Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.CNC1CCCCC1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[CH:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]=2[C:2]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:3][CH:4]=1
Reactant: Ic1cccc2c1oc1ccccc12
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)oc1c(-n3cncn3)cccc12
Temperature: 140 °C
Yield: 60 %

Procedure:
A mixture of 4-iododibenzo[b,d]furan (5 g, 17.00 mmol), 1H-1,2,4-triazole (3.52 g, 51.0 mmol), CuI (0.162 g, 0.850 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (0.537 mL, 3.40 mmol) and K3PO4 (7.58 g, 35.7 mmol) in DMF (50 mL) was heated at 140° C. for 48 h. After cooling to room temperature, the reaction mixture was filtered through a short plug of Celite®, and the solid was washed with DCM. The combined filtrate was evaporated and purified by column chromatography on silica gel with DCM as eluent to yield 1-(dibenzo[b,d]furan-4-yl)-1H-1,2,4-triazole (2.4 g, 60%) as white powder.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])([O-:12])=[O:11]>ClCCCl>[NH2:17][C:16](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Solvent: ClCCCl
Product: COC(=O)C(C(=O)OC)=C(N)c1cccc([N+](=O)[O-])c1
Yield: 65.8 %

Procedure:
To a mixture of dimethyl malonate (100 g) and 3-nitrobenzonitrile (112 g) in 1,2-dichloroethane (500 ml) was added stannic chloride (177 g) at once with a syringe and refluxed for 1 hour with stirring. The white precipitates were collected by filtration, dissolved in a mixture of acetone (2 l) and water (2 l) and adjusted to pH 9.0 with 20% aqueous sodium hydroxide. The resulting white solid was filtered off, and the filtrate was extracted with methylene chloride (2 l). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting precipitates were recrystallized from a mixture of diethyl ether and methylene chloride to give dimethyl (α-amino-3-nitrobenzylidene)malonate (139.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:42]([C:45]1[NH:46][CH:47]=[CH:48][N:49]=1)([CH3:44])[CH3:43]>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:46]3[CH:47]=[CH:48][N:49]=[C:45]3[CH:42]([CH3:44])[CH3:43])=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: CC(C)c1ncc[nH]1
Product: Cc1c(Cc2ccc(-n3ccnc3C(C)C)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 2-isopropyl-1H-imidazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:10]=[CH:23]/[CH:24]=[O:25])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(-c2ncccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cccc(-c2ncccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 12) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7](S(C2C=CC(C)=CC=2)(=O)=O)[N:6]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][N:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(OCCF)c3cc([N+](=O)[O-])cnc32)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cnc2[nH]nc(OCCF)c2c1
Temperature: 55 °C

Procedure:
A mixture of 3-(2-fluoroethoxy)-5-nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridine (0.273 g, 0.718 mmol) and aqueous K2CO3 (1.8 mL, 2M) in MeOH (14 mL) was heated at 55° C. for 1 hour. After cooling to room temperature, the mixture was diluted with 10% aqueous citric acid, extracted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated to give 3-(2-fluoroethoxy)-5-nitro-1H-pyrazolo[3,4-b]pyridine. The material was purified by silica gel flash column chromatography (1% MeOH in CH2Cl2) to afford 3-(2-fluoroethoxy)-5-nitro-1H-pyrazolo[3,4-b]pyridine along with a byproduct. LRMS (ESI pos) m/e 207.0 (M−F).
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:28]([C:26]2[S:27][C:23]([Br:22])=[CH:24][CH:25]=2)(=[O:30])=[O:29])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.53 g NaH (60%) with 40.0 ml THF is cooled down to −30° C. and 3.1 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition it is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Then 5.0 g of 5-bromothiophene-2-sulfonylchloride is added by −30° C. The mixture is stirred at ambient temperature for 24 h. The NaH is hydrolyzed with water and the solution is extracted with ethyl acetate. The title compound is isolated by flash chromatography. By this method 4.5 g of colorless crystals are obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:17][CH3:18].[CH3:19]I.O>CN(C)C=O>[Br:3][C:4]1[CH:9]=[C:8]([N:10]([CH3:19])[C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH:7]=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C)C(=O)C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.48 g, 12 mmol) was added to a stirred, cooled (0° C.) solution of 2-bromo-4-(trifluoroacetamido)anisole (Description 4(b); 2.98 g, 10 mmol) in dimethylformamide (30 ml). The mixture was stirred at 0° C. for 30 minutes, then methyl iodide (0.75 ml, 1.70 g, 12 mmol) was added. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 3 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (4×50 ml) then brine (50 ml), dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/CH2Cl2 (50:50 increasing to 30:70), to give the title compound as a colorless solid (2.72 g, 87%); δH (250MHz, CDCl3) 3.32 (3H, s, N--CH3), 3.94 (3H, s, ArOCH3), 6.91 (1H, d, J 8.7Hz, 6-H), 7.18 (1H, dd, J 8.7, 2.4Hz, 5-H), 7.46 (1H, d, J 2.4Hz, 3-H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:4]2[CH:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C>[N:18]1([C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:11]=[C:4]3[CH:3]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: Nc1cc(Br)cc2nc(-c3ccccc3)nn12
Solvent: CN(C)C=O
Product: Nc1cc(N2CCOCC2)cc2nc(-c3ccccc3)nn12
Yield: 49.1 %

Procedure:
A mixture of 40 mg (0.138 mmol) 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 241 μl (2.8 mmol) morpholin and 225 mg (0.69 mmol) CS2CO3 in 200 μl DMF was heated 20 h to 140° C. filtration and subsequent purification with reversed phase column chromatography with an acetonitrile/water gradient yielded 20 mg (49%) of the title compound, MS m/e M+H+ (100%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=3)[C:2]([CH3:1])=[N:3]2)=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:17]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12

Procedure:
1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehyde was prepared from 3-Methyl-1H-indazole-5-carbaldehyde and 1-Bromomethyl-4-chloro-2-trifluoromethyl-benzene following general procedure A.
Reaction SMILES: [I:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[I:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: COc1c(I)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1c(I)cccc1C(=O)Cl
Temperature: 82 °C
Reaction time: 0.03 h

Procedure:
To 3-iodo-2-methoxy-benzoic acid (8.29 g, 29.8 mmol) was added thionyl chloride (15 mL). The resulting solution was stirred for 2 minutes then heated to 82° C. and stirred at this temperature for 30 minutes. The solution was then concentrated under reduced pressure to give the title compound. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=O)=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22].O(Cl)Cl.[P+5]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:6]([CH:12]=[N:11][CH:10]=2)[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:23]
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(Br)cc1F
Agent: ClOCl
Agent: [P+5]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 95 °C
Yield: 48 %

