Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.[Br:19]Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:19][C:8]1[C:6]2[NH:7][C:2]([CH3:18])([CH3:1])[NH:3][C:4](=[O:17])[C:5]=2[S:10][C:9]=1[C:11]1[CH:12]=[N:13][NH:14][C:15]=1[CH3:16]
Reactant: BrBr
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1[nH]ncc1-c1sc2c(c1Br)NC(C)(C)NC2=O
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a vigorously stirred solution of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.080 g, 0.305 mmol) in acetic acid (2 mL) was added slowly bromine (0.019 mL, 0.366 mmol). After 5 min, the mixture was poured into excess saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was mixed with acetone (5 mL), PTSA (3 mg) and DMF (1 mL). The mixture was stirred for 30 min at 70° C. and poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to give a yellow solid. This solid was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (65.4 mg, 63%) as a yellow solid:
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+].[OH-].[Na+].O1CCOCC1>C(O)C>[CH:1]1([CH:4]([OH:5])[C:6]2[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C(=O)C2CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C(O)C2CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To ethyl 4-(cyclopropanecarbonyl)benzoate (400 mg, 1.83 mmol) in ethanol (10 mL) was added at room temperature NaBH4 (69 mg, 1.83 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was then concentrated in vacuo and NaOH (1.5 g, 9.38 mmol) and dioxane (1.5 mL) were added and the reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was concentrated in vacuo to half the volume and pH was adjusted to 2 with 3 N HCl. The aqueous layer was extracted with ethyl acetate (3×10 mL), and the combined organics were washed with brine solution (5 mL), dried over MgSO4 and concentrated in vacuo to give 4-[cyclopropyl(hydroxy)methyl]benzoic acid (300 mg, 85%). ESI-MS m/z calc. 192.2. Found 193.5 (M+1)+; Retention time: 0.78 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.89 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 5.33 (d, J=4.4 Hz, 1H), 4.04 (dd, J=7.3, 4.3 Hz, 1H), 1.12-0.87 (m, 1H), 0.54-0.20 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH:25]([NH:27][C:28]([CH2:30][NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:29])[CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([OH:21])[CH2:19][CH2:18][CH:17]([N:23]3[CH2:26][CH:25]([NH:27][C:28](=[O:29])[CH2:30][NH:31][C:32](=[O:43])[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=4)[CH2:24]3)[CH2:16][CH2:15]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2(O)CCC(=O)CC2)c1
Product: CC(C)(C)OC(=O)Nc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of [3-(1-hydroxy-4-oxo-cyclohexyl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:12]N1C(=O)CCC1=O>CC(C)=O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[C:10]([I:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Clc1c(Br)cnc2[nH]cc(I)c12
Temperature: 23 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (5.19 g, 22.4 mmol) and N-iodosuccinimide (5.55 g, 24.6 mmol) were suspended in 100 mL acetone. The mixture was stirred at 23° C. for 2 h and diluted with 150 mL water and 20 mL of saturated sodium thiosulfate solution. The precipitate was filtered and residual water was removed by dissolving the solids in dry benzene and followed by evaporation (2×100 mL) to yield 5-Bromo-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (7.68 g, 21.5 mmol, 96%). 1H NMR (500 MHz, DMSO-d6) δ 12.65 (bs, 1H), 8.45 (s, 1H), 7.87 (d, J=3 Hz, 1H). MS: m/z 356.8/358.8 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][C:17]([N:19]1[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][C@H:20]1[CH3:34])=[O:18])[CH3:6].O1CCCC1.O.[OH-].[Li+]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:8]([CH:13]=1)[CH2:7][N:5]([CH2:4][C:3]([OH:35])=[O:2])[CH3:6]
Reactant: COC(=O)CN(C)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN(C)CC(=O)O

Procedure:
To a solution of [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-methyl-amino]-acetic acid methyl ester (0.051 g, 0.10 mmol) in 1:1 tetrahydrofuran:water (1 ml) and lithium hydroxide hydrate (0.016 g, 0.38 mmol) was added. After 1.5 hours the reaction was concentrated and the title compound isolated by chromatography on silica gel (0.045 g, LRMS: 492.4).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][S:7][C:8]1[C:13]([NH:14][C:15](=[O:18])[CH2:16]O)=[C:12]([S:19][CH3:20])[CH:11]=[C:10]([CH3:21])[N:9]=1.C(N(CC)CC)C.[Br-:29].[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[CH3:6][S:7][C:8]1[C:13]([NH:14][C:15](=[O:18])[CH2:16][Br:29])=[C:12]([S:19][CH3:20])[CH:11]=[C:10]([CH3:21])[N:9]=1
