc(C=O)cc2)C1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(C)C(C)=O)C4)cc3)nc2c1
Temperature: 150 °C
Yield: 87.2 %

Procedure:
A solution of 2-amino-4,6-dimethoxybenzamide (0.797 g, 4.07 mmol) and N-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide (1.0 g, 4.07 mmol) in DMA (75 mL) was treated with NaHSO3 (0.466 g, 4.5 mmol) and p-TsOH (0.078 g, 0.41 mmol). The mixture was heated at 150° C. for 15 hours, cooled to room temperature, diluted with CH2Cl2 (200 mL), and washed with saturated NaHCO3 (100 mL) and water (200 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (1.5 g, 88%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 8.10 (d, J=8.8 Hz, 2H), 6.55-6.67 (m, 3H), 6.44 (d, J=2.2 Hz, 1H), 4.67-5.22 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43-3.60 (m, 2H), 3.22-3.26 (m, 2H), 2.76-2.89 (m, 3H), 1.91-2.27 (m, 5H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc2c3ccccc3n(C3CCCCO3)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
10 mmol of 2-bromo-9H-carbazole, 0.1 mmol of pyridinium toluene-4-sulphonate, and 50 mmol of 3,4-dihydro-2H-pyran was added to dichloromethane at room temperature and let stir for 2 hours before the temperature was raised to 50° C. for 2 hours further. The solution was cooled, concentrated under reduced pressure, and subjected to column chromatography of silica with dichloromethane as the eluent. After concentrating under reduced pressure, 2-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-carbazole was isolated in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][NH2:16])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([C:13]2[O:14][C:24](=[O:25])[NH:16][N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1sc(N)nc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccccc2)c(-c2n[nH]c(=O)o2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Amino-4-phenyl-thiazole-5-carboxylic acid hydrazide (1 g, 4.3 mmol) was suspended in tetrahydrofurane (50 mL). Triethylamine (5 mL, 40 mmol) and carbonyldiimidazole (0.83, 5.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. The crude product was purified by flash column chromatography, eluted with the ethyl acetate/hexanes (1/1) to give the product as a solid. Yield: 20%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[S:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[S:18][C:19]([CH3:26])([CH3:25])[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C(C)(C)Sc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccc2c(-c3ccccc3F)noc2c1Cl)C(=O)O

Procedure:
A mixture of 5.0 g of ethyl 2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate, 30 ml of 15% sodium hydroxide and 30 ml of methanol is heated under reflux for 2 hr. The reaction mixture is poured into ice/conc hydrochloric acid. The precipitate is collected, dried and recrystallized from toluene to afford 2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionic acid, mp 149° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[F:28])[CH3:17].O1CCCC1.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:23][C:22]=1[F:28])[CH3:17]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene-1-one (Intermediate 13, 0.298 g, 1.43 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.44 g, 1.43 mmol), triethyl amine (Intermediate 13, 3 mL), anhydrous tetrahydrofuran (7 mL), copper(I)iodide (0.04 g, 0.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 14-16% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.43 g, 77%).
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[N:26]=[N:25][C:24]([CH2:27][C:28]#[N:29])=[N:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:30]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[C:30]1(=[C:27]([C:24]2[N:25]=[N:26][N:22]([C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:23]=2)[C:28]#[N:29])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: N#CCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(=C1CCCC1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
To a flask charged with dry sodium hydride (0.32 g, 13.3 mmol) was added (2-trityl-2H-tetrazol-5-yl)-acetonitrile (2.34 g, 6.67 mmol). The solids were swirled to mix, cooled to 0° C., and 25 mL THF was added quickly, resulting in vigorous H2 evolution and a bright yellow foam. The mixture was stirred at 0° C. for 5 min, at which time the ice bath was removed and stirring continued for 10 min. Cyclopentanone (0.65 mL, 7.33 mmol) in 10 mL THF was added quickly resulting in a clear orange solution. The mixture was stirred for 2 h, partitioned between EtOAc and sat. NH4Cl (aq), and the organic phase dried (MgSO4) and concentrated. Flash chromatography of the residue (CH2Cl2) furnished 2.05 g (74%) of cyclopentylidene-(2-trityl-2H-tetrazol-5-yl)-acetonitrile as a white solid. 1H NMR (CDCl3) δ 7.32 (m, 9H), 7.10 (m, 6H), 2.86 (m, 4H, —CH2CCH2—), 1.84 (m, 4H, —CH2CH2CH2CH2—).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C@H:11]([NH2:13])[CH3:12]
Reactant: COc1cc(Cl)c([C@@H](C)N[S@](=O)C(C)(C)C)cc1C
Agent: Cl
Solvent: CO
Product: COc1cc(Cl)c([C@@H](C)N)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To ((R)—N—((R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (0.64 g, 2.1 mmol) was added 10% hydrogen chloride in methanol (10 ml), and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated and dried in vacuo to give the title compound (crude 0.63 g) as white solid. This amine was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(OC(C)C)(=O)C>[Cu].CN(C=O)C>[F:15][C:9]([F:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
2-Bromopyridine (20 g), ethyl bromodifluoroacetate (27.2 g) and DMF (120 mL) were added and stirred for 10 minutes under nitrogen. Copper powder was added to the reaction mixture and heated to 70-80° C. for 45 minutes. The reaction mixture was cooled to RT and 400 mL of isopropyl acetate (IPAc) was added. The reaction mixture was quenched with the aqueous potassium dihydrogen phosphate at 0-10° C. and stirred for 30 minutes. The reaction mixture was filtered off and the residue obtained was washed with ethyl acetate. The organic layer was collected and washed with brine solution and dried over sodium sulphate then distilled under vacuum. (Crude weight=20 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([N:11]([CH3:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[N:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>>[CH3:24][N:11]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:8]1[C:6]2[N:7]=[C:2]([NH:37][C:34]3[CH:35]=[N:36][C:31]([N:28]4[CH2:27][CH2:26][O:25][CH2:30][CH2:29]4)=[CH:32][CH:33]=3)[N:3]=[CH:4][C:5]=2[S:10][CH:9]=1
Reactant: COc1cc(N(C)c2csc3cnc(Cl)nc23)cc(OC)c1OC
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: COc1cc(N(C)c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc(OC)c1OC
Yield: 76.7 %

