Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[C:4]([O:18]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1
Reactant: COc1cc(Cl)c2nc(-c3ccc(O)cc3)oc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nc3c(Cl)cc(O)cc3o2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
To a suspension of 4-chloro-2-(4-hydroxyphenyl)-6-methoxybenzoxazole (240 mg) in dichloromethane (5 mL) cooled at −78° C. was added boron tribromide (5 mL, 1M solution in dichloromethane, 5.7 eq.). The mixture was stirred at −78° C. for 10 min, warmed to room temperature and stirred for 3 h. The mixture was poured onto ice/water and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. Chromatography on a silica gel column (eluant: acetone-dichloromethane, gradient from 0:100 to 5:95) and trituration of the resulting solid in dichloromethane afforded the title compound (53 mg) as a solid. NMR (DMSO-d6): 10.31 (s, 1H), 10.17 (s, 1H), 7.98 (d, 2H, J=8.4 Hz), 7.06 (s, 1H), 6.95 (d, 2H, J=8.4 Hz), 6.87 (s, 1H); MS: 262 (MH+); HPLC tR: 1.99 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)=[O:28].N1C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH:27]=[O:28])[C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Reactant: O=Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 17.6 %

Procedure:
4-(1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (226 mg), 2-formylphenyl boronic acid (200 mg), and copper (II) acetate (200 mg) were suspended in anhydrous tetrahydrofuran (5 ml), and pyridine (0.2 ml) was added thereto. The reaction mixture was stirred at room temperature for 5 days, filtered through a short column filled with silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 51 mg of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:23])[CH2:5][N:6]([C:20](=[O:22])[CH3:21])[CH:7]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8]1>[Pd]>[ClH:1].[CH3:2][O:3][C:4](=[O:23])[CH2:5][N:6]([C:20](=[O:22])[CH3:21])[CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: COC(=O)CN(C(C)=O)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Product: COC(=O)CN(C(C)=O)C1CCNCC1

Procedure:
Prepared from N-acetyl-N-[1-benzyl-4-piperidinyl]glycine methyl ester hydrochloride by exhaustive hydrogenation over palladium-on-charcoal (10%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)(=O)C>[N:13]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]3)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CC1Cc2cc(F)ccc2C1=O
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC1Cc2cc(-n3ccnc3)ccc2C1=O
Temperature: 175 °C

Procedure:
A stirred melt of 5-fluoro-2-methyl-1-indanone (4.9 g) and imidazole (9.8 g) was heated under nitrogen at 175° C. for 2 hours. The warm melt was diluted with ethyl acetate (100 ml), the resulting solution extracted with dilute hydrochloric acid, and the acidic extract treated with potassium carbonate to pH 6. Extraction of the mixture with ethyl acetate with dichloromethane failed to dissolve all of the solids and the mixture was filtered to remove a solid by-product, 5-(1H-imidazol-1-yl)-2-methyl-1H-inden-1-one, 0.92 g, m.p. 215°-217° C. (from toluene). The combined aqueous and organic solutions were evaporated to leave an aqueous mixture which deposited a sticky solid; further product was obtained by ethyl acetate extraction. The combined crude product (5.36 g) was purified by medium pressure column chromatography (silica gel, chloroform) to give 5-(1H-imidazol-1-yl)-2-methyl-1-indanone, 3 g (47%), m.p. 103°-106° C., which was used directly in the next stage.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].CO>C(O)(=O)C>[NH2:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(N)c1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: NC(C(=O)O)c1c[nH]c2ccccc12
Reaction time: 0.83 h

Procedure:
A mixture of 2 g of ethyl α-aminoindole-3-acetate, excess dilute NaOH solution, and a few mL of MeOH was stirred occasionally for 25 minutes. Since a solution had not been obtained, the mixture was heated on a steam bath for ten minutes. The resulting solution was allowed to stand at ambient temperature for 50 minutes. The solution was acidified with acetic acid. The solid which separated was collected by filtration and washed with H2O giving 1.50 g (86%) of the title compound as small buff plates, m.p. 217° (dec).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C@@H:10]([OH:21])[C@H:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[ClH:22]>CCOC(C)=O>[NH2:13][C@H:11]([CH3:12])[C@@H:10]([C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1)[OH:21].[ClH:22]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](N)[C@H](O)c1ccc2c(c1)OCC2

Procedure:
t-Butyl (1R,2R)-1-(2,3-dihydrobenzofuran-6-yl)-1-hydroxypropan-2-ylcarbamate (1.58 g, 5.39 mmol) was stirred in a solution of HCl in EtOAc (1M, 20 ml) at 60° C. for 2 h. After cooling the solid precipitate was filtered and dried to afford the subtitle compound as hydrochloride (1.22 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CCCCBr
Product: CCCCOc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared in a similar manner as Example 115c from 2-hydroxy-6-nitrobenzonitrile (Example 115d) and butyl bromide to provide 2-nitro-6-butoxybenzonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])/[CH:18]=[CH:19]\[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[C:17]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCCCC

Procedure:
The procedure of Example 1 is repeated using 11.92 grams of 2, 6-di-tert-butyl-4-mercaptophenol, 11.41 grams of di-n-butyl maleate, and 0.5 gram of triethylamine. The product is purified by dry column chromatography to give a clear syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24](Cl)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[CH2:34]1[NH:39][CH2:38][CH2:37][N:36]2[C:40](=[O:43])[CH2:41][CH2:42][CH:35]12>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24]([N:39]3[CH2:38][CH2:37][N:36]4[C:40](=[O:43])[CH2:41][CH2:42][CH:35]4[CH2:34]3)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1
Reactant: O=C1CCC2CNCCN12
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)N2CCN3C(=O)CCC3C2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 25 %

Procedure:
To a stirred solution of (3SR,4RS)-3-[(RS)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (22 mg, 0.051 mmol) in CH2Cl2 (3 mL) were added Et3N (0.015 ml, 0.11 mmol) and hexahydro-pyrrolo[1,2-a]pyrazin-6-one (commercially available) (9 mg, 0.064 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 7 mg (25%) the title compound as light yellow oil. ES-MS m/e: 539.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:28][CH2:29]2)[N:17]=1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: COc1cc(OC)nc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Yield: 123.8 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl) acetamide (0.93 g), 1-(4,6-dimethoxypyrimidin-2-yl)piperazine (0.94 g) and potassium carbonate (0.97 g) in dimethylformamide (10 ml) was stirred at 80° C. for 1.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (2.0 g). The obtained brown oil was crystallized from ethyl acetate:diisopropyl ether(1:3, 40 ml) to give the title compound (1.3 g) as pale-yellow crystals, m.p.=130-131° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=CC=2OC)=CC=1)[C:29](OC)=[O:30]>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:30][CH3:29])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-2-methoxy-6-(2-methoxyphenylthiomethyl)benzoate (Intermediate 76).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=1.O>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccn1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
Trimethylacetyl chloride (4.22 g, 35.0 mmol) was added dropwise to a solution of 2-amino-4-chloropyridine (3.00 g, 23.3 mmol) in pyridine (11 mL) at 0° C. The resulting solution was stirred for 12 h at r.t. Water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4). The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate and hexane (2/8), to give the title compound as a colourless solid (4.9 g, 99%).
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)C.[OH-].[K+]>O1CCCC1.O>[CH3:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:12])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cc1csc(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(CC(=O)O)cs1
Yield: 78.1 %

Procedure:
Prepare a solution of (2-methylthiazol-4-yl)acetic acid ethyl ester (17 g, 92 mmol) in tetrahydrofuran/water (1:1, 400 mL). Add potassium hydroxide (10.3 g, 184 mmol). Stir the reaction at room temperature for 1 hour. Concentrate the solution in vacuo to remove the tetrahydrofuran then acidify with 1N HCl. Extract the aqueous solution with CHCl3. Wash the resulting organic phase with brine (200 mL), dry (Na2SO4), filter and concentrate in vacuo to afford (2-methylthiazol-4-yl)acetic acid (11.3 g) as a solid. 1H NMR (CDCl3) δ 7.00 (s, 1H), 3.85 (s, 2H), 2.71 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:10])=[N:4][C:5](Cl)=[N:6][C:7]=1[CH3:8].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1>>[CH3:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[N:6][C:7]=1[CH3:8]
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1nc(Cl)nc(O)c1C
Product: Cc1nc(N2CCc3ccccc3C2)nc(O)c1C
Yield: 80.8 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 5,6-dimethyl-2-chloro-4-hydroxypyrimidine (6.0 g, 37.8 mmol) prepared in the Step 2 of Example 65 and 1,2,3,4-tetrahydroisoquinoline(10 ml, 79.9 mmol) were used as starting materials, 7.8 g of the titled compound was prepared. (Yield: 81%)
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22]([C:25]([CH3:31])([CH3:30])[C:26]([F:29])([F:28])[F:27])=[CH:23][N:24]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+:34].CO>C(#N)C>[CH3:1][C:2]([CH3:32])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22]([C:25]([CH3:31])([CH3:30])[C:26]([F:29])([F:27])[F:28])=[CH:23][N:24]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O-:5])=[O:4].[Na+:34]
Reactant: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(C)(C)C(F)(F)F)[nH]3)cn2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(C)(C)C(F)(F)F)[nH]3)cn2)cc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In acetonitrile (4 mL) was suspended 2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoic acid (175 mg), and 2N aqueous sodium hydroxide solution (391 μL) was added dropwise to the suspension. After adding acetonitrile (1 mL), the reaction mixture was stirred at room temperature overnight. Methanol was added until the reaction mixture became uniform solution, and tar-state insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained solid residue was pulverized by ether, collected by filtration, washed with ether, and dried at room temperature in vacuum to obtain sodium 2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate (174 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:11][C:9]1[C:10]2[C:2]([S:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1cccc(S)c1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)c1
Temperature: 70 °C
Yield: 41 %

Procedure:
5-Bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.74 mmol) was dissolved in 3 mL dimethylformamide. 3-Methoxybenzenethiol (140 mg, 1.10 mmol), copper(I) iodide (205 mg, 1.1 mmol) and potassium carbonate (152 mg, 1.1 mmol) were added. The reaction vessel was sealed and submitted to three vacuum-nitrogen cycles. The reaction was heated at 70° C. for 5 h. The mixture was poured into water-ice and extracted twice with ethyl acetate. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to obtain 128 mg (70% yield) of the title compound as a solid. Purity 83%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:23])=[N:6][C:7]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1)[CH3:2]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]2[C:7](=[N:6][C:5]=1[CH3:23])[N:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]2[OH:20])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(OCC)c(C)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1O

Procedure:
16.1 g of the Compound VI obtained as above was added to 160 ml of boiling Dowtherm (produced by Dow Chemical Co.) and refluxed for 1 hour. After cooling, the precipitated crystals were collected by filtration to obtain 11.8 g of crude crystals which were then recrystallized from dimethylformamide to yield ethyl 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (Compound VII where R2 =R3 =C2H5), m.p. 279°-282° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=S)[CH:14]2C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:22])C>[Ni]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:22])[CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C(=S)Nc2c(OCc3ccccc3)cccc21
Reactant: CCO
Agent: [Ni]
Product: O=C1Cc2cccc(OCc3ccccc3)c2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
7-Benzyloxy-3-methylthiooxindole (610 mg, 2.1 mmol), (EP 8226), was dissolved in hot ethanol (60 ml). The mixture was allowed to cool and Rainey Nickel (40 ml volume, prewashed with ethanol) was added and the mixture was stirred at ambient temperature for 1.5 hours. The insolubles were removed by filtration and the filter pad was thoroughly washed with ethanol. The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (40/60) to give 7-benzyloxyoxindole (395 mg, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].OS(O)(=O)=O.O.[OH-].[Na+].[CH3:28]O>>[CH3:28][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80 %

Procedure:
2-(2-Nitro-phenylamino)-benzoic acid (560 mg, 2.2 mmol) is dissolved in methanol (10 mL) and concentrated H2SO4 (0.16 mL, 98%) is added into it. The mixture is then refluxed for 60 hr. After it is cooled down to room temperature, 100 mL of water is added and the pH of this solution is adjusted to pH 7 by adding 1.0 M NaOH aqueous solution. An orange solid is formed and it is filtered and rinsed with more water. Air drying of this orange solid affords 470 mg (80%) of 2-(2-Nitro-phenylamino)-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.CCN(CC)CC.[F:23][C:24]([F:32])([F:31])[C:25]1[CH:29]=[C:28]([NH2:30])[NH:27][N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:23][C:24]([F:32])([F:31])[C:25]1[CH:29]=[C:28]([NH:30][C:13]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=2)=[O:15])[NH:27][N:26]=1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (100 mg, 0.350 mmol) in dry NMP (2 ml) was added NEt3 (0.097 ml, 0.699 mmol) followed by 3-(trifluoromethyl)-1H-pyrazol-5-amine (48.0 mg, 0.318 mmol). The mixture was stirred at RT for 5 minutes, before treating with HATU (133 mg, 0.350 mmol). The resulting orange solution was stirred at RT for 10 minutes and then partitioned between EtOAc (50 ml) and 1M NaOH (30 ml). The organic portion was separated and washed with 1M NaOH (20 ml), water (20 ml), dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with iso-hexane/EtOAc (gradient of 0 to 50% EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH:17][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([O:21][CH3:20])[CH:23]=3)[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C#N)C1
Product: COc1cccc(C(=O)Nc2sc3c(c2C#N)CCN(C(=O)OC(C)(C)C)C3)c1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid 1,1-dimethylethyl ester (compound A2) and 3-methoxybenzoyl chloride.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:32])[CH:25]2[O:30][CH3:31].O>CCOCC>[CH3:31][O:30][CH:25]1[C:26]2[C:22](=[C:21]([CH2:20][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:24]1[CH3:32]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: COC1c2cccc(CBr)c2CC1C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COC1c2cccc(CC3c4ccccc4-c4ccccc43)c2CC1C
Temperature: -80 °C
Reaction time: 12 h

Procedure:
To a solution of 3.32 g (0.20 mol) of 9H-fluorene in 500 ml of ether 80 ml of 2.5 M (0.20 mol) n-BuLi in hexanes was added at 0° C. This mixture was stirred for 12 h, cooled to −80° C., and then a solution of 5.10 g (0.20 mol) of 4-(bromomethyl)-1-methoxy-2-methylindane in 150 ml of ether was added dropwise by vigorous stirring for 30 min at this temperature. The resulting mixture was stirred for 24 h at room temperature, and then 500 ml of water was added. The organic layer was separated, and the aqueous layer was extracted with 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 60 mm, l 150 mm; eluent: hexanes/ether=20/1). Yield 5.31 g (78%) of a mixture of the diastereomers A and B.