Reactant: [Br-]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CO
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1cc(C)nc(SC)c1NC(=O)CBr
Temperature: 11 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Under cooling with ice, methanesulfonyl chloride (31.7 g, 276.7 mmol) was added dropwise to a solution of N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hydroxyacetamide (65.0 g, 251.6 mmol), triethylamine (30.5 g, 301.4 mmol), and 4-dimethylaminopyridine (3.07 g, 25.13 mmol) in DMF (455 mL) while the reaction mixture was maintained at 11° C. or lower, followed by stirring for 0.5 hours under cooling with ice. After HPLC was performed to confirm that starting materials had been completely consumed, the crystals (triethylamine hydrochloride) that precipitated were collected through filtration, followed by washing with DMF (195 mL). The filtrate and the wash liquid were combined, and sodium bromide (51.8 g, 503.5 mmol) was added to the resultant mixture. The reaction mixture was stirred under heat at an internal temperature of 55 to 60° C. for 3 hours. Subsequently, water (650 mL) was added to the reaction mixture, and the resultant mixture was stirred at an internal temperature of 21 to 25° C. for 2 hours. The crystals that precipitated were collected through filtration, followed by washing with water and drying through air blow. The crude target product was dissolved in methanol (500 mL) through heating, and the reaction mixture was cooled. The crystals that precipitated were collected through filtration, followed by drying through air blow at 60° C., to thereby yield N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-bromoacetamide (54.38 g, yield: 67.3%, HPLC: 99.32%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52]1>ClCCl.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:51]2[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52]2)=[O:17])=[CH:18][CH:19]=1
Reactant: OC1CCNC1
Reactant: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Cc2nc3ccccc3[nH]2)cc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (5 g, 0.019 mol) in methanol was treated with sodium hydroxide (1.50 g, 0.037 mol) and water, heated to 65° C., stirred for 3 h and concentrated under reduced pressure. The resultant residue was dissolved in water and acidified with concentrated HCl. The resultant precipitate was removed by filtration and dried under vacuum overnight to provide 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (82.0%). 1H NMR-(400 MHz, DSMO-d6): 7.96 (d, J=8 Hz, 2H), 7.91 (m, J=9 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 7.52 (m, J=6 Hz, 2H), 4.65 (s, 2H). LCMS (ESI+) 253 (M+H). A portion of 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (5.0 g, 0.020 mol) was dissolved in dichloromethane, cooled to 0° C., treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.50 g, 0.023 mol), 1-hydroxybenzotriazole (HOBT) (3.21 g, 0.024 mol), and diisopropylethylamine (6.41 g, 0.049 mol), stirred at room temperature for 30 min, cooled to 0° C., treated with a solution of 3-pyrrolidinol (1.89 g, 0.021 mol) in dichloromethane, stirred at room temperature for 24 h and diluted with water. The phases were separated and the organic phase was washed sequentially with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over sodium sulfate and concentrated to dryness under reduced pressure to provide [4-(1H-benzoimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (34%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 7.47 (s, 4H), 7.38 (d, J=7.6 Hz, 2H), 4.87 (s, J=4.2 Hz, 1H), 4.21 (d, 2H), 3.48 (m, 4 H), 1.85 (m, 2H). LCMS (ESI+) 322 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][O:21]1
Reactant: C=Cc1cccc([N+](=O)[O-])c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CO2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Methyl-1-nitro-3-vinylbenzene (2 g, 12.26 mmol) was dissolved in DCM (50 ml) then cooled to 0° C. and added mCPBA (3.17 g, 14.14 mmol) then stirred at room temperature for 16 hrs. When TLC showed starting materials, more mCPBA (1.58 g, 7.07 mmol) was added. The reaction was stirred for another 16 hrs. The reaction was washed with saturated aqueous Na2S2O3, NaHCO3, brine; then dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography through a 120 g ISCO Redi-Sep column eluting with 0-20% ETOAc/hexane to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.C1COCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14])(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(O)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OS(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 1-(4-hydroxy-2-trifluoromethyl-phenyl)-ethanone (29.74 g; 145.7 mmol) in CH2Cl2 (300 mL) and THF (120 mL) was added Et3N (24.4 mL; 174.8 mmol), at 0° C. To the resulting mixture was added dropwise a solution of methanesulfonyl chloride (12.5 mL; 160.3 mmol) in CH2Cl2 (60 mL), at 0° C. Subsequently the mixture was stirred overnight at RT, and poured in ice-water. The layers were separated and the organic layer was washed with 1 M aqueous HCl and water; dried (MgSO4), filtered and concentrated in vacuo to afford methanesulfonic acid 4-acetyl-3-trifluoromethyl-phenyl ester (40.47 g), which was used as such.