Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:14][CH3:15])[C@@H:2]1[O:8][C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[C@H:5]([OH:6])[C@H:3]1[OH:4].[Na+]>O>[O:1]([CH2:14][CH3:15])[C@@H:2]1[O:8][C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCO[C@@H]1O[C@@H]([C@H](O)C(=O)[O-])[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Product: CCO[C@@H]1O[C@@H]([C@H](O)C(=O)O)[C@H](O)[C@H]1O

Procedure:
50 g (0.2 mole) of sodium ethyl β-D-galactofuranoside uronate prepared according to Example No. 10 are solubilized in water (10% solution).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC(C)=O.O>[CH3:34][O:33][C:29](=[O:32])[CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: C=CC(=O)OC
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Yield: 55 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (550 mg, 1.8 mmol), 550 mg (4 mmol) of K2CO3 and 0.2 mL of methyl acrylate in 40 mL of acetone was heated to maintain reflux for 100 hours (additional methyl acrylate was added at various times). After cooling, the mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution and dried (Na2 SO4). After concentrating, the residue was chromatographed on silica (eluted with CH2Cl2 →1% MeOH/CH2Cl2) and crystallized from CH2Cl2 /ether to give 375 mg (55% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]-propanic acid methyl ester, mp, 113°-115° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].[H-].[Na+].[CH2:29]([N:33]=[C:34]=[O:35])[CH2:30][CH2:31][CH3:32]>O1CCCC1.C(OCC)C>[CH2:29]([NH:33][C:34]([O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])=[O:35])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN=C=O
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCNC(=O)OCCC1OC1(C)C1C(OC)C(OC(=O)N2CCOCC2)CCC12CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (11.1 mg) in anhydrous tetrahydrofuran (1 ml) was added sodium hydride (60% oil dispersion, 2.4 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and butyl isocyanate (4.5 mg) was added. After stirred for 2 hours at ambient temperature, the solvent was diluted with diethyl ether (2 ml) and washed with water, dried, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate) to afford 4-[3-(2-butylcarbamoyloxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (10.8 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[S:4][C:3]=1[CH:9]=[O:10].[BH4-].[Na+]>C(O)C>[OH:10][CH2:9][C:3]1[S:4][C:5]([CH3:8])=[C:6]([CH3:7])[C:2]=1[CH3:1]
Reactant: Cc1sc(C=O)c(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(CO)c(C)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.9 G. of 3,4,5-trimethyl-2-thiophenecarboxaldehyde were dissolved in 20 ml. of ethanol. The resulting solution was cooled to 0°-5° C. and 125 mg. of sodium borohydride were added in small portions. The resulting reaction mixture was stirred at room temperature for 3 hours, poured into ice water, extracted with ethyl acetic, dried with sodium sulfate, filtered and evaporated. The resulting crystalline 2-hydroxymethyl-3,4,5-trimethyl-thiophene had m.p. 45°-48° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:9]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:26][C@@H:27]5[C@H:32]6[CH2:33][C@@H:29]([CH:30]=[CH:31]6)[C@@H:28]5[C:34]([NH2:36])=[O:35])=[C:4]4[N:10]=3)=[C:12]([O:24][CH3:25])[CH:13]=2)[CH2:19][CH2:20]1)(=[O:39])[CH3:38]
Reactant: COc1cc(CN2CCNCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(C)=O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@@H]3C4)c(Cl)cnc2[nH]1
Yield: 33.1 %

