Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[CH3:37].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[CH3:37][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:15][N:16]=2)[CH2:21][CH2:22]1)[C:32]([OH:34])=[O:33]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5C)CC4)nc3)cc21

Procedure:
3-methyl-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-3-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H29N5O3 (m/e) 483, obsd 484 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([CH2:16][CH2:17][CH:18]=C)[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]([F:20])([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17][CH:18]=[O:22]
Reactant: C=CCCC(F)(F)CCOCCCCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=CCCC(F)(F)CCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
Intermediate 16 (110 mg, 0.39 mmol) was dissolved in a mixture of THF (3 mL) and water (1 mL). To this solution was added sodium metaperiodate (272 mg, 1.27 mmol) and osmium tetroxide (4% water solution, 0.15 ml). The suspension was stirred 12 hours at room temperature, filtered and concentrated. The residue was purified by column chromatography on silica gel using methylene chloride/acetone (10:1) as eluent, to afford the title compound (89 mg, 81%) as oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC1(COCc2ccccc2)CC(OC(=O)Nc2ccccc2)C(C)(C)O1
Yield: 100 %

Procedure:
The alcohol of Example 3 (1 g) was dissolved in benzene (15 ml) and phenylisocyanate (600 mg) and a few drops of triethylamine were added. The mixture was refluxed for 20 hours. The solvent was then evaporated and the residue was taken up in ethyl acetate, washed with dilute hydrochloric acid and then with brine, dried over magnesium sulphate and evaporated down. The residue was purified on a silica column using 5% acetone in petrol as eluant. 1.4 g, corresponding to a 100% yield, of the desired product, as a viscous oil, were obtained. NMR showed the presence of both geometric isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)[CH:10]=[CH:11][C:6]=2[NH:5][CH:4]([C:19]([F:22])([F:21])[F:20])[O:3]1.[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>CN(C=O)C.[Cl-].[Na+].O>[C:26]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)=[CH:8][C:7]=2[C:2]([CH3:23])([CH3:1])[O:3][CH:4]1[C:19]([F:22])([F:20])[F:21])(=[O:28])[CH3:27]
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3csc(C#N)c3)cc21
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3csc(C#N)c3)cc2C(C)(C)OC1C(F)(F)F
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.25 g, 0.74 mmol) was dissolved in DMF (10 mL), NaH (0.09 g, 2.22 mmol) was added and the mixture was stirred for 30 minutes prior to the addition of acetyl chloride (0.079 mL, 1.11 mmol). Upon disappearance of the starting material the reaction mixture was poured into brine (100 mL) and the product extracted with ether (150 mL), dried over sodium sulfate and concentrated. The residue was purified by a flash column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 4-[1-acetyl-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.1 g, 36%) as an amorphous solid: 1H-NMR (DMSO-d6) δ 8.58 (s, 1H), 8.5 (s, 1H), 7.83-7.80 (m, 2H), 7.64 (d, 1H, J=8.74 Hz), 6.42 (q, 1H, J=10 Hz), 2.24 (s, 3H), 1.73 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1C(O)=O.CN(C=O)C.C(Cl)(=O)[C:19]([Cl:21])=[O:20]>CC1OCCC1>[S:1]1[CH:2]=[C:3]([C:19]([Cl:21])=[O:20])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: O=C(Cl)c1csc2ccccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To benzothiophene carboxylic acid (7 g) in MeTHF (6.5 Vols, 45.5 mL) is added a catalytic amount of DMF (0.01 eq.). Then, oxalyl chloride (1.1 eq.) is charged slowly to control the gaz release. After 16 h of stirring at 20° C., the end of the reaction is controlled by HPLC. MeTHF (6.5 Vols) is next added and the reaction mixture is concentrated to 5 volumes to remove the excess of oxalyl chloride. The resulting benzo[b]thiophene-3-carbonyl chloride is stored in a MeTHF solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:30])[C:17](=O)[C:16]3[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:30])[C:17]3=[N:32][NH:33][C:19](=[O:20])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(O)(c1ccc(F)cc1)C(c1nccn1C)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-3-hydroxy-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (60 mg) in 85% hydrazine monohydrate (0.2 mL) and methanol (2 mL) was stirred at room temperature for 1 hr. Then the solvent was removed under reduced pressure. The residue was purified by prep-TLC (methanol:dichloromethane=1:20) to give the title compound (50 mg, yield 80%). LC-MS (ESI) m/z: 378 (M+1)+; 1H-NMR (400 MHz, DMSO-d6); 3.44 (s, 3H), 5.24 (s, 1H), 6.84 (s, 1H), 6.98-7.06 (m, 4H), 7.11-7.13 (d, J=8.0 Hz, 1H), 7.38-7.42 (m, 3H), 7.46 (s, 1H), 7.56-7.60 (t, J=8.0 Hz, 1H).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1>O.Cl.C(OCC)C>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[N+:14]=[N-:1]
Reactant: O=N[O-]
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 194 %

