Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([F:19])[C:13]=4[CH:12]=[C:9]3[C:10]=2[CH:11]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:19][C:14]1[C:13]2[CH:12]=[C:9]3[N:8]([C:18]=2[CH:17]=[CH:16][CH:15]=1)[CH2:7][CH2:6][C:5]1[N:4]=[CH:3][C:2]([C:37]2[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]4[O:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=4[CH:36]=2)=[CH:11][C:10]3=1
Reactant: Fc1cccc2c1cc1n2CCc2ncc(Br)cc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 40.8 %

Procedure:
A mixture of 2-bromo-11-fluoro-5,6-dihydroindolo[2,1-f][1,6]naphthyridine (50 mg, 0.16 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (87 mg, 0.17 mmol), potassium carbonate (43 mg, 0.32 mmol) and Pd(dtbpf)Cl2 (10 mg) in 1,4-dioxane/water (1/0.1 mL) was stirred at 100° C. for 6 hours under nitrogen atmosphere. The mixture was filtered through Celite pad and concentrated, and then the residue was diluted with water and EA. After extraction with EA, the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford the desired product (40 mg, yield: 41.7%) through the prep-HPLC. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 8.19 (s, 1H), 7.93˜7.96 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.19˜7.24 (m, 2H), 7.15˜7.17 (m, 2H), 7.02 (s, 1H), 6.77˜6.82 (m, 1H), 5.88 (br s, 1H), 4.41˜4.44 (m, 2H), 3.45˜3.49 (m, 2H), 3.18 (s, 3H), 2.99 (d, J=4.80 Hz, 3H), 2.84 (s, 3H). MS (M+H)+: 613.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22](Cl)(=[O:24])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:18]1[S:19][CH:20]=[CH:21][C:17]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:23])=[O:24]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1CCc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2sccc2CCc2ccccc2)c1Br
Yield: 48 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 3-phenethyl-2-thiophenesulfonyl chloride in 48% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc(C)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with p-toluidine according to general procedure A provided methyl ester of Compound 12 as a yellow oil (69% yield). 1H NMR (CDCl3, 500 MHz): δ=7.68 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.19 (m, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 5.77 (s, 1H), 3.91 (s, 3H), 2.34 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.4, 144.6, 139.8, 131.9, 131.5, 130.2, 129.5, 121.3, 120.8, 119.7, 117.5, 52.2, 20.9.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[CH:10]=[O:11].Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].O>C(OCC)C>[CH3:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([O:6][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:14]=1)[CH:10]=[O:11]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc(O)cc(C=O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
After adding 1.11 g of imidazole to a solution of 2.02 g of 3-hydroxy-5-methylbenzaldehyde [CAS No. 60549-26-0] in 20 ml of DIVEF, the reaction mixture was cooled to 0° C. Next, 3.56 ml of chlorotriisopropylsilane was added and the mixture was stirred at room temperature for 19 hours and 10 minutes. Water was added to the reaction mixture, and extraction was performed twice with diethyl ether. The organic layer was washed twice with water and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-diethyl ether) to give the title compound (3.86 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].[NH2:19][C:20]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=1[OH:29]>>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([OH:29])=[C:20]([NH:19][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:2]([OH:1])=[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:9]=2)[CH:25]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Product: CC(C)(C)c1cc(C(=O)Nc2cc(N)ccc2O)cc(C(C)(C)C)c1O

Procedure:
4-hydroxy-3,5-di(tert.-butyl)benzoic acid and 2-amino-4-nitrophenol are treated in the same manner as described in Preparation 5-(1) and Preparation 1-(2) to give N-(5-amino-2-hydroxyphenyl)-4-hydroxy-3,5-di(tert.-butyl)benzamide are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:33]I.N1C=CN=C1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([I:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(I)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A round bottom flask was charged with 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 0.027 mol), triphenylphosphine (10.5 g, 0.0401 mol), iodine (10.16 g, 0.0401 mol), imidazole (2.72 g, 0.0401 mol), and methylene chloride (90 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the collected solids were washed with methylene chloride. The combined organic layers were concentrated. The resulting crude product was dissolved in ethyl acetate, and the organic phase was washed with water. The ethyl acetate layer was washed with a 3:1 mixture of water and methanol to remove triphenylphosphine oxide. The ethyl acetate layer was then washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude product was loaded onto a 330 gram silica gel column. Flash chromatography afforded 3-iodo-pyrrolidine-1-carboxylic acid tert-butyl ester (6.9 g, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 4.31-4.42 (m, 1H), 3.84 (dd, J=12.60, 6.30 Hz, 1H), 3.67-3.79 (m, 1H), 3.54-3.64 (m, 1H), 3.40-3.49 (m, 1H), 2.20-2.32 (m, 2H), 1.48 (s, 8H). MS cald. for C5H71NO2 [(M-C4H9)+] 241, obsd. 241.7, 282.7 [(M-C4H9+41)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:21](=[O:22])[C:20]3[CH:19]=[C:18](Br)[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[N:41]=[C:40]([O:42][CH3:43])[C:39](B(O)O)=[CH:38][N:37]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:21](=[O:22])[C:20]3[CH:19]=[C:18]([C:39]4[C:40]([O:42][CH3:43])=[N:41][C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Intermediate AI) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white foam. tR=5.79 min (HPLC 4); ESI-MS: tR=1.26 min, [M+H]+ 596/598 (LC-MS 1).
Reaction SMILES: Cl[C:2]1[C:21]([I:22])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[NH:24]1[CH2:27][CH:26]([CH2:28][OH:29])[CH2:25]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([I:22])[C:2]([N:24]3[CH2:27][CH:26]([CH2:28][OH:29])[CH2:25]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Reactant: OCC1CNC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 88.1 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3) and 3-azetidinemethanol hydrochloride to afford a beige solid. HPLC (Condition 7) tR=6.5 min, UPLC-MS (Condition 8) tR=1.1 min, m/z=510.0/512.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N+:6]([O-:20])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(F)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
Methyl 5-fluoropicolinate (440 mg, 2.836 mmol) was dissolved in CHCl3 (10 ml), followed by addition of mCPBA (954 mg, 4.254 mmol), and then the resulting mixture was stirred at room temperature for 15 hours. A saturated aqueous Na2S2O3 solution (15 ml) was added to the resulting reaction liquid, followed by extraction with 5% MeOH/MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (2% MeOH/MC), to obtain 318 mg of colorless oil (66%).
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH:6]=1.[CH2:21]([O:28]/[N:29]=[C:30]1\[CH2:31][CH2:32][C:33]2[C:38]\1=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:21]([O:28]/[N:29]=[C:30]1\[CH2:31][CH2:32][C:33]2[C:38]\1=[CH:37][CH:36]=[C:35]([C:2]1[C:3]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:4][N:5]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)[CH:6]=1)[CH:34]=2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(-n2cc(Br)c(-c3ccncc3)n2)nc1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(-n2cc(-c3ccc4c(c3)CC/C4=N\OCc3ccccc3)c(-c3ccncc3)n2)nc1
Temperature: 80 °C
Yield: 39 %

Procedure:
To 6-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)nicotinonitrile (0.26 g; Example 6, step 1) in 16 mL acetonitrile and 4 mL water was added (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (0.34 g; Example 2, Step 4) and 0.33 g potassium carbonate. The reaction mixture was purged with nitrogen and 46 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The reaction mixture was heated to 80° C. for 1.5 hours, filtered through celite, the filter cake was washed with acetonitrile. The filtrate was evaporated to yield crude product, which was purified by chromatography, eluting with a 10:1 mixture of dichloromethane-methanol to afford 0.15 g (36% yield) product as a pale yellow solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 483.2 by positive ESI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=S)[C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Reactant: C1CCNCC1
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(N1CCCCC1)=NC2
Yield: 57 %

Procedure:
A stirred solution of 8-chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (VIIIa) (2.65 g., 0.01 mole) and piperidine (25 ml.) was refluxed for 18 hours, under nitrogen. The solution was mixed with cold water and extracted with methylene chloride. The extract was washed with water, then brine, dried (Na2SO4) and concentrated in vacuo. The solid residue was mixed with ethyl acetate and collected by filtration; it was recrystallized from a methylene chloride/methanol/ethyl acetate mixture to give 1.39 g., melting point 238°-243° (soften 235) and 0.40 g., melting point 225°-232° (soften 220) of the titled compound (Ia) (57% yield). The analytical sample had: melting point 248°-249.5° (soften 235°), uv (EtOH) λ max 214 mμ (ε34,850), 235 (sh, 13,200), 287 (sh, 2950), 293 (3050). The ir and nmr spectra support the proposed structure.
Reaction SMILES: [CH2:1]1[O:25][C:24]2[C:3](=[CH:4][C:5]3[C:22]([CH:23]=2)=[CH:21][C:20]2[C:19](=[O:26])[C:18]4[C:9](=[CH:10][C:11]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:8](=[O:27])[C:7]=2[CH:6]=3)[O:2]1.C([BH-](CC)CC)C.[Li+].Cl>C1COCC1>[OH:27][CH:8]1[C:9]2[C:18](=[CH:17][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:19]([OH:26])[C:20]2[CH:21]=[C:22]3[C:5]([CH:4]=[C:3]4[O:2][CH2:1][O:25][C:24]4=[CH:23]3)=[CH:6][C:7]1=2
Reactant: O=C1c2cc3ccccc3cc2C(=O)c2cc3cc4c(cc3cc21)OCO4
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1c2cc3ccccc3cc2C(O)c2cc3cc4c(cc3cc21)OCO4

Procedure:
A solution of 57 mg of 2,3-methylenedioxy-6,13-pentacenequinone dissolved in 25 mL of THF was added to 1.6 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and they were allowed to react with each other at room temperature for 1 hour in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 6,13-dihydro-6,13-dihydroxy-2,3-(methylendioxy)pentacene almost stoichiometrically.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1.O>[O:33]1[CH2:38][CH2:37][CH:36]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:11])([F:12])[F:13])[CH2:35][CH2:34]1
Reactant: OC1CCOCC1
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(OC2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g 4-Hydroxy-3-trifluoromethyl-benzonitrile, 5.6 g triphenylphosphine and 1.2 g tetrahydro-4H-pyran-4-ol was suspended in 15 mL tetrahydrofuran at 0° C. before 4.92 g di-tert-butylazodicarboxylate (DBAD) as a solution in 5 mL tetrahydrofuran was added over 15 min. The reaction was warmed to ambient temperature. Additional 2.8 g triphenylphosphine, 0.55 g (5.3 mmol) tetrahydro-4H-pyran-4-ol and 2.46 g di-tert-butylazodicarboxylate (DBAD) in tetrahydrofuran were added and the reaction was stirred overnight. After this time, the reaction was diluted with water and extracted with ethyl acetate (×2). The organic phase was separated and then it was washed with 2N sodium hydroxide, water and saturated sodium chloride, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel chromatography (SiO2: heptane/ethyl acetate) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([OH:25])[C:23]#[CH:24].C(N(CC)CC)C>CC#N.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.[Cu]I>[F:19][CH:18]([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][CH2:22][OH:25])[CH:3]=2)=[O:21])=[CH:12][CH:13]=1
Reactant: O=C(C(=O)c1cccc(Br)c1)c1ccc(OC(F)F)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(C(=O)c1cccc(C#CCO)c1)c1ccc(OC(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 1-(3-bromophenyl)-2-(4-(difluoromethoxy)phenyl)ethane-1,2-dione (0.500 g, 1.41 mmol), prop-2-yn-1-ol (0.395 g, 7.04 mmol), bis(triphenylphosphine)palladium(II) chloride (0.099 g, 0.14 mmol), copper(I) iodide (0.021 g, 0.11 mmol) and triethylamine (0.62 g, 6.11 mmol) in CH3CN (3 mL) was stirred at 60° C. overnight. The solvent is removed and the material is absorbed onto celite and purified by flash chromatography (silica, 25:75 ethyl acetate/hexanes) to afford 1-(4-(difluoromethoxy)phenyl)-2-(3-(3-hydroxyprop-1-ynyl)phenyl)ethane-1,2-dione (0.326 g, 70%) as an off white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[C:6]([Cl:19])[C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:19][C:6]1[C:5]2[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(Cl)cc2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2c(c(Cl)cc3c(=O)c4ccccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.1 %

