Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:22]=1[NH2:23].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:22]=1[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COCCOc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COCCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Temperature: 102.5 °C
Yield: 73.4 %

Procedure:
A mixture of 4-chloro-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile (1.00 g, 3.59 mmol), 2,4-dichloro-5-methoxyaniline (727 mg, 3.77 mmol) and pyridine hydrochloride (620 mg, 5.34 mmol) in 18 mL of 2-ethoxyethanol is heated at 100-105° C. for 2 hours. The reaction mixture is cooled to room temperature and then poured into ice cold saturated sodium bicarbonate. The solids are collected, washed with water and then treated with methanol and dichloromethane. The mixture is filtered and the filtrate is concentrated. The solid residue is slurried with hexane, and the solids are collected by filtration to provide 1.15 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 170-172° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].[OH-].[Na+]>C(Cl)Cl>[CH3:25][CH2:24][CH2:23][CH2:22][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:32])=[CH:34][CH:35]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 92 mg of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride is added 100 mg of triethylamine followed by 130 mg of 4-(n-butyloxy)benzoyl chloride. The reaction mixture is stirred at room temperature for 24 hours and then treated with 4 ml of 1N sodium hydroxide. The mixture is extracted with 10 ml of ethyl acetate and the extract washed with 1N sodium hydroxide and 5 ml of brine. The organic layer is dried over anhydrous sodium sulfate and filtered through hydrous magnesium silicate. The filtrate is concentrate in vacuo to a residue which is stirred with ether-hexanes to give 160 mg of the desired product as a white solid:mass spectrum (CI), 361 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:22]([CH:10]3[CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:25]([F:27])([F:28])[F:26])[CH:4]=4)[CH2:13][N:12]([C:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[O:15])[CH2:11]3)[O:23][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F
Product: Cc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F

Procedure:
100 mg (about 0.24 mmol) of the compound from Example 160A and 55 mg (0.36 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 67 mg (54% of theory).
Reaction SMILES: [C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:34][CH2:35][CH3:36])[C:9]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([OH:30])[C:23]=3[CH2:31][CH2:32][CH3:33])=[CH:10][CH:11]=2)[O:6]1)([O:3]C)=[O:2].[OH-].[Na+]>CO.O>[CH2:31]([C:23]1[C:24]([OH:30])=[C:25]([CH2:28][CH3:29])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:9]1[C:8]([CH2:34][CH2:35][CH3:36])=[C:7]2[C:12]([CH2:13][CH2:14][CH:5]([C:1]([OH:3])=[O:2])[O:6]2)=[CH:11][CH:10]=1)[CH2:32][CH3:33]
Reactant: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)O)CC3)ccc(CC)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
1.26 g (2.5 mmole) of the methyl ester from Example 8 was dissolved in 25 ml of methanol in a single neck 100 ml round bottom flask. Next a solution of 202 mg (5 mmole) of sodium hydroxide in 10 ml water was added. The resulting mixture was stirred with the aid of a magnetic stirring bar for 2 hours at room temperature. The methanol was removed by rotary evaporation and the residue was acidified with dilute hydrochloric acid to pH 2. The acidified solution was extracted three times with 30 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered and the ethyl acetate removed by rotoevaporation to furnish 1.16 g (95%) of the title compound, mp 101°-102°. Calc: C, 71.87; H, 8.32; Found: C, 71.71; H, 8.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][N:19]2[CH:27]=[CH:28][CH:29]=[C:18]2[CH2:17]1)=[O:15].C(O)(=O)C.C=O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][N:19]2[C:27]([CH2:14][N:16]([CH3:22])[CH3:17])=[CH:28][CH:29]=[C:18]2[CH2:17]1)=[O:15]
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)n1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(CN(C)C)n4Cc4ccccc43)c(Cl)c2)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a stirred solution of [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H,11H-pyrrolo-[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.61 g), N, N, N′, N′, tetramethyldiamino-methane (0.82 g), and glacial acetic acid (0.48 g) in methanol (25 ml) was added a solution of 37% aqueous formaldehyde (4 ml). The mixture was warmed to 40° C. for 10 minutes. After stirring one hour at room temperature, the reaction was concentrated in vacuo, redissolved in dichloromethane, and extracted sequentially with aqueous sodium bicarbonate and water (4×). The organic phase was dried over anhydrous sodium sulfate, and filtered through a plug of silica gel, eluted with ethyl acetate. Evaporation of the solvent in vacuo afforded an oil, which on trituration with hexane yielded 0.36 g of the title compound as a colorless powder, m.p. 100-102° C.; MS (+FAB), m/z: 482 (M+Na)+, 460 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1(O)[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH2:6]1.C([Li])CCC.CN([CH:26]=[O:27])C>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: COCOC1(O)C=C(OC)C(OC)=C(OC)C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1cc(OC)c(OC)c(OC)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30.4 g of 1-methoxymethyloxy-3,4,5-trimethoxyphenol prepared in Referential Example 10 was dissolved in 250 ml of anhydrous ether, and 100 ml of n-butyllithium (1.6 M n-hexane solution) was dropwise added thereto at -20° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hr, and 14.6 ml of DMF was added thereto. 100 ml of ice water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; n-hexane ethyl acetate=6 : 4) to prepare 25.5 g of the product compound as a light yellow oleaginous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[I:9].[F:10][C:11]([F:18])([F:17])[C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:14]2[CH:15]=[CH:16][C:12]([C:11]([F:18])([F:17])[F:10])=[N:13]2)[CH:5]=[CH:4][C:3]=1[I:9]
Reactant: Fc1ccc(I)c(Cl)c1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccn(-c2ccc(I)c(Cl)c2)n1
Temperature: 135 °C
Yield: 78.8 %

