Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][C:13]1[C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=2)=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:11][N:5]1[C:6](=[O:7])[CH:8]([C:28](=[O:29])[NH:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:14]3[C:13]([Cl:12])=[CH:18][C:17]([Cl:19])=[CH:16][N:15]=3)=[CH:26][CH:25]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C=Nc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ncc(Cl)cc3Cl)cc2)C(=O)N(C)C1=O
Reaction time: 18 h

Procedure:
7.8 g (0.05 mol) of 1,3-dimethylbarbituric acid and 14 g (0.05 mol) of 4-(3,5-dichloropyrid-2-yloxy)phenylisocyanate are suspended in 50 ml of xylene. 1 g of triethylamine is added dropwise to the suspension and the temperature rises to 45°-50° C. After further addition of 50 ml of xylene the mixture is stirred for 18 hours at this temperature. Then 1/3 of the xylene is distilled off. After cooling, the precipitate is isolated by filtration, washed with xylene, suspended several times in HCl and the suspension is thoroughly washed with water and dried, affording 1,3-dimethyl-5-[4-(3,5-dichloropyrid-2-yloxy)phenylcarbamoyl]barbituric acid of the formula ##STR25## with a melting point of 234°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19](N)=[CH:18][CH:17]=1.CC1C=CC(C)=C(C)C=1C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Solvent: O
Solvent: Cc1ccc(C)c(C)c1C
Product: COc1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])cc1
Yield: 33.4 %

Procedure:
A mixture of 10 g of 4-chloro-1,2-dinitrobenzene, 6.5 g of 4-methoxyaniline and 16 g of 1,2,3,4-tetramethylbenzene is refluxed for 15 hours. After cooling, water is added, the mixture is extracted with AcOEt, washed with a 1N solution of HCl , with a 1N solution of NaOH and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is taken up with iso ether, a gummy insoluble material is separated off and the filtrate is chromatographed on alumina using iso ether as the eluent to give 4.6 g of the expected product after crystallization from isopropanol. M.p.=98° C.
Reaction SMILES: ClC1C=CC(NC(C2C(C(F)(F)F)=CC([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=CN=2)=O)=CC=1C(=O)NC1CC1.Cl[C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[C:37]([C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([C:54](=[O:59])[NH:55][CH:56]3[CH2:58][CH2:57]3)[CH:48]=2)=[O:45])=[CH:36][N:35]=1.FC(F)(F)CO>>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:44]([C:37]2[CH:36]=[N:35][C:34]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:39][C:38]=2[C:40]([F:43])([F:42])[F:41])=[O:45])=[CH:48][C:49]=1[C:54](=[O:59])[NH:55][CH:56]1[CH2:58][CH2:57]1
Reactant: O=C(NC1CC1)c1cc(NC(=O)c2cnc(Cl)cc2C(F)(F)F)ccc1Cl
Reactant: O=C(NC1CC1)c1cc(NC(=O)c2ncc(OCC(F)(F)F)cc2C(F)(F)F)ccc1Cl
Solvent: OCC(F)(F)F
Product: O=C(NC1CC1)c1cc(NC(=O)c2cnc(OCC(F)(F)F)cc2C(F)(F)F)ccc1Cl

Procedure:
Analogously to the preparation of (Ib-2), N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-5-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)pyridine-2-carboxamide is synthesized from 2-chloro-N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-4-(trifluoromethyl)pyridine-5-carboxamide and 2,2,2-trifluoroethanol.
Reaction SMILES: C([NH:4][C:5]1[C:6]([F:25])=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=O)C>CO>[NH2:4][C:5]1[C:6]([F:25])=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Solvent: CO
Product: COC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Yield: 90.3 %