Procedure:
A solution of 262 mg of sodium nitrite dissolved in 2.0 ml of water was dropped into a solution of 3.09 g of 4-fluorophenylhydrazine hydrochloride in 20 ml of concentrated hydrochloric acid and 10 ml of diethyl ether under cooling with ice. Temperature of the reaction solution was raised to room temperature followed by stirring for 3 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 1.01 g of the crude title compound as a brown oily substance.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17]Br)=[CH:11][CH:10]=1)C1C=CC=CC=1.[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1>>[N:19]1([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc2[nH]cnc2c1
Product: Oc1ccc(OCCn2cnc3ccccc32)cc1

Procedure:
In a manner analogous to that described in Example 1(b), from 1-benzyloxy-4-(2-bromoethoxy)benzene and benzimidazole, 4-[2-(1-benzimidazolyl)ethoxy]phenol was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].Cl[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1O
Reactant: Clc1ncccc1-c1ccncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dissolved 2,6-dimethyl-3-nitrophenol (1.96 g, 11.7 mmol) and 4-(2-chloropyridin-3-yl)pyrimidine (1.50 g, 7.83 mmol) in dimethylsulfoxide (15.0 ml) and added cesium carbonate (5.10 g, 15.7 mmol). Reaction mixture was heated to 1200C in a sealed tube for 8 hours. Reaction mixture was then allowed to cool to room temperature and then poured into 250 mL of rapidly stirring water in an Erlenmeyer flask. After 10 minutes, the opaque brown aqueous solution was cooled to 0° C. and allowed to stand for 10 minutes, then filtered. The precipitate was collected as the title compound. MS m/z=323 (M+H)+. Calc'd for C17H16N4O3: 324.34.
Reaction SMILES: [NH:1]1C2=NC=CC2=C[NH:3][CH2:2]1.C([O:12][C:13](=O)[CH:14]([C:21]([O:23]CC)=O)[CH2:15][C:16]([O:18][CH2:19]C)=[O:17])C.C(N)=N>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:14]1[C:21]([OH:23])=[N:1][CH:2]=[N:3][C:13]=1[OH:12]
Reactant: C1=CC2=CNCNC2=N1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: N=CN
Product: COC(=O)Cc1c(O)ncnc1O