Procedure:
To a solution of 2-chloro-4-fluoro-1-iodo-benzene (3.6 g, 14.3 mmol) and 3-trifluoromethyl-1H-pyrazole (1.9 g, 14.4 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (2.4 g, 17.2 mmol), and the resulting mixture was heated at 135° C. for 12 h. The reaction mixture was cooled to room temperature, poured in cold water (80 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexanes to afford the title compound (4.2 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH:17]=[N:16][N:15]=[N:14]1.[OH-].[Na+].Cl>CO>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:18])=[O:2])[CH:11]=1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.3 %

Procedure:
(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid: To a cooled (0° C.) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to rt and stirred at rt for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2-tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid weighing 1.76 g. The solid was dissolved in EtOAc and filtered through a plug of silica gel, eluting with EtOAc. The green filtrate was concentrated to give a greenish solid weighing 1.36 g. Recrystallization from EtOAc gave an off-white solid weighing 0.476 g. Additional product was obtained by concentrating the filtrate from recrystallization, adding methanol, sonicating, and collecting the solid product by filtration. A total of 0.829 g (57%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid methyl ester was obtained. LCMS m/z 265.1 (M+H)+; 287.2 (M+Na)+. 1H NMR (CDCl3, 500 MHz) δ: 8.80 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.8, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.25 (d, J=16.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 3.78 (s, 3H). To a white suspension of this ester (0.140 g, 0.529 mmol) in MeOH (3.0 mL) was added 1.0 M sodium hydroxide (1.587 ml, 1.587 mmol). The resulting suspension was stirred vigorously at rt for 2.5 h. The yellow suspension was neutralized with 1.0 N HCl (1.60 mL), and concentrated to give a beige solid. The solid was partitioned between 1.0 N HCl and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 0.137 g (100%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid as a white solid. LCMS m/z 251.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ: 12.72 (s, 1H), 9.87 (s, 1H), 8.24 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8.8, 2.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 6.98 (d, J=16.0 Hz, 1H), 6.70 (d, J=16.0 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:6]=2[CH:5]=1
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2o1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2nc(NC(=O)c3ccccc3)oc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of N-(6-nitrobenzoxazol-2-yl)benzamide (2.03 g, 7.17 mmol) in dimethylformamide (60 mL), palladium on charcoal (1.52 g, 10% Pd, 1.43 mmol Pd) was added and the air was replaced with hydrogen (1 bar). The mixture was stirred for 2 h at 60° C. and then overnight at r.t. The palladium was removed by filtration through a pad of celite. After concentration to 20 mL, water was added and the resulting precipitate was separated by filtration to obtain N-(6-aminobenzoxazol-2-yl)benzamide (0.823 g, 3.25 mmol, 45%) as a brown solid. LC/ESI-MS: m/z=254 [M+H]+; m/z=252 [M−H]−; Rt=1.92 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])=[CH2:2].[F:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH2:25][CH2:26][CH3:27])[C:21](I)=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:4]=[C:3]([CH:9]=[CH:8][CH:7]=1)/[CH:1]=[CH:2]/[C:21]1[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[N:23][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)=[N:19][CH:20]=1
Reactant: C=Cc1cccc(N)c1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1/C=C/c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-vinylaniline (19 μL), N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 51 mg) and palladium(II) acetate (3 mg) in acetonitrile (1.5 mL), triethylamine (68 μL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour, and then stirred at 80° C. for 14 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 50% hexane in ethyl acetate) to obtain (E)-5-(3-aminostyryl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (F11, 14 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10](=[O:13])[C:9]=2[CH:14]=1)=[O:4].[C:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([OH:17])=[O:16].Cl.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11](/[CH:21]=[C:20]3/[CH2:19][C:18](=[CH:25][CH:24]=[CH:23]/3)[C:15]([OH:17])=[O:16])[C:10](=[O:13])[C:9]=2[CH:14]=1)=[O:4]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CO2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(=O)C(/C=C1\C=CC=C(C(=O)O)C1)O2