Procedure:
Into 10 ml of boron trifluoride methanol complex, methanol solution was added 0.25 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate, and the mixture was heated for 3 hours while stirring. Thereafter, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain 0.2 g of methyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-22].
Reaction SMILES: Cl[CH:2](Cl)[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:4].[Na].Cl.C[OH:27]>>[OH2:4].[O:27]=[CH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:4]
Reactant: COC(=O)c1cc(C(=O)C(Cl)Cl)ccc1OCc1ccccc1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COC(=O)c1cc(C(=O)C=O)ccc1OCc1ccccc1
Product: O
Reaction time: 0.33 h

Procedure:
5-(Dichloroacetyl)-2-(phenylmethoxy)benzoic acid, methyl ester (2.4 g) was added to sodium (0.34 g) in dry methanol (80 ml). The solution was boiled for 20 min. 0.1 N Hydrochloric acid (40 ml) was added and the solution was boiled for 30 min. The methanol was evaporated off and the mixture was extracted with ether (3×50 ml). The extracts were dried (MgSO4) and evaporated to leave crude 5-(oxoacetyl)-2-(phenylmethoxy)benzoic acid, methyl ester, hydrate as a gum.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:37]1[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)cc[nH]1
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 1. LC-MS Method 1tR=1.23 min, m/z=389, 447 (M+1); 1H NMR (CD3OD) 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.S(=O)(=O)(O)[OH:16]>[OH-].[Na+]>[OH:13][C:9]1[CH:10]=[CH:11][C:12]2[C:3]([CH2:4][C:5]([OH:14])=[O:16])=[CH:2][O:6][C:7]=2[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1coc2cc(O)ccc12
Yield: 83 %

Procedure:
A mixture of 4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (10.9 g, 51.8 mmol) and 1 M aqueous sodium hydroxide solution (500 mL) was heated under reflux for 2 hr. The reaction mixture was allowed to cool, acidified with conc. sulfuric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (6-hydroxy-1-benzofuran-3-yl)acetic acid (8.27 g, 83%) as brown crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([C:28]([O:30][CH3:31])=[O:29])[CH:17]=2)[C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[C:33]1[S:34][CH:35]=[C:36](C)[C:37]=1[C:38]([O:40][CH3:41])=[O:39].[CH2:43]1COCC1>>[CH2:3]([C:7]1[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([C:28]([O:30][CH3:31])=[O:29])[CH:17]=2)[C:9]([CH2:13][O:14][CH2:43][C:33]2[S:34][CH:35]=[CH:36][C:37]=2[C:38]([O:40][CH3:41])=[O:39])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2)c(C(=O)OC)c1
Reactant: COC(=O)c1c(C)csc1Br
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(Cl)c(COCc2sccc2C(=O)OC)n1Cc1ccc(-c2ccccc2)c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A suspension of 145 mg of 80% NaH in anhydrous THF heated to 60° C. is added with 1 g of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2-methoxycarbonyl-1,1'-biphenyl-4-yl)methyl]-1H-imidazole dissolved in 8 ml of THF. The resulting solution is stirred at 60° C. for 1 h, cooled to 25° C. and 0.7 g of methyl 2-bromo-methylthien-3-yl-carboxylate are added dissolved in THF. After 1 hour the mixture is filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by F.C. (eluent ethyl acetate/hexane 4:6). 0.84 g of a glassy oil are obtained (62% yield). 1H NMR (CDCl3), δ: 0.88 (t, 3 H); 1.35 (m, 2 H); 1.67 (m, 2 H); 2.61 (t, 2 H); 3.64 (s, 3 H); 3.83 (s, 3 H); 4.53 (s, 2 H); 5.00 (s, 2 H); 5.24 (s, 2 H); 7.02-7.87 (m, 10 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][C:12](=O)[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1C=CC=CC=1.CN(C=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CC(=O)CC2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c1CC(N1CCCC1)CC2
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 8-acetamido-2-tetralone (0.4 g, 2 mmol), pyrrolidine (0.28 g, 4 mmol) and tosic acid (10 mg) in benzene:DMF (5:1, 12 mL) was heated at reflux with a Dean-Stark trap for 4 h. The solvent was evaporated and the residue dissolved in 1:1 MeOH:THF (10 mL). Acetic acid (1 mL) and sodium cyanoborohydride (0.25 g, 4 mmol) were added, and the reaction stirred for 16 h. The solvent was evaporated and the residue taken up in water:methylene chloride. The aqueous layer was basified with 12.5% NaOH, and back extracted. The combined organic phase was dried over sodium sulfate, filtered and evaporated. The residue solidified upon standing, and was crystallized from tolune:hexane to give the product (0.36 g).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][C:8]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-:17].[K+].[CH2:19]([OH:21])[CH3:20]>O>[C:1]1([C:7]2[CH:14]=[CH:13][C:20]([C:19]([OH:17])=[O:21])=[CH:9][C:8]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCO
Reactant: CCc1cc(C#N)ccc1C1=CCCCC1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CCc1cc(C(=O)O)ccc1C1=CCCCC1

Procedure:
4-(1-Cyclohexen-1-yl)-3-ethylbenzonitrile (D11) (824 mg, 3.91 mmol) and potassium hydroxide (2.19 g, 39.1 mmol) in ethanol (36 mL) and water (8 mL) were heated at 90° C. (block temperature) for 20 h. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (120 mL) and aqueous hydrochloric acid (2M, 50 mL) before the organic phase was washed with further hydrochloric acid (2M, 50 mL), dried (phase separator) and concentrated in vacuo to give the title compound as a yellow oil (808 mg, 3.51 mmol). LCMS (ES): C15H18O2 requires 230; found 229 (M−H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13]O)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[F:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][Cl:3])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1Oc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Fc1ccc(Oc2ccccc2CCl)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
8.5 g of thionyl chloride are added dropwise over a 10 minutes span to a stirring mixture of 13.0 g of 2-(4-fluorophenoxy)benzyl alcohol in 80 Ml of benzene at ambient temperature. After total addition, the reaction mixture is stirred for 16 hours before being carefully poured onto 350 ml of crushed ice containing 8 ml of sodium bicarbonate. The mixture is stirred until the ice melts. The layers separate and the benzene layer is successively washed twice with 40 ml portions of a half saturated sodium bicarbonate solution, washed twice with 40 ml portions of water, washed once with 25 ml saturated sodium chloride solution, dried and rotary evaporated to provide a clear liquid. The liquid is distilled at 106°-109° C. and 0.16 mm to provide a clear colorless liquid of 2-(4-fluorophenoxy)benzyl chloride.
Reaction SMILES: [OH-:1].[K+].F[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[F:14].[CH3:15]O>>[F:14][C:5]1[CH:6]=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=1[O:1][CH3:15]
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Product: COc1ccc(S(C)(=O)=O)cc1F
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of potassium hydroxide (85%; 824 mg, 12.5 mmol) in methanol (5 mL) was added to a refluxing solution of 1,2-difluoro-4-methanesulfonyl-benzene (2.00 g, 10.4 mmol) in methanol (10 mL) over 20 min. The resulting mixture was heated at reflux for 1 h and then cooled to room temperature. The solvent was evaporated, water was added, and the resulting precipitate was filtered off, washed with water, and dried in vacuo to give 2-fluoro-4-methanesulfonyl-1-methoxy-benzene (1.8 g, 85%) as a white solid which was used directly in the next step without purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([PH:10](=[O:14])[O:11][CH2:12][CH3:13])[CH3:9].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].[O:20]1[CH2:34][CH:21]1[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>O1CCCC1.ClCCl.[Cl-].[Zn+2].[Cl-]>[C:27]1(=[O:28])[N:23]([CH2:22][CH:21]([O:20][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:34][P:10]([CH2:8][CH3:9])(=[O:14])[O:11][CH2:12][CH3:13])[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: CCO[PH](=O)CC
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC)CC(CN1C(=O)c2ccccc2C1=O)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4.55 g of anhydrous triethylamine and 5.0 g of ethyl ethylphosphinate in 100 ml of anhydrous tetrahydrofuran under an inert atmosphere is treated with 4.89 g of chlorotrimethylsilane. The resulting suspension is stirred for 20 hours at room temperature and the solid removed by filtration. Concentration in vacuo affords a cloudy, colourless oil which is treated with 5.10 g of anhydrous N-(2,3-epoxypropyl)-phthalimide and 1.0 g of anhydrous zinc chloride. The mixture is heated to 66° C. under an inert atmosphere for 3 hours, cooled to 20° and diluted with dichloromethane. The organic solution is washed with 100 ml of a 10% aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Removal of the solvents and chromatography on silica gel affords ethyl 3-phthalimido-2-trimethylsilyloxy-propyl(ethyl)phosphinate as a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[C:13]([O:15]C)[C:12]([O:17]C)=[C:11]([Cl:19])[C:10]=2[Cl:20])=[O:8])=[CH:5][CH:4]=[N:3]1.Br>>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:17])=[C:11]([Cl:19])[C:10]=2[Cl:20])=[O:8])=[CH:5][CH:4]=[N:3]1
Reactant: COc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OC
Agent: Br
Product: Cn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Yield: 83.8 %

Procedure:
A mixture of 6.25 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dimethoxyphenyl)-methanone and 70 ml of aqueous 47% hydrobromic acid is refluxed for 3 hours and the reaction mixture is evaporated to remove solvent. The residue is dissolved in aqueous 10% sodium hydroxide solution and the solution is adjusted to pH 3-4 by addition of acetic acid. The mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent under reduced pressure. The residue is crystalized from isopropyl ether and the crystals are collected by filtration to give 4.77 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)-methanone. Yield: 84%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([NH2:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:12]=3)[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc2c(N)n[nH]c2c1
Product: COc1ccc(-c2cn3[nH]c4cc(OC)ccc4c3n2)cc1

Procedure:
Compound 7-methoxy-2-(4-methoxyphenyl)-5H-imidazo[1,2-b]indazole (W302) was prepared using the general procedure for cyclization between 6-methoxy-1H-indazol-3-amine (90 mg, 0.3 mmol) and 2-bromo-1-(4-methoxyphenyl)ethanone (72 mg, 0.31 mmol), as white solid (50 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 HO, 7.85-7.81 (m, 3 H), 7.16-7.12 (m, 3 H), 6.99 (dd, J=8.8, 2.4 Hz, 1 H), 3.90 (s, 3 H), 3.84 (s, 3 H); MS (ESI) m/z 294 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5][N:4]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[NH2:2][C:3]1[CH2:8][CH:7]([C:9]([O:11][CH3:16])=[O:10])[CH2:6][CH2:5][N:4]=1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC1=NCCC(C(=O)O)C1
Agent: Cl
Product: COC(=O)C1CCN=C(N)C1
Temperature: 25 °C
Yield: 27 %

Procedure:
2-Amino-3,4,5,6-tetrahydropyridine-4-carboxylic acid HCl (1.54 g, 8.6 mmol) was suspended in anhydrous methanol (100 ml), and thionyl chloride (0.6 ml, 8.6 mmol) was added dropwise with stirring at room temperature. The resulting solution was refluxed overnight and then evaporated to dryness in vacuo. The resulting crude white solid was recrystallized from methanol/ether to give white crystals 452 mg (27%) mp 180°-181° C., identified as product by 300 MHz nmr and ir 1733 cm-1. Calculated: C 43.64, H 6.8, N 14.55; found: C 43.42, H 6.65, N 14.66.
Reaction SMILES: [Na].[F:2][C:3]([F:21])([S:17]([OH:20])(=[O:19])=[O:18])[C:4]([O:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)=[O:5].[Br-].[SH+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.O>C(#N)C>[CH:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH:7]1[O:6][C:4]([C:3]([F:21])([F:2])[S:17]([O-:20])(=[O:18])=[O:19])=[O:5])[CH2:16]2.[SH+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)C(F)(F)S(=O)(=O)O
Agent: C1CC[SH+]C1
Agent: [Br-]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C(OC1C2CC3CC(C2)CC1C3)C(F)(F)S(=O)(=O)[O-]
Reaction time: 15 h

Procedure:
1.08 Parts of sodium salt of 2-adamantyl difluorosulfoacetate obtained in Example 5 (2) was dissolved in 10.8 parts of acetonitrile. To the solution, 0.93 parts of 1-oxo-2-phenylethyl)tetrahydrothiophenium bromide and 9.3 parts of ion-exchanged water were added. The added mixture was stirred for 15 hours. After the stirring, the resulting mixture was concentrated, and then the concentrate was extracted with 50 parts of chloroform twice. The organic layers were combined and then washed with ion-exchanged water. The washed organic layer was concentrated. The concentrate was washed with 30 parts of tert-butyl methyl ether and the solid deposited was collected by filtration to obtain 1.25 part of 12-oxo-2-phenylethyl)tetrahydrothiophenium (2-adamantyloxycarbonyl)difluoromethanesulfonate in the form of white solid, which is called as acid generator B6.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13])C.[Cl-].[NH4+].[CH4:29]>O1CCCC1.C(OCC)C>[C:2]1([C:12]([C:29]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)([CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:18][CH2:19]2)[OH:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1
Reactant: C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A Grignard solution was prepared by the addition of 94.2 g (0.6 mole) of bromobenzene in 250 ml of dry (freshly distilled from lithium aluminum hydride) tetrahydrofuran to a mixture of 12.5 g (0.5 mole) of magnesium chips in 500 ml of dry tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 15 min to complete formation. To this Grignard reagent at ambient temperature, was added a solution of 44.2 g (0.179 mole) of the base of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 250 ml of tetrahydrofuran in a stream. The solution was stirred overnight at ambient temperature and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted once with 500 ml of methylene chloride and twice with 250 ml of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated to give a gum as residue. The gum was dissolved in 500 ml of ethyl ether treated with activated charcoal, filtered through Celite®, and then concentrated to give a gum as residue. The gum crystallized when triturated with petroleum ether (30°-60° C.). The solid was collected by filtration and dried to yield 49.0 g (77%) of title compound as a white solid. An analytical sample, mp 89.5°-90.5° C., was prepared by recrystallization from 2-propanol.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>Cl.C(O)(C)C>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[NH:4][CH:5]=[N:6]3)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2ncnc3nc[nH]c23)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 102.8 %

Procedure:
A mixture of 6-chloropurine (1.0 g, 6.47 mmol), 3-bromoaniline (0.78 mL, 7.12 mmol), and conc HCl (4 drops) in isopropanol (10 mL) is stirred at 80° C. for 5 h. Upon cooling, it precipitates. The solid is filtered and washed with isopropanol and air dried to yield N6-(3-bromophenyl)adenine (1.93 g, 91%) as a light yellow solid. 1H NMR (DMSO) δ 11.38 (1H, s), 8.78 (1H, s), 8.75 (1H, s), 7.90 (1H, d, J=8.0 Hz), 7.38-7.34 (2H1, m).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[OH:17][C:3]1[C:4]2[S:8][C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])=[N:6][C:5]=2[CH:15]=[CH:16][CH:2]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cccc(O)c2s1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
General Procedure for 1-(6-bromo-7-alkoxy-2-benzothiazolyl)-3-ethyl-urea compounds 9–13. A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6 and potassium carbonate (1.05 eq) in anhydrous DMF was stirred at about 20° C. for about 0.5 hour, and was cooled down to about 0° C. The mixture was treated with an alkyl halide (1.0 eq), and was stirred at about 0–85° C. for about 16 hours. To the reaction mixture was added methanol. The solid was filtered off and washed with methanol. The solvent was evaporated and the residue was dissolved in DMF. The crude reaction solution was purified by preparature LC/MS to give pure desired product.