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XLII) (254 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 mL) and treated with acetic anhydride (1 mL, 10.0 mmol) and triethylamine (1.0 mL, 7.2 mmol) for one hour at ambient temperature. The reaction was concentrated and the product was purified by reverse phase chromatography (Gilson) to afford following neutralization of desired fractions a pale yellow solid as the title compound (91 mg, 30%). Mp 109-113° C. 1H NMR (d-chloroform): 11.12 (br s, 1H), 8.34 (d, J=7 Hz, 1H), 7.99 (s, 1H), 7.11 (m, 2H), 6.37 (m, 3H), 5.72 (d, J=7 Hz, 1H), 5.36 (m, 1H), 5.22 (t, J=8 Hz, 1H), 4.10 (s, 3H), 3.66 (m, 2H), 3.59 (s, 2H), 3.50 (m, 2H), 3.17 (s 1H), 2.92 (s, 1H), 2.85 (d, J=7 Hz, 1H), 2.48 (m, 4H), 2.34 (d, J=8 Hz, 1H), 2.10 (s, 3H), 1.73 (d, J=7 Hz, 1H). MS: 550.2 (M+H). HPLC retention time: 1.70 minutes (G Method).
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=3)[N:11]([CH3:32])[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH3:32][N:11]1[C:10]2[CH2:9][NH:8][CH2:20][CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:16]=2
Reactant: CC(C)[Si](Oc1ccc2c(c1)c1c(n2C)CN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](Oc1ccc2c(c1)c1c(n2C)CNCC1)(C(C)C)C(C)C

Procedure:
A solution of 9-methyl-6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (175 mg) and 0.5 mL of trifluoroacetic acid in 3 mL dichloromethane was stirred for 4 h. The solvent was removed to afford 9-methyl-6-triisopropylsilanyloxy-2,3,4,9-tetrahydro-1H-β-carboline trifluoroacetate (125 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:4]1([CH3:10])[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Oc2cccc(C)c2)cc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
21.8 g of sodium hydride (55% in oil) are placed in 100 ml of absolute pyridine and treated dropwise during 1 hour with 54.1 g of m-cresol in 200 ml of pyridine. After completion of the reaction, 1.2 g of cuprous chloride are added and subsequently 93.5 g of 4bromoanisole are added dropwise during 1 hour at reflux temperature. After refluxing for 4 hours, the pyridine is distilled off, the mixture being heated at the end up to 170° C. (internal temperature). After 2 hours, 350 ml of water are added dropwise with ice-cooling, followed by 500 ml of diethyl ether and a further 150 ml of water. The mixture is filtered with suction over Celite and the phases are separated. The organic phase is washed in sequence with 200 ml of 2 N hydrochloric acid, three times with 100 ml of 2 N sodium hydroxide each time, with 200 ml of water and with 200 ml of saturated sodium chloride solution. After drying over sodium sulfate and evaporation, there is obtained a brown-red oil which is filtered over a five-fold amount of silica gel with n-hexane/diethyl ether and then distilled to yield pure p-(m-tolyloxy)anisole; b.p. 106°-108° C./0.04 Torr; nD20 =1.5738.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([Br:17])=[CH:10][C:9]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(=O)C)(=[O:3])[CH3:2].C.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:14][C:13]1[CH:12]=[C:11]([Br:17])[CH:10]=[C:9]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CC(=O)Nc1c(N)cc(Br)cc1OCc1ccccc1
Yield: 65.5 %

Procedure:
A suspension of 23 g (56 mmol) N-acetyl-N-(2-benzyloxy4-bromo-6-nitro-phenyl)-acetamide, 5.5 g (34 mmol) iron(III) chloride and 13.8 g activated charcoal in 600 ml methanol was heated to reflux. To the reaction mixture were added 28 ml hydrazine hydrate (95%) to maintain gentie reflux. After complete reaction (2 h), the reaction mixture was cooled down and filtered through celite. The filter cake was washed thoroughly with dichloromethane/methanol and the filtrate was evaporated to dryness. The residue was partitioned between dichloromethane/methanol and water. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and evaporated. The residue was recrystallized from boiling ethyl acetate/n-heptane to give 12.3 g (65%) of the title compound as a colourless solid. m.p. 185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(-c2ccc(C)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2csc(/C=C/C(=O)O)c2)cc1
Reaction time: 144 h
Yield: 54.6 %

Procedure:
To a solution of methyl (E)-3-[4-(4-methylphenyl)thiophen-2-yl)acrylate (2.40 g) in tetrahydrofuran (50 ml) was added 2N sodium hydroxide (6.0 ml) at room temperature, and the mixture was stirred for 6 days. Precipitated crystal was collected by filtration and washed with tetrahydrofuran. To the crystals was added 1N hydrochloric acid (20 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give (E)-3-[4-(4-methylphenyl)thiophen-2-yl]acrylic acid (1.24 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>CO.[Pd]>[NH2:11][C:10]1[C:2]([F:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 40 h
Yield: 99 %