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[O:17]=[C:18]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[CH2:19][C:20](OC(C)(C)C)=[O:21]>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:18](=[O:17])[C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cnccn1
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1NC(=O)CC(=O)c1cnccn1

Procedure:
The title compound was prepared from the reaction of tert-butyl 2-amino-4-bromophenylcarbamate (Example B1; 1 mmol) and tert-butyl 3-oxo-3-(pyrazin-2-yl)propanoate (Example C3; 1 mmol) according to the general procedure D. Obtained as a yellow solid (81%), MS (EI) 435 [(M+1)+].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[N:10]=[C:9]1[Cl:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 7-benzyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (6.0 g, 16.13 mmol) in DMF (50 mL) was added NCS (3.23 g, 24.19 mmol) and the resulting mixture was stirred at room temperature for 8 h. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (5.1 g, 77.9% yield) as light yellow oil. Product tlc [petroleum ether/ethyl acetate (15:1) iodine detection, Rf 0.6)
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:5])C.[CH2:37]([NH2:39])[CH3:38]>CO>[CH2:37]([NH:39][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:8][N:7]=1)=[O:5])[CH3:38]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reaction time: 2 h

Procedure:
5-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester (10.0 g, 20.6 mmol) was added to a solution of ethylamine in methanol (60 ml, 2.0M) and the suspension heated, oil bath temperature 75° C., for ˜2 hrs. The resulting solution was allowed to cool and concentrated to a pale brown oil, dichloromethane (150 ml) was added and the solution washed with water (100 ml) and saturated aqueous sodium chloride solution (75 ml). The solution was dried over anhydrous sodium sulphate and concentrated to a brown oil, solidified on standing (9.9 g, ˜quant).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)[CH3:2].[OH2:8].N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:1]([O:4][CH:5]1[CH2:6][CH:13]2[CH2:14][CH:10]1[CH:11]=[CH:12]2)(=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: O
Product: CC(=O)OC1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
11 g of 2-hydroxymethyl-5-norboronene were dissolved in 21 ml of pyridine, and 11 ml of acetic anhydride were added dropwise to the mixture, followed by stirring at room temperature for 12 hours. The resultant reaction mixture was poured into 100 ml of water, and the organic layer was then extracted with 100 ml of ethyl acetate. Afterward, the thus extracted organic layer was washed with 0.5 N hydrochloric acid, a 3% aqueous sodium carbonate solution and saturated saline in this order. This organic layer was dried over magnesium sulfate, and ethyl acetate was distilled off under reduced pressure, thereby obtaining 13 g of 2-acetoxy-5-norbornene. Next, 13 g of 2-acetoxy-5-norbornene were added dropwise to a mixture of 50 ml of 90% formic acid and 13 ml of 30% aqueous hydrogen peroxide under ice-cooling, followed by stirring at room temperature for 12 hours. Formic acid was distilled off under reduced pressure, and 30 ml of methanol, 13 g of sodium hydroxide and 25 ml of water were added to the resultant residue and reaction was then carried out at 45 to 50° C. for 1 hour. After the reaction solution was allowed to cool, the resultant organic layer was extracted with 100 ml of ethyl acetate, washed with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5 g of 2,3-dihydroxy-5(6)-hydroxymethylnorbornane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:21]=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C(#N)C>[Br-:10].[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:20]=[CH:21][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:11][C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:4]=1
Reactant: BrCc1cnc2ccccc2n1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2cnc3ccccc3n2)cn1Cc1cnc2ccccc2n1