Procedure:
N7-Methyl-N2-(6-morpholinopyridin-3-yl)-N7-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,7-diamine (16 mg, 76% yield) was prepared in the same manner as Step of Example 1 using 2-chloro-N-methyl-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-7-amine (15 mg, 0.041 mmol) and 6-morpholinopyridin-3-amine (9 mg, 0.049 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]N1C(=O)CCC1=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10][Br:43])=[CH:4][CH:3]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(C(=C(CBr)n2cnnn2)c2ccc(F)cc2)cc1

Procedure:
A solution of 3,3-bis(4-fluorophenyl)-2-(tetrazol-1-yl)-2-propenol (108 mg, 0.34 mmol), triphenylphosphine (118 mg, 0.45 mmol) and N-bromosuccinimide (74 mg, 0.42 mmol) in tetrahydrofuran (5 mL) was stirred in an inert atmosphere for a period of 1.5 hours. The suspension (triphenylphosphine oxide precipitate) was diluted with hexanes (25 mL) and the suspension was filtered. The filtrate was concentrated under reduced pressure and the semi-crystalline solid was filtered through a short silica gel column eluted with 5-10% ethyl acetate in hexanes. The title compound, 108 mg (84%), was obtained after removal of solvents under reduced pressure.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CC(N(C)C)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2cccc(NCc3ccccn3)n2n1)C1CC1
Temperature: 150 °C

Procedure:
To a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.05 g, 0.178 mmol) in dimethylacetamide (1 mL) in a microwave vial, 2-aminomethylpyridine (0.096 g, 0.89 mmol) was added and the solution was heated in the microwave at 150° C. for 15 min. The crude was purified straight away by preparatory chromatography after filtration. LCMS method: 2, RT: 2.07 min, MI: 309 [M+1]. NMR (1H, DMSO, 300 MHz): 10.91 (s, 1H), 8.57 (d, 1H), 7.77 (t, 1H), 7.30-7.49 (m, 4H), 6.85 (d, 1H), 6.08 (d, 1H), 4.67 (d, 2H), 2.07 (brs, 1H), 0.83 (d, 4H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:12]([N-]C(C)C)([CH3:14])[CH3:13].[Li+].C(Br)C=C.Cl>O1CCCC1.C1CCCCC1>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:14][CH:12]=[CH2:13])#[N:11]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: C1CCCCC1
Product: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3,4-Dichlorophenylacetonitrile (80 g) was dissolved in anhydrous tetrahydrofuran (800 ml) under a nitrogen atmosphere, cooled to −70° C., and lithium di-isopropylamide (320 ml of a 1.5M solution in cyclohexane) added. The mixture was stirred at −70° C. for 30 minutes, allyl bromide (63 g) added over 15 minutes and the mixture stirred for a further 30 minutes. 2N Aqueous hydrochloric acid solution (600 ml) was then added and the mixture extracted twice with diethyl ether. The organic extracts were combined and the solvent removed under reduced pressure. The resulting residue was dissolved in dichloromethane, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a red mobile oil. This was chromatographed on silica gel eluting with 4:1, by volume, hexane:dichloromethane to give 4-cyano-4-(3,4-dichlorophenyl)but-1-ene (94.8 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[CH2:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1
Reactant: C=Cc1nc(C(=O)OC)cc(N)c1F
Agent: [Pd]
Solvent: CCO
Product: CCc1nc(C(=O)OC)cc(N)c1F
Reaction time: 0.75 h
Yield: 90.2 %

Procedure:
Pd/C (0.976 g, 0.459 mmol) was added to a 500 mL Parr bottle and methyl 4-amino-5-fluoro-6-vinylpicolinate (0.9 g, 4.59 mmol) dissolved in ethanol (50 ml) was added. The Parr bottle was placed on a Parr shaker, purged with nitrogen gas three times, and pressurized to 43 psi with hydrogen gas. The reaction mixture was shaken on the Parr Shaker for 45 min The catalyst was removed via filtration through celite. The celite was washed with ethyl acetate. The filtrates were combined and concentrated under vacuum to provide the title compoud as a white solid (820 mg, 4.14 mmol, 90% yield); 1H NMR (400 MHz, DMSO-d6) δ 1.17 (t, J=7.6 Hz, 3H), 2.68 (qd, J=7.6, 2.7 Hz, 2H), 3.80 (s, 3H), 6.39 (s, 2H), 7.34 (d, J=6.7 Hz, 1H; 19F NMR (376 MHz, DMSO-d6) δ −147.65; ESIMS m/z 199 ([M+H]+), 197 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([CH3:26])([CH3:25])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([CH3:26])([CH3:25])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(C=CS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(Cc1c[nH]c2c(CCS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Yield: 79.6 %

Procedure:
To a solution of {2-[7-(2-methanesulfonyl-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (0.40 g, 1.02,mmol) in methanol (20.0 mL) is added 10% Pd/C (0.10 g) in methanol (2.0 mL). The reaction mixture is purged with hydrogen and hydrogenation is carried out with a hydrogen balloon overnight. The reaction mixture is filtered and the filtrate is evaporated to dryness to give 320 mg of {2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (80%). FDMS m/e=395.2 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=1[C:15](=[O:28])[NH:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH3:2].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:30])=[CH:9][C:8]=1[C:15](=[O:28])[NH:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)CCc1ccc(CO)cc1C(=O)NCc1cccc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(COc2ccccc2C)cc1C(=O)NCc1cccc2ccccc12
Reaction time: 8 h

Procedure:
To the solution of the compound prepared in Example 4 (300 mg) and 2-methylphenol (0.12 ml) in tetrahydrofuran (4 ml) were added triphenylphosphine (300 mg) and diethyl azodicarboxylate (0.5 ml, 40% toluene solution) at room temperature and the mixture was stirred overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (330 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(Cl)ncnc1-c1ccccc1
Yield: 37 %

Procedure:
Into a recovery flask equipped with a reflux pipe, 4.9 g of 4,6-dichloro-5-methylpyrimidine, 3.7 g of phenylboronic acid, 2.3 mL of PCy3, 20 g of cesium carbonate, 0.41 g of Pd2(dba)3, and 40 mL of dioxane were put, and the air in the flask was replaced by argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 300 W) for 100 minutes. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography (silica gel) using a mixed solvent of dichloromethane and hexane as a developing solvent in a volume ratio of 7:3, to give 4-chloro-5-methyl-6-phenylpyrimidine (yellow oily substance, 37% in yield). Note that the irradiation with microwaves was performed using a microwave synthesis system (MicroSYNTH, manufactured by Milestone General K.K.). The synthesis scheme of Step 1 is shown by (a-3).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[NH4+:51].[OH-]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[NH:51])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: [NH4+]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=N)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.143 mmol) in methanol (2 mL) was added 29.5% NH4OH (0.1 mL) at room temperature, and the mixture was stirred under nitrogen for 2 h. 29.5% NH4OH (0.1 mL) was refilled and the mixture was stirred for 3 h. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with chloroform. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (52 mg, 52%) as a blue solid: 1H NMR (500 MHz, CDCl3) δ 15.80 (br s, 1H), 11.97 (s, 1H), 8.20 (br s, 1H), 7.90 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.49 (s, 1H), 5.27 (s, 1H), 5.00 (br s, 1H), 4.76 (br s, 1H), 4.70 (d, J=9.0 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.75-3.67 (m, 2H), 3.60 (s, 3H), 3.58-3.54 (m, 2H), 3.40 (s, 3H), 3.32-3.28 (m, 2H), 3.12 (t, J=9.5 Hz, 1H), 2.54 (br s, 1H), 2.36 (s, 3H), 1.34 (d, J=5.5 Hz, 3H); MS (ESI+) m/z 697 (M+H); HPLC 96.6% (AUC), tR 10.34 min.