Procedure:
To a solution of 2-(4-Bromo-2-fluorophenylamino)-6-formylaminomethylnicotinic acid methyl ester (11.8 g, 30.9 mmol) in toluene (550 mL) was added phosphorous (V) oxychloride (3.16 mL, 34 mmol) and the reaction mixture heated at 95° C. for 1 hour. The reaction mixture was concentrated in vacuo and treated with aqueous saturated sodium hydrogen carbonate solution then extracted twice with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in DCM) to yield the title compound as a brown oil (5.4 g, 49%). LCMS (Method B): RT=3.56 min, M+H+=364/366.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N+:43]([O-:45])=[O:44])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Agent: Cl
Product: O=[N+]([O-])c1ccccc1CS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F
Reaction time: 2 h
Yield: 87 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-(2-nitrophenyl)methansulfonamide (20 mg, 0.032 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 17 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-1-(2-nitrophenyl)methansulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:7][C:8](=[O:10])[CH:9]=1)=[O:6])[CH2:2][CH3:3].C(C1CC(=O)OC1=O)=CC>>[CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[O:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: CCCC1=CC(=O)OC1=O
Agent: CC=CC1CC(=O)OC1=O
Product: C=CCC1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After 120 minutes, the reaction product was allowed to cool to room temperature, and gas chromatographic analysis of the product confirmed a product distribution of 44.9% propyl maleic anhydride and the balance propenyl succinic anhydride.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OC)=O.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH2:27]([NH:30][C:12]([C:3]1[C:2](=[O:1])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)=[O:14])[CH2:28][CH3:29]
Reactant: O=C(O)c1cnc2ccccn2c1=O
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2ccccn2c1=O
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
A mixture containing 7.2 g (0.0378 mol) of 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 g (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.25 ml (0.044 mol) of methyl chloroformate dissolved in 20 ml of chloroform is dropped to the above mixture at -20° C. during 20 minutes. After stirring for 5 minutes, 2.6 g (0.04 mol) of n-propylamine dissolved in 80 ml of chloroform are dropped at -18° C. during 60 minutes. The reaction mixture is stirred for 1 hour at the same temperature, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 7.1 g (77.5%) of the named compound as light yellow crystals after recrystallization from ethanol, m.p.: 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:4]2[N:3]=1.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:19])[C:18]([I:20])=[C:4]2[N:3]=1
Reactant: Cc1cc2nc(Cl)cc(-c3ccc(F)c(F)c3)n2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1nn2c(-c3ccc(F)c(F)c3)cc(Cl)nc2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
5-Chloro-7-(3,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (301 mg) is dissolved in CH2Cl2 (50 mL). N-Iodosuccinimide (NIS, 500 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for about 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound (301 mg) is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 8.04 (m, 1H), 7.78 (m, 1H), 7.38 (q, J=8.7 Hz, 1H), 6.85 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNCC1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCCC1)CO2
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.6 g, 1.5 mmol), piperidine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash chromatography through a small plug of silica (DCM/MeOH, 5:95). Yield: 0.4 g, 85%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 248° C. MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 310 (M+, 2), 207 (3), 99 (7), 98 (bp).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([O:12][C@@H:13]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]1[O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][NH:7]2)#[CH:2].I[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([CH3:56])[CH:50]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([C:2]#[C:1][C:3]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:4]=2[C:5]([O:12][C@@H:13]2[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]2[O:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[N:6][NH:7]3)=[CH:50][C:51]=1[CH3:56]
Reactant: Cc1cc(I)ccc1O
Reactant: C#Cc1cccc2[nH]nc(O[C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]3OC(=O)C(C)(C)C)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C#Cc2cccc3[nH]nc(O[C@@H]4O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]4OC(=O)C(C)(C)C)c23)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 4-ethynyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (66 mg) in triethylamine (1 mL) were added 4-iodo-2-methylphenol (25 mg), tetrakis(triphenylphosphine)palladium (0) (12 mg) and copper (I) iodide (4 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=3/1-2/1-1/1) to give the title compound (47 mg).
Reaction SMILES: C[N:2]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[C:3]1[C:4]2[CH:12]=[C:11]([CH3:13])[O:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1.[H-].[Na+].S(OC)(OC)(=O)=O.Cl>CCOC(C)=O.CCCCCC.CN(C=O)C>[CH3:9][C:7]1[N:8]=[C:3]([NH:2][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:4]2[CH:12]=[C:11]([CH3:13])[O:10][C:5]=2[N:6]=1
Reactant: CSc1ccc(N(C)c2nc(C)nc3oc(C)cc23)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2nc(C)nc3oc(C)cc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,2,6-Trimethyl-N-[4-(methylsulfanyl)phenyl]furo[2,3-d]pyrimidin-4-amine (Composition No. 125) To a 25 mL round bottom flask was weighed N (143 mg, 0.5 mmol) and was added DMF (2 mL) to afford a solution. The flask was purged with argon for five min followed by cooling down to 0° C. using ice bath. Sodium hydride (36 mg, 1.5 mmol) was added to the solution at 0° C. The solution was stirred for 30 min at 0° C. under argon atmosphere. Dimethyl sulfate (150 mg, 1.2 mmol) was introduced to the reaction mixture with the help of a syringe and the flask was warmed to room temperature. The mixture was stirred at room temperature for another 3 h at the end of which 1 N hydrochloric acid (5 mL) was added carefully to quench the reaction. The reaction solvent was removed under reduced pressure and the residue was suspended in water (20 mL). The suspension was extracted using ethyl acetate (10 mL×2). Combined organic extracts were washed with brine (10 mL) dried (anhydrous sodium sulfate) and concentrated under reduced pressure. Silica gel (200 mg) was added and solvent evaporated to afford a plug. Column chromatography by elution with hexane:ethyl acetate (5:1) afforded 78 mg (52%) of Composition No. 125 as a light yellow solid: Rf 0.5 (AcOEt/Hexane, 1:3); 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 2.49 (s, 3H), 2.54 (s, 3H), 3.47 (s, 3H), 4.73 (s, 1H), 7.30-7.32 (d, 2H,), 7.38-7.39 (d, 2H); Anal. Calcd. for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04, S, 10.71. Found C, 64.26; H, 5.68; N, 13.90, S, 10.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=12
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-Chloro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[C:18]#[CH:19]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:20][CH2:17][C:18]#[CH:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: C#CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 131° C. and MS: m/e=249 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and prop-2-ynylamine.