Procedure:
A mixture of 4-allyl-2-chloro-3-hydroxy-9-oxo-9H-xanthene (2.9 g), m-chloroperbenzoic acid (3.5 g) and chloroform (300 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (10 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The obtained 4-chloro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene was dissolved in acetone (300 ml) and, to the stirred solution, a mixture of chromium trioxide (3.3 g), water (17 ml) and concentrated sulfuric acid (5 g) was added dropwise at room temperature. After standing overnight, to the mixture was added isopropanol (10 ml) and the resulting mixture was filtered and the filtrate was evaporated to dryness under vacuum. After adding water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.7 g of 4-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 292°-295° C. This compound showed a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH2:34][CH2:35][CH:36]=1)CCC>O1CCOCC1.CN(C=O)C.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>[NH2:1][C:2]1[N:7]=[C:6]([C:32]2[O:33][CH2:34][CH2:35][CH:36]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1SCCc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1C1=CCCO1
Temperature: 100 °C
Yield: 8.5 %

Procedure:
To a stirred solution of 290 mg (0.72 mmol) trifluoromethanesulfonic acid 2-amino-5-cyano-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-4-yl ester in 10 ml dioxane and 2 ml DMF under argon at room temperature were added 283 mg (0.79 mmol) tributyl-(4,5-dihydro-furan-2-yl)-stannane and 50 mg (0.07 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 1 h, then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate then 5/95 methanol/ethyl acetate) followed by trituration in ether afforded 20 mg (9%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a light brown crystalline solid. ES-MS m/e (%): 348 (M+Na+, 30), 326 (M+H+, 100).
Reaction SMILES: [NH:1]([C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH2:2].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]([NH:2][NH:1][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)C(=O)NN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 2-hydrazinyl-2-oxoacetate (9-2) (0.516 g, 3.91 mmol) in dichloromethane (14 mL) was added EEDQ (0.78 g, 3.175 mmol) at room temperature and it was stirred for 15 min. Then 2-(tert-butoxycarbonylamino)acetic acid (9-3) (0.55 g, 3.175 mmol) was added. The mixture was stirred at room temperature for overnight. Solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with gradient eluant (PE/EA=3/1 to 1/1). The product was obtained as a white solid (0.787 g, 85%). 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.99 (s, 1H), 5.19 (s, 1H), 4.40 (dd, J=21.7, 7.2 Hz, 2H), 3.93 (d, J=6.1 Hz, 2H), 1.57-1.32 (m, 12H); LRMS (ESI) calculated M+Na for C11H19N3NaO6: 312.2. Found: 312.1.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]([C:20]1([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH2:22][CH2:21]1)#[N:19].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]([C:20]1([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][C:7]3[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:10]=2)=[O:27])[CH2:21][CH2:22]1)#[N:19]
Reactant: Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c2)CC1
Yield: 91.9 %

Procedure:
Using 3-(4-nitrophenoxy)aniline (3.21 g, 13.9 mmol) produced in Example A12(i), 3-(1-cyanocyclopropyl)benzoic acid (2.70 g, 14.4 mmol) produced in Example A1(iii), pyridine (100 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.20 g, 16.7 mmol) and N,N-dimethylpyridine-4-amine (122 mg, 997 μmol) as starting materials, and in the same manner as in Example A12(ii), the title compound (5.1 g, 91%) was obtained as a yellow amorphous substance.