Procedure:
To 2-fluoro-3-nitro-benzoic acid (70, 6.77 g, 36.6 mmol) in 150 mL of methanol, Palladium on carbon (5:95 Palladium:Carbon, 0.338 g, 0.159 mmol) is added under a balloon of hydrogen. The reaction is stirred at room temperature for 40 hours, then a new balloon of hydrogen is attached, and the reaction continued for 5 hours. The reaction is filtered and the filtrate is concentrated under vacuum to provide the desired compound (71, 5.62 g). MS (ESI) [M−H+]−=154.1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:34][CH2:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCC3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of the above {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (50.2 mg, 0.13 mmol) in CH2Cl2 (0.8 mL) was added cyclohexylmethylamine (44.1 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 3 h and then purified by silica gel column chromatography using 50:1 CH2Cl2;MeOH as an eluent to afford 32 mg (54%) of the desired product as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C@H:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:22][O:21][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:6]=[C:7]([C:18](=[O:20])[NH:41][C@@H:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH3:40])[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(OC)c(=O)c(C(=O)N[C@H](C)c2ccc(F)cc2)cn1CC(OC)OC
Reaction time: 2 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.500 g, 1.59 mmol), was suspended in acetonitrile (6 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.550 mL, 3.17 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.242 mg, 1.74 mmol) and HATU (0.661 g, 1.74 mmol). The reaction mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic layer was separated and washed with HCl (10% aq), sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to afford crude (R)-methyl 1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate which was used without purification in the next step: LCMS-ESI+ (m/z): [M+H]+ calculated for C21H26FN2O2: 437.17; found: 437.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23]>CN(C=O)C.O>[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
18.2 g (0.13 mol.) of potassium carbonate and 18.74 g (13.03 ml, 0.11 mol.) benzyl bromide is added to 2-bromo-4-chlorophenol (1) (25 g, 0. 12mol) in DMF (25 ml) under nitrogen. The reaction mixture is heated (oil bath temperature 115° C.) for 1.5 hours and then allowed to cool and left to stand overnight at RT. The reaction mixture is diluted with distilled water (100 ml) and then extracted with Et2O (2×100 ml). The organic extracts are combined, washed with 1M sodium hydroxide (100 ml) and concentrated in vacuo to leave a colorless oil. This oil is purified by flash chromatography (SiO2, pentane) to yield a colorless oil which crystallised on standing to give the title compound as a colorless solid, (29.14 g, 81%), m.p. 49-50.5° C. δH (250 MHz, CDCl3), 7.55 (d, J=2.6 Hz, 1H), 7.46 (m, 5H), 7.19 (dd, J=8.9, 2.5 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.13 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.O=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@:17]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])[OH:18])=[CH:13][C:12]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1.Br[C:39]1[CH:40]=[N:41][CH:42]=[N:43][CH:44]=1>CN(C)C=O.[Cu](I)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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@:17]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])[OH:18])=[CH:13][C:12]=1[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[C:37][C:39]2[CH:40]=[N:41][CH:42]=[N:43][CH:44]=2)=[CH:34][CH:35]=1
Reactant: Brc1cncnc1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4cncnc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
37 mg copper iodide, 67 mg bis-(triphenylphosphine)-palladium dichloride and 0.46 mL triethylamine are added to an oxygen-free solution of 0.35 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 0.2 g 5-bromo-pyrimidine in 1 mL dimethylformamide. The solution is stirred under argon atmosphere at 60° C. for 16 h. The reaction mixture is filtered through Celite and evaporated down. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[C@@H:17]([O:18][CH2:19]SC)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1.C(NC1C2N=CN(C=2N=CN=1)[C@@H]1O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O)C1)(=O)C1C=CC=CC=1.[N-:76]=[N+:77]=[N-:78].[Na+].[NH4+].[F-]>C(Cl)Cl>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][OH:24])[C@@H:17]([O:18][CH2:19][N:76]=[N+:77]=[N-:78])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Agent: [F-]
Agent: [NH4+]
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
To 0.4 g N6-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (0.76 mmol) dissolved in 7 mL dry CH2Cl2 was treated with 0.4 mL cyclohexene and 155 μL SO2Cl2 (1.91 mmol) at 0° C. for 2 h. During this time the starting material completely converted to 7a which was shown by disappearance of the starting material and appearance of 3′-OH analog (5a) in TLC (EtOAC:Hex/7:3, Rf˜0.3; the 3-CH2Cl (7a) could not detected in TLC due to decomposition in TLC plate to 5a). Then solvent was removed by rotary evaporation and kept about 10 minutes in high vacuum pump. Then dissolved in 5 mL dry DMF and treated with 400 mg NaN3 (6.6 mmol) at room temperature for 3 h. Then the reaction mixture was partitioned in H2O/CH2Cl2, the combined organic part was dried over Na2SO4 and concentrated by rotary evaporation. The crude sample was then dissolved in 5 mL MeOH and treated with 300 mg NH4F (8.1 mmol) more than 38 h. Then MeOH was removed by rotary evaporation. After partioning in H2O/EtOAc, the combined organic part was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (100% EtOAc to 98:2, EtOAc/MeOH) resulting 150 mg of 9a as white powder (48% yield in three steps). HR-MS: Obs. m/z 411.1530, calcd for C18H19O4N8 411.1529 [M+H]+. 1H-NMR (CDC3): δH 8.84 (brs, 1H), 8.70 (brs, 1H), 8.08 (m, 1H), 7.76-7.54 (m, 5H), 6.47 (t, J=5.6 Hz, 1H), 4.83 (m, 2H), 4.78 (m, 1H), 4.39 (m, 1H), 4.09 (d, J=12.78 Hz, H5′, 1H), 3.88 (d, J=12.78 Hz, H5″, 1H), 3.09 (m, H2′, 1H), and 2.65 (m, H2″, 1H) ppm.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2ncnc(Cl)c2cc1OCC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCC
Yield: 65 %

Procedure:
As described in Example 50 the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.117 g, 0.4 mmol) was reacted with 4-chloro-6,7-diethoxyquinazoline (0.101 g, 0.4 mmol) from Example 13A, and Cs2CO3 (0.130 g, 0.4 mmol) in isopropanol (10 mL) at 70° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-ylthio)phenyl]urea as solid (0.131 g, 65%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.03 (s, 1H), 8.68 (s, 1H), 7.84 (s, 1H), 7.50 (d, 1H), 7.44 (t, 1H), 7.33 (m, 2H), 7.29 (d, 1H), 6.49 (s, 1H), 4.26 (m 4H), 1.45 (m, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][C:22]([N+]([O-])=O)=[C:21](/[CH:28]=[CH:29]/[N:30](C)C)[CH:20]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CC(O)=O.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[NH:30][CH:29]=[CH:28]3)=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/c1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: O=c1c2ccccc2nc(-c2ccc3[nH]ccc3c2)n1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Zn dust (2.0 g, 30.0 mmol) was added to a solution of (E)-3-(4-bromophenyl)-2-(3-(2-(dimethylamino)vinyl)-4-nitrophenyl)quinazolin-4(3H)-one (1.5 g, 3.0 mmol) in AcOH (25 mL). The mixture was stirred at room temperature overnight, then heated to reflux temperature for 1 hour. After cooling to 0° C., the reaction mixture was basified with 1 N NaOH and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 40% EtOAc in CH2Cl2, afforded 3-(4-bromophenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one (0.225 g, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
100 g of 4-hydroxy-3-methoxybenzaldehyde was dissolved in 700 ml of dimethylformamide, further 100 g of anhydrous potassium carbonate and 90 ml of benzyl bromide were added thereto, and the mixture was stirred for 1.5 hours at 80° C. After the completion of the reaction, the reaction solution was poured into 1 liter of water and extracted with 300 ml of ethyl acetate three times. The ethyl acetate layer was washed with water twice and dried over anhydrous magnesium sulfate and then concentrated. The residue obtained was crystallized from methanol, affording 142.95 g of 4-benzyloxy-3-methoxybenzaldehyde (89% yield).