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.37 g, 10 mmol) will be dissolved in a minimum amount of acetonitrile and potassium hydroxide (0.62 g, 11 mmol) will be added. The mixture will be stirred at reflux until the potassium hydroxide is consumed, approximately 30 min. 2-(Bromomethyl)quinoxaline (2.23 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the potassium bromide generated. A second addition of 2-(bromomethyl)quinoxaline (2.23 g, 10.0 mmol) will be made to the reaction solution, which will be returned to reflux for 6 h. Removal of the volatile components under reduced pressure should yield the product.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[NH:9][C:8]=2[N:7]=[CH:6]1)[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[C:23](=O)([O-])[O-].[K+].[K+]>>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:11]1[C:12](=[O:14])[C:13]2[N:5]([CH2:4][O:3][CH2:1][CH3:2])[CH:6]=[N:7][C:8]=2[N:9]([CH3:23])[C:10]1=[O:15]
Reactant: BrCCCCCBr
Reactant: CCOCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCOCn1cnc2c1c(=O)n(CCCCCBr)c(=O)n2C

Procedure:
22.4 g (0.1 mol) of 7-ethoxymethylxanthine were stirred at 70° C. for 1.5 hours with 45.9 g (0.2 mol) of 1,5-dibromopentane and 27.6 g of activated potassium carbonate. The solution was filtered and concentrated, and the oily residue which remained was chromatographed (eluent: ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[O:21]1[CH:26]2[CH:22]1[CH2:23][O:24][CH2:25]2.C(N(CC)CC)C>ClCCl>[OH:21][C@@H:22]1[CH2:23][O:24][CH2:25][C@H:26]1[O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: C1OCC2OC12
Reactant: O=C(OCc1ccccc1)N1CCC(OCCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(OCCO[C@@H]2COC[C@H]2O)CC1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Benzyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (6.70 g, 24.0 mmol) produced in Reference Example 1 (1b) and 3,4-epoxytetrahydrofuran (1.03 g, 12.0 mmol) were dissolved in dichloromethane (5.0 mL). To the resulting mixture, a boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added at room temperature, followed by stirring for 16 hours. More boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added, followed by further stirring for two hours. Triethylamine (1.82 g, 18.0 mmol) was then added, and the resulting reaction liquid was directly purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, ethyl acetate:methanol, 100:0-95:5, V/V) to give the desired title compound (2.14 g, yield 49%).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][CH:24]([NH2:26])[CH3:25]>>[CH:24]([NH:26][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:25])[CH3:23]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)N
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)C
Temperature: 100 °C
Yield: 47 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 45 mg, 0.152 mmol) and propan-2-amine (38.8 μl, 0.456 mmol, Aldrich), heating at 100° C. for 30 min. Purification by silica gel (100% DCM to 3% MeOH/DCM) provided 2-(3-(isopropylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4 (5H)-one (47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.46 Hz, 6H) 2.56 (s, 3H) 2.90 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.80, 2.25 Hz, 2H) 4.30 (dq, J=13.23, 6.48 Hz, 1H) 6.88 (d, J=7.04 Hz, 1H) 6.96 (br. s., 1H) 7.12 (s, 1H) 7.33 (t, J=7.82 Hz, 1H) 7.57 (dd, J=7.92, 1.27 Hz, 1H) 7.90 (dd, J=7.63, 1.17 Hz, 1H) 12.23 (br. s., 1H). MS (ESI, pos. ion) m/z: 336.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([B:11]([OH:16])[OH:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1cccc2ccsc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OB(O)c1cc2cccc(Cl)c2s1
Temperature: -30 °C
Yield: 96.2 %

Procedure:
To a solution of 7-chlorobenzo[b]thiophene (1.0 g, 5.92 mmol) in THF (25 mL) at −78° C. was added nbutyllithium (7.41 mL 11.8 mmol, 1.6 M solution). The reaction was allowed to warm to −30° C. then was cooled back to −78° C. and triisopropyl borate (2.23 g, 11.8 mmol) was added. The mixture was allowed to warm to 0° C., saturated ammonium chloride added and the organic phase separated off and concentrated in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) and the mixture was washed with DCM. The aqueous phase was acidified with 2N sulfuric acid, and the resulting precipitate isolated by filtration and dried under vacuum to yield 7-chlorobenzo[b]thiophene-2-boronic acid (1.21 g, 96%) as white solid. 1H NMR (400 MHz, CDCl3) δ=7.41 (t, J=7.70 Hz 1H), 7.50 (d, J=7.70 Hz, 1H), 7.91 (d, J=7.70 Hz, 1H), 8.03 (s, 1H), 8.63 (s, 2H); MS (ES+): m/z 211.86 [M+].