Procedure:
5-Methoxycarbonylbenzofuran-3-(2H)one (4.9 g) was dissolved in warm dioxan (50 ml). 3-Carboxybenzaldehyde (4.5 g) was then added followed by concentrated hydrochloric acid (10 ml). The mixture was heated on a steam bath for 15 minutes with formation of yellow crystals. After cooling and addition of an equal volume of water, the crystalline product was filtered off and recrystallised from dimethylformamide to give the title compound, m.p. 280° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Sn](CCCC)(CCCC)CCCC)(=[O:5])=[O:4].C1(C)C(C([O:33][C@@H:34]2[C@@H:38]([CH2:39][O:40]C(C3C(C)=CC=CC=3)=O)[O:37][C@@H:36]([N:50]3[C:54]4=[N:55][CH:56]=[CH:57][C:58](I)=[C:53]4[CH:52]=[CH:51]3)[CH2:35]2)=O)=CC=CC=1.[Cl-].[Li+]>O1CCOCC1.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>[C@@H:36]1([N:50]2[C:54]3=[N:55][CH:56]=[CH:57][C:58]([C:7]4[N:6]([S:3]([N:2]([CH3:1])[CH3:24])(=[O:4])=[O:5])[CH:10]=[CH:9][N:8]=4)=[C:53]3[CH:52]=[CH:51]2)[O:37][C@H:38]([CH2:39][OH:40])[C@@H:34]([OH:33])[CH2:35]1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2ccc3c(I)ccnc32)C[C@@H]1OC(=O)c1ccccc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1S(=O)(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)n1ccnc1-c1ccnc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 120 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
N-Dimethylaminosulfonyl-2-(tributylstannyl)imidazole (930 mg, 2.0 mmol) was added to a solution of 1-[2-deoxy-3,5-di-O-(toluoyl)-β-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine (596 mg, 1.0 mmol), lithium chloride (42 mg, 1.0 mmol), and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in dioxane (10 mL), followed by stirring at 120° C. for 4 hr. The reaction solution was concentrated and was then purified with a silica gel column, and methanolic ammonia (30 mL) was added thereto. The resulting mixture was stirred at room temperature for 24 hr. The reaction solution was concentrated and purified with a silica gel column and then with HPLC to yield 218 mg (54%, second stage yield) of 1-(2-deoxy-β-D-ribofuranosyl)-4-(N-dimethylaminosulfonyl-2-imidazolyl)-pyrrolo[2,3-b]pyridine. 1-(2-Deoxy-β-D-ribofuranosyl)-4-(N-dimethylaminosulfonyl-2-imidazolyl)-pyrrolo[2,3-b]pyridine (200 mg, 0.49 mmol) was dissolved in 80% acetic acid, followed by stirring at 60° C. for 3 hr. The reaction solution was concentrated, and aqueous ammonia was added thereto for further concentration. Subsequently, 1-(2-deoxy-β-D-ribofuranosyl)-4-(2-imidazolyl)-pyrrolo[2,3-b]pyridine (dDia: 109 mg, 74%) was obtained through purification by HPLC.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([OH:25])=O)[CH2:6][S:7][CH2:8][CH:9]=[C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])[CH3:11])(=[O:3])[CH3:2].[NH2:26][NH2:27]>ClCCl.C1COCC1>[NH:26]([C:23](=[O:25])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][S:7][CH2:8]/[CH:9]=[C:10](\[CH3:11])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:16])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[NH2:27]
Reactant: NN
Reactant: CC(=O)N[C@@H](CSCC=C(C)CCC=C(C)CCC=C(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)NN
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In 50 mL round bottom flask, N-acetyl-S-farnesyl-L-cysteine (368 mg, 1.0 mmole) was dissolved in dichloromethane (10 mL). N-Cyclohexylcarbodiimide,N′-methyl polystyrene HL (1.7 g, 3.3 mole, from NovabioChem) was added followed by sufficient dichloromethane to swell the resin and keep the reaction mobile and the mixture gently magnetically stirred in 30 minutes. 5 mL of hydrazine in THF (1M) was added to the reaction solution and the reaction mixture was stirred in 3 hours at room temperature. The used resin was removed by filtration and washed with dichloromethane. Evaporation of the filtrate provided crude reaction mixture. The desired product was purified by preparative HPLC (305 mg, 80% yield) to yield Compound I: 1H-NMR (500 MHz, CDCl3): δ 1.60 (s, 6H), 1.67 (s, 6H), 1.70 (S, 3H), 1.92-2.09 (m, 8H), 2.75 (dd, J=7.9, 13.9 Hz, 1H), 2.88 (dd, J=5.7, 13.6 Hz, 1H), 3.20 (d, J=7.9 Hz, 2H), 4.51 (dd, J=7.6, 13.6 Hz, 1H), 5.10 (m, 2H), 5.24 (t, J=7.6 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.1, 16.2, 17.6, 17.7, 23.2, 23.4, 23.5, 25.7, 25.8, 26.2, 26.3, 26.5, 26.7, 30.0, 31.8, 31.9, 32.9, 33.2, 39.6, 39.7, 39.9, 51.3, 51.4, 119.6, 120.3, 123.6, 124.2, 131.4, 131.6, 135.5, 135.6, 135.8, 140.2, 140.3, 170.2, 171.1; ES-MS: mass calcd for Chemical Formula: C20H35N3O2S 381.2 (M+). Found (M+Na) m/z 404.3.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])([CH3:8])[CH3:7]>CC(O)=O.C(Cl)Cl>[Cl:4][CH:12]([S:9]([CH:6]([CH3:8])[CH3:7])(=[O:11])=[O:10])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CS(=O)(=O)C(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C(Cl)S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 157.9 %

Procedure:
Sulfuryl chloride (0.248 mL, 3.05 mmol) was added dropwise to a solution of 1-(isopropylsulfonyl)propan-2-one (418 mg, 2.55 mmol) in 1:1 AcOH/DCM (16 ml) at 0° C. The reaction was stirred at rt for 4 h. The solvent was removed in vacuo, then diluted with dichloromethane. The organic layer was washed (2×) with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated to leave 800 mg of a colorless oil. The material was used without further purification.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1>>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([O:19][CH:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: CC(C)CCCC(C)Br
Reactant: COC(=O)c1ccc(O)c(OC)c1
Product: COC(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
By the procedure described in Example 1, 2 -bromo-6-methylheptane is reacted with vanillic acid methyl ester to produce 4-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-benzoic acid methyl ester (boiling point = 198°-200° C/0.1 mmHg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Br:10]Br.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.O>[Br:10][C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: O=C(O)Cc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(Br)s1
Temperature: 25 °C

Procedure:
To a solution of 2-(thiophen-2-yl)acetic acid (2 g, 14 m mol) in HOAc (10 ml) was added dropwise bromine (2.25 g, 14 mmol) at 10˜20° C. for 30 min. The mixture was allowed to warm to room temperature for 3 hours. Then it was diluted with water (100 ml), neutralized to pH=5 with anhydrous sodium carbonate and extracted with EtOAc (100 ml×3). Dried over Na2SO4, filtered and concentrated to afford crude product as brown oil. MS (ESI): m/z 220.9 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][CH:4]([CH2:3][CH2:2][Cl:1])[CH:5]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[O:6]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: c1ccccc1
Product: O=C1CCc2cc(C3OCCOC3CCCl)ccc2N1

Procedure:
10 Grams (39.7 mM) of 6-(4-chlorobutyryl)-3,4-dihydrocarbostyril was dissolved in 300 ml of benzene, then to this solution was added 7.4 g (120 mM) of ethylene glycol and 300 mg of p-toluenesulfonic acid, and the whole mixture was refluxed by heating under dehydrating in Dean-Stark extractor for 6 hours. The reaction mixture was cooled and neutralized with an aqueous solution saturated with sodium hyfrogen carbonate, then extracted with chloroform. The chloroform extract was washed with water then dried with anhydrous magnesium sulfate, then concentrated by removing the solvent by evaporation. The residue thus obtained was purified by means of a silicagel column chromatography (eluent: chloroform:methanol=40:1) to yield 10.5 g of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril.