Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[C:8](=O)(OCC)[O:9]CC.[H-].[Na+]>>[CH3:1][O:2][CH2:3][CH:4]1[CH2:5][O:6][C:8](=[O:9])[O:7]1
Reactant: CCOC(=O)OCC
Reactant: COCC(O)CO
Agent: [H-]
Agent: [Na+]
Product: COCC1COC(=O)O1

Procedure:
A mixture of 14 g (0.132 mol) of 3-methoxypropane-1,2-diol (S)and 31.16 g (0.264 mol) of diethyl carbonate in the presence of 0.108 g of 50% sodium hydride is heated until distillation of the alcohol formed. After completion of the reaction, the aimed product is distilled.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21](=[O:38])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:21]([OH:38])[CH:22]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:16])[CH3:17])[CH:12]([CH3:13])[CH3:14]
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.564 g, 14.92 mmol) and ethanol (60 mL) was stirred 10 minutes and then 1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (7.66 g, 14.92 mmol in 10 mL of ethanol) was added with two 30 mL ethanol rinses. The reaction mixture was stirred at ambient temperature overnight. The white solid that precipitated was collected by filtration and dried to yield 5.72 g (74%) of (1R*, 2R*)-1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol, which was suitable for use without further purification and had: m.p. 188-189° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].CN1CCOCC1>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Cyclopentyl chloroformate was added to a stirred solution of the amino ester (A) (0.15 g.) and N-methylmorpholine (0.27 g.) in dichloromethane (3 ml.) at 0°-5° C., under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at 0°-5 ° C., the cooling bath removed, and stirring continued for 1 hour. The mixture was then poured into 1M hydrochloric acid (15 ml.), and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound (0.18 g., 89%) as a colorless oil; NMR: 1.66(m, 6H), 1.82(m,2H), 3.83(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s,2H, CH2.Ar), 5.04(m,1H, --CHO--), 7.09(m, 3H), 7.22(d,1H), 7.42(dd, 1H), 7.48(d,1H), 7.57(br,1H), 9.18(br,1H, CONH), 10.57(s,1H, H1 -indole).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].CN([CH:24]=[O:25])C>C1COCC1>[Cl:13][C:14]1[C:15]([F:20])=[CH:16][N:17]=[CH:18][C:19]=1[CH:24]=[O:25]
Reactant: Fc1cnccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cncc(F)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
To a solution of diisopropylamine (6.4 mL, 45.6 mmol) in THF (50 mL) at −30° C. was added n-butyllithium (2.5 M in hexanes, 18.2 mL, 45.6 mmol) over 15 minutes and the resulting mixture stirred for 15 minutes then cooled to −78° C. A solution of 4-chloro-3-fluoro-pyridine (5.0 g, 38.0 mmol) in THF (10 mL) was added dropwise over 15 minutes then the resulting mixture was stirred at −78° C. for 18 hours. DMF (3.5 mL, 45.6 mmol) was added and the reaction was warmed to room temperature. The mixture was quenched with ammonium chloride (sat. aq., 300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in cyclohexane) to afford the title compound as a pale orange solid (5.1 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 10.47 (s, 1H), 8.88 (s, 1H), 8.70 (s, 1H).
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1
Reactant: COc1ccc2c(c1)CCC(N=[N+]=[N-])C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(N)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.0 g (30 mmol) of 2-azido-6-methoxytetralin 15 ml of TMF were added dropwise in the course of 15 minutes at 0° C. to a suspension of 1.7 g (44 mmol) of lithium aluminum hydride in 70 ml of THF. The mixture was stirred for 30 minutes at room temperature and refluxed for 1 hour. After cooling to 0° C., excess alanate was destroyed with isopropanol, and the mixture was diluted with ether and washed with saturated tartrate and saturated NaCl solution. After the organic phase had been dried and concentrated, the resulting colorless oil was further employed directly. Yield 5.1 g (96% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9]C.[OH-].[Na+]>Br>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([OH:9])[CH:4]=1
Reactant: COc1cc(N)ccc1Br
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Br)c(O)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
4-Bromo-3-methoxyaniline (5.0 g, 25 mmol) was added to 48% hydrobromic acid (20 mL), and the reaction mixture was stirred at 80° C. for 16 hr. After completion of the reaction, the mixture was allowed to cool to room temperature, and adjusted to pH 7-8 by adding 8N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→100/0) to give the title compound (2.0 g, 43%) as a white powder.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28]1([CH2:32][C:33](O)=[O:34])[CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:32][C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])[CH2:31][CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CCC1
Agent: Cl
Product: O=C(CC1CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (81 mg, 76%), MS (ISP) m/z=427.5 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyclobutane-acetic acid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:26])[CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CCNCC(O)c2ccc(O)c(O)c2)cc1OC
Yield: 104.1 %

Procedure:
3.0 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,4-dibenzyloxybenzylalcohol hydrochloride are suspended in a mixture of 80 ml of isopropanol and 20 ml of water. One g of 10 % palladium-carbon is added to the solution. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 1 hour under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated to dryness under reduced pressure, and the residue thus obtained is recrystallized from aqueous isopropanol. 2.1 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,4-dihydroxybenzylalcohol hydrochloride are obtained. Yield: 90 % M.p. 98° - 109°C (decomp.)
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[N+:5]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])([O-:7])=[O:6].[N:15]#[C:16][NH2:17]>C(O)C>[N+:1]([O-:4])([OH:3])=[O:2].[N+:5]([C:8]1[CH:9]=[C:10]([NH:11][C:16]([NH2:17])=[NH:15])[CH:12]=[CH:13][CH:14]=1)([O-:7])=[O:6]
Reactant: N#CN
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1cccc([N+](=O)[O-])c1

Procedure:
42 ml (0.6 mol) of nitric acid (65%) are added dropwise to a yellow suspension of 82.88 g (0.6 mol) of 3-nitroaniline in 200 ml of ethanol. After the exothermic reaction has subsided, 75.7 g (0.9 mol) of cyanamide (50% in water) are added and the reaction mixture is boiled at reflux for 21 hours. After cooling to 0°, the mixture is filtered and washed six times with ethanol/diethyl ether (1:1). Drying under HV at 40° yields 3-nitrophenyl-guanidine nitrate; m.p. 205°-207°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.O.[OH-].[K+].Br[C:15](P(=O)(OCC)OCC)([F:17])[F:16]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH:15]([F:17])[F:16])=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: OCc1cc(Br)ccc1S
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: OCc1cc(Br)ccc1SC(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(5-Bromo-2-sulfanylphenyl)methanol (0.50 g, 2.8 mmol) was dissolved in acetonitrile (11.4 mL) followed by the addition of water (11.4 mL) and solid potassium hydroxide (2.56 g, 45.6 mmol). The mixture was plunged into a −78° C. bath and when the mixture began to freeze diethyl [bromo(difluoro)methyl]phosphonate (1.22 g, 4.56 mmol) was added all at once and the cold bath was removed. The mixture was allowed to warm to ambient temperature and was stirred for 20 minutes. The mixture was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-25% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[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.[CH3:22][C:23]1(C)C[CH2:26][CH2:25][NH:24]1>>[CH2:23]([N:24]([CH2:25][CH3:26])[C:2]1[CH:3]=[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)[CH3:22]
Reactant: CC1(C)CCCN1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Product: CCN(CC)c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 100 °C
Yield: 50 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 82 mg, 0.290 mmol) and 2,2-dimethylpyrrolidine (57.6 mg, 0.581 mmol; ChemBridge, San Diego, Calif.) and heating at 100° C. for 16 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(3-(diethylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (50% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (s, 6H) 1.96-2.06 (m, 4H) 2.87 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.85, 2.35 Hz, 2H) 3.78 (t, J=6.16 Hz, 2H) 6.95 (br. s., 1H) 7.07 (d, J=2.15 Hz, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.66 (dd, J=8.02, 1.17 Hz, 1H) 7.89-7.94 (m, 1H) 8.62 (s, 1H) 11.99 (br. s., 1H). MS (ESI, pos. ion) m/z: 362.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:38](O)[CH:39]=[CH2:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(Cl)Cl>[CH2:40]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH:39]=[CH2:38]
Reactant: C=CCO
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution containing 7-hydroxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl)phenyl)-2H-chromen-2-one (0.550 g.) in tetrahydrofuran (6 mL) and methylene chloride (6 mL) was added allyl alcohol (0.226 mL) and triphenylphosphine (0.641 g.). Diisopropylazodicarboxylate (0.437 mL) was then added dropwise to the solution. The resultant mixture was allowed to stir for about one hour (or until the starting material was consumed). The solution was concentrated under reduced pressure and extracted with methylene chloride (3×) and water. The organic layers were dried over magnesium sulfate, the magnesium sulfate was filtered and the solvent was concentrated under reduced pressure to provide an orange oil. The oil was purified via silica gel chromatography (6–10% methanol/methylene chloride) to afford 7-prop-2-enyloxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl) Phenyl)-2H-chromen-2-one (0.245 g., 40% yield). MS (m/z) 550 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[C:4](/[C:25]1[CH:26]=[C:27]([C:31]([NH2:33])=[NH:32])[CH:28]=[CH:29][CH:30]=1)=[CH:5]/[C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20](=[O:23])(=[O:22])[NH2:21])=[CH:10][CH:9]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]([C:25]1[CH:26]=[C:27]([C:31]([NH2:33])=[NH:32])[CH:28]=[CH:29][CH:30]=1)[CH2:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20](=[O:22])(=[O:23])[NH2:21])=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Agent: [Pd]
Solvent: CO
Product: COCC(CC(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Yield: 107.2 %

Procedure:
To a solution of 3-((1E)-1-(methoxymethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)-benzenecarboxamidine (5 mg, 0.01 mmol) in 4 ml methanol was added 10% Pd on carbon (1 mg). Mixture was treated with hydrogen at 1 atmosphere under balloon for 1 hr. Reaction was filtered through a pad of Celite, concentrated and lyophilized to give 3-(1-(methoxymethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}-ethyl)benzenecarboxamidine (5 mg, 100%) as a fluffy white powder. ES-MS (M+H+): 467.15
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[F:22][C:23]1[CH:24]=[C:25]([NH:26][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[N+:19]([O-:21])=[O:20])[CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: Nc1cccc(F)c1
Product: O=[N+]([O-])c1c(Nc2cccc(F)c2)ccc2ccccc12

Procedure:
1-Nitro-2-naphthyl triflate and 3-fluoroaniline were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH3:34].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH3:34])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Br)c1ccc(F)cc1
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a suspension of 200 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 211 mg of potassium carbonate in 2 ml of N,N-dimethylformamide, 155 mg of 1-(1-bromoethyl)-4-fluorobenzene was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 3 ml of water and extracted with ethyl acetate (3 ml×2), the resulting organic layers were combined, washed with water (3 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 171 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([Br:17])=[C:10]([CH3:18])[CH:9]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:20][Si:2]([CH3:1])([CH3:21])[CH2:3][CH2:4][O:5][C:6](=[O:19])[NH:7][C:8]1[CH:9]=[C:10]([CH3:18])[C:11]([Br:17])=[C:12]([NH2:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OCC[Si](C)(C)C)cc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(NC(=O)OCC[Si](C)(C)C)cc(N)c1Br
Temperature: 85 °C
Yield: 86.1 %

Procedure:
Iron powder (6.1 g, 109 mmol) was added to a suspension of (4-bromo-3-methyl-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (Example 294: step c (4.1 g, 10.9 mmol)) and NH4Cl (5.84 g, 109 mmol) in EtOH (27 mL) and water (54 mL). The reaction was heated at 85° C. for 14 h. The cooled mixture was filtered through celite and the solids were washed with 1:1 EtOAc/MeOH (200 mL). The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc (100 mL) and H2O (30 mL). The organic solution was washed with water (30 mL), and brine (50 mL). Drying and concentration of the solution yielded the title compound (3.24 g, 86%) as a brown solid which was used without further purification. 1H NMR (CDCl3) δ 6.96 (s, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 4.26 (m, 2H), 4.16 (s, 2H), 2.35 (s, 3H), 1.06 (m, 2H), 0.08 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:36])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:36])[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1)OCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl {[trans-4-(8-chloroimidazo[1,5-α]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.49 g, 0.00374 mol) in DMF (0.6 mL) was added NIS (1.0 g, 0.0045 mol). The reaction mixture was stirred at 55° C. overnight then diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude mixture thus isolated was chromatographed over silica gel eluting with hexane hexane:EtOAc 1:1 to afford 1.7 g of the title compound. MS (ES+): m/z 525.01 [MH+].
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].[BH4-].[Na+].O.Cl>C(O)C>[OH:26][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:9])[O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]=1[CH2:24][OH:25]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(CO)c1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added sodium borohydride (4 mmol). The reaction was stirred overnight at room temperature. Water (3 mL) was added to the reaction. The solution was acidified to a pH of 6 with dilute HCl. All of the solvent was removed by rotatory evaporation. The residue was redissolved in ethanol and dried over magnesium sulfate, filtered, and evaporated by a rotatory evaporator to give a white solid product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[C:6]#[N:7].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>C1COCC1.[Zn].C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:12][C:13]1[N:14]=[C:15]([CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=2[F:11])[C:6]#[N:7])[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccc(Br)n1
Reactant: N#Cc1ccc(F)c(CBr)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(Cc2cccc(Br)n2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 34.4 %

Procedure:
A solution of 3-(bromomethyl)-4-fluorobenzonitrile (from Step A above, 17.7 g, 83.3 mmol) in THF was cooled to 0° C. and then 160 mL of Zn/THF solution (124.4 mmol) was added. After stirring at 0° C. for 45 minutes, the reaction was stirred at ambient temperature for an additional 20 minutes. To this reaction mixture was added 2,6-dibromo pyridine (19.73 g, 83.3 mmol) and tetrakis(triphenylphosphine)palladium (5.00 g, 4.30 mmol), and heated to 90° C. for 1.5 hours until the reaction was complete by TLC. The reaction was cooled to room temperature, filtered through celite, and concentrated. The crude residue was purified via silica gel chromatography (hexanes/methylene chloride) to give the title compound (8.34 g).