Procedure:
Dihydropyrrolo[2,3-d]pyrimidine derivatives may be prepared as shown in FIG. 39. 2-Ethoxycarbonyl-succinic acid diethyl ester (200) was heated with formamidine to provide (4,6-Dihydroxypyrimidin-5-yl)-acetic acid methyl ester (201). Halogenation of compound (201) with (for example) POCl3 gave the dichloropyrimidine derivative (202). Treating compound (142) with base (e.g., KH) in THF and an electrophile R3X affords the intermediate (203). Reduction with an agent such as DIBAL-H gives the alcohol, which was activated with (for example) MsCl in the presence of base (e.g., TEA) to provide the mesylate intermediate (204). Treating the mesylate (204) with (for example) p-methoxybenzylamine yielded the dihydropyrrolo[2,3-d]pyrimidine derivative (205). SNAr reaction of the compound (205) with 1-Boc-piperazine formed the intermediate (206). Deprotection of the compound (206) with acid (e.g., TFA) gave the free amine (207). Amide coupling of the free amine (207) with an appropriately substituted/protected amino acid and followed by deprotection (if necessary) gave the product (208).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:9]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:9]2[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Nc1nnc(C2CCC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclobutyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24]O)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][O:12][C:11](=[O:13])[CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1ccccc1CCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Yield: 54.6 %

Procedure:
A mixture of 3-(2-methoxyphenyl)propionic acid (5.0 g, 27.8 mmol), 2-(p-toluenesulfonyl)ethanol (5.5 g, 27.8 mmol), and p-toluenesulfonic acid hydrate (p-TsOH.H2O) (0.5 g) in 100 mL of toluene was refluxed with Dean-Stark trap for 5 h. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution (2×), dried over MgSO4, and concentrated to give 3-(2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 59, 5.5 g, 88%) as a light brown liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([F:26])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:13]4[C@@H:14]([CH3:18])[CH2:15][S:16][C:17]=2[C:12]=34)[CH:5]=[C:4]([CH3:27])[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].S([O-])(O)(=O)=O.[K+].S([O-])([O-])(=O)=O.[K+].[K+]>C(O)(=O)CC>[CH3:27][C:4]1[CH:5]=[C:6]([C:8]2[C:9]([F:26])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:13]4[CH:14]([CH3:18])[CH2:15][S@:16](=[O:29])[C:17]=2[C:12]=34)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2SC[C@@H]4C)cc(C)n1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)O
Product: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2[S@@](=O)CC4C)cc(C)n1
Yield: 30 %

Procedure:
(S)-10-(2,6-Dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid (U.S. Pat. No. 4,839,355, Example 7f) (192 mg) and 153.7 mg of a mixture of potassium monopersulfate, potassium hydrogen sulfate and potassium sulfate (mole ratio 2:1:1) (Oxone®) (0.5 mM of potassium monopersulfate) in 20 ml of aqueous propionic acid (20% water) were combined at 0° C. with stirring. The mixture was allowed to come to room temperature, stirred for 4 hours and concentrated to dryness. Saturated sodium chloride solution was added to the mixture which was then extracted with chloroform. The chloroform extract was dried over sodium sulfate and concentrated to dryness. The resulting residue was treated with ethyl alcohol to give 60 mg (30% yield) of the title compound as a solid which was collected by filtration; m.p. 294.0°-295.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13])[CH:8]=[CH:7]2.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([O:13][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[CH:7]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(Cn1ccc2cccc(Br)c21)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(Cn1ccc2cccc(Br)c21)c1ccccc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 96.5 %

Procedure:
To 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (0.70 g) were added DMF (7.0 mL), tert-butyl(chloro)dimethylsilane (0.47 g), and imidazole (0.23 g), followed by stirring at room temperature for 25 hours. To the reaction mixture was added a 10% aqueous citric acid solution (15 mL), followed by extraction with ethyl acetate, and the obtained organic layer was washed with brine. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=99/1-90/10) to obtain 7-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-1H-indole (0.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (72 mg), potassium carbonate (30 mg), and 1,2-dibromoethane (62 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 40 mg (yield 45%) of N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (45 mg), potassium carbonate (30 mg), and morpholine (80 μl) were dissolved in N,N-dimethylformamide (2 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 42 mg (yield 56%) of the title compound.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=2[Se:10][C:9]=1[C:17]([O-:19])=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=2[Se:10][C:9]=1[C:17]([NH2:2])=[O:19])[CH3:5]
Reactant: CN(C)N=Nc1c(C(=O)[O-])[se]c2c1CCCC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1c(C(N)=O)[se]c2c1CCCC2
Temperature: 25 °C
Reaction time: 66 h
Yield: 18 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (60 mL) was added a mixture of ethyl and methyl esters of 3-[(dimethylamino)diazenyl]-4,5,6,7-tetrahydrobenzo[2,1-d]selenophene-2-carboxylate (600 mg) in THF (6 mL) for 5 min. A catalytic amount of PEG-400 was added and stirred at rt for 66 h. The solution was poured into ice cooled water and extracted with chloroform (3×150 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as a pale brown color solid (100 mg, 18%), which was recrystallized from chloroform-hexane (70 mg), mp 198-202° C. IR (Neat) νmax 3347, 3163, 2932, 2860, 1631, 1342, 1313, 1220, 1103, 1020, 878 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, s, —CONH2), 6.07 (1H, s, —CONH2), 3.51 (3H, br s, —NCH3), 3.14 (3H, br s, —NCH3), 2.80-2.82 (2H, m, H-4), 2.64-2.65 (2H, m, H-7), 1.72-1.80 (4H, m, H-5,6); 13C NMR (100 MHz, CDCl3): δ 165.9, 149.5, 145.9, 132.6, 129.5, 29.0, 28.6, 23.1, 22.7; LC-MS (positive ion mode): m/z 321, 323 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Clc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cnc(Cl)c2)nc1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
A vial was charged with 4-chloro-1H-imidazole (450 mg, 4.4 mmol), 2-chloro-5-nitropyridine (1.04 g, 6.58 mmol), potassium carbonate (1.21 g, 8.78 mmol), and acetonitrile (10 mL). The vial was capped and heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-(4-chloro-1H-imidazol-1-yl)-5-nitropyridine (675 mg, 68%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 9.35 (d, J=2.4 Hz, 1H), 8.78 (dd, J=9.0, 2.6 Hz, 1H), 8.64 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CCOCC>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:20])=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C(O)c2ccccn2)cc1
Reaction time: 0.25 h

Procedure:
To one mole of butyl lithium (15% in hexane) at -40° C under nitrogen is added gradually a solution of 142 g (0.9 mol) of 2-bromopyridine in 340 ml. of ether, maintaining the temperature below -40° C. After stirring for 15 minutes at this temperature, a solution of 122 g (0.9 mol) of 4-methoxybenzaldehyde in 250 ml of ether is added, with the temperature below -15° C. The reaction mixture is stirred for 40 minutes at this temperature, quenched in 1.5 l ice water. The solid is filtered and washed with cold ether to give 4-methoxyphenyl-2-pyridylcarbinol, m.p. 126°-130° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[N:25](COCC[Si](C)(C)C)[C:24]4[C:23](=[O:34])[N:22]([CH2:35][CH2:36][CH3:37])[C:21](=[O:38])[N:20]([CH2:39][CH2:40][CH3:41])[C:19]=4[N:18]=3)[CH:14]=[N:13]2)[CH:6]=[CH:7][CH:8]=1>C(O)C.Cl.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[NH:25][C:24]4[C:23](=[O:34])[N:22]([CH2:35][CH2:36][CH3:37])[C:21](=[O:38])[N:20]([CH2:39][CH2:40][CH3:41])[C:19]=4[N:18]=3)[CH:14]=[N:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(CO)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC#Cc4cccc(CO)c4)c3)nc2n(CCC)c1=O
Yield: 51.7 %

Procedure:
To a solution of 8-{1-[3-(3-hydroxymethyl-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (25 mg) in ethanol (3 ml), aq. HCl (2 N, 1 ml) was added and the reaction mixture was refluxed for 2 hrs. The volatiles were evaporated and the residue obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4 and concentrated under vacuum. The residue obtained was purified by column to obtain 8-{1-[3-(3-hydroxymethyl-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (10 mg, 52%) as white solid.