Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][CH:15]=1>CN(C=O)C>[N+:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:10][CH:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[CH3:9])=[CH:15][CH:16]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: CC(O)c1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 57.9 %

Procedure:
To a stirred solution of 1-(2-aminopyridin-4-yl)ethanol (22) (73 mg, 0.528 mmol) in DMF (1.5 mL), under nitrogen at 0° C., was added sodium hydride (32 mg, 0.793 mmol, 60 wt %). The resulting mixture was stirred at 0° C. for 40 min, and a solution of 1-fluoro-4-nitronaphthalene (101 mg, 0.528 mmol) in DMF (1.5 mL) was added dropwise. The resulting dark-red mixture was stirred at 0° C. for a further 5 min, and then at RT. After a further 40 min, the reaction was quenched by the addition of 1.0 mL of NH4Cl solution. Water (20 mL) and EtOAc (20 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL×3). The combined organic extracts were washed with brine, dried and the solvents removed under reduced pressure. The crude material was purified by column chromatography (12 g), eluting with 0 to 80% EtOAc in iso-hexane, to give 4-(1-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-amine (23) (94.6 mg, 57%) as an orange gum: m/z 310 (M+H)+ (ES+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH:26]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]>CCOC(C)=O.[Pd].[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2C2=CCC(O)CC2)cc1)c1nc2ccccc2[nH]1
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2nccnc2[C@H]2CC[C@@H](O)CC2)cc1)c1nc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
1H-benzimidazol-2-yl(4-((3-(4-hydroxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)-phenyl)methanone (0.27 g, 0.66 mmol) was suspended in 20 mL of EtOAc in a pressure tube. Palladium on carbon, 10% (0.20 g) was added. The mixture was hydrogenated at 50 psi. After 60 hours the mixture was filtered through a plug of celite and eluted with 50 mL of 9:1 chloroform:isopropanol. The solvent was removed under reduced pressure. The residue was taken up in 50 mL of dichloromethane. The mixture was sonicated for 5 minutes to dissolve the starting material. Manganese dioxide (0.84 g, 9.7 mmol) was added. After 2 hours, the mixture was filtered through celite, eluted with 50 mL of 9:1 chloroform/isopropanol, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0 to 2.5% MeOH/dichloromethane). Two products of identical mass that co-eluted were isolated. The mixture was further purified by preparatory HPLC (Phenomenex Gemini column [C18, 10 micro, 150×30 mm] 15% to 100% MeCN/water over 20 min at 35 mL/min) affording 1H-benzimidazol-2-yl(4-((3-(cis-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)phenyl)methanone (MS m/z: 401 (M+1) and 1H-benzimidazol-2-yl(4-((3-(trans-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)-phenyl)methanone. MS (ESI, pos. ion) m/z: 401 (M+1). IC50 (uM) +++++.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(=O)CC>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc(F)c(C(F)(F)F)c1

Procedure:
A mixture of 4-fluoro-3-trifluoromethyl-phenol (10.000 g; 55.525 mmol), potassium carbonate (9.591 g; 69.406 mmol), and methyl bromoacetate (6.38 ml; 69.406 mmol) in butanone (380 ml) was heated at reflux for 1 h30. Filtration, concentration to dryness under reduced pressure, and purification by FC (heptane/EA, 4/1) afforded (4-fluoro-3-trifluoromethyl-phenoxy)-acetic acid methyl ester as a colorless oil (13.300 g; 95%). LC-MS: tR=0.95 min.; [M+H]+: no ionisation.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[Br:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Br:13])=[CH:7][C:8]([F:12])=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[Br:11]
Reactant: O=[N+]([O-])O
Reactant: Fc1cc(Br)c(OCCCl)c(Br)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(Br)c(OCCCl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 1-(2-chloroethoxy)-2,6-dibromo-4-fluorobenzene (65.8 g, 0.20 mol) in concentrated sulfuric acid (165 ml) maintained at room temperature using a water bath was slowly added a solution of nitric acid in sulfuric acid (10 ml HNO3 in 165 ml H2SO4). The reaction was allowed to stir at room temperature for 1 hour then poured into ice (1.5 L) and extracted with methylene chloride (2×300 ml). The combined organic layers were washed with aqueous sodium bicarbonate (150 ml) and dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to afford 73.3 g (97.1%) a white crystalline solid: mp 56-57° C.; MS EI m/e 375/377/379/381; 1H NMR (CDCl3) δ3.91 (2H, t, J=5.9 Hz), 4.29 (2H, d, J=5.9 Hz), 7.54 (8.1 Hz).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=O)=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=[O:27])=[CH:18]1>>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=[O:27])=[CH:18]1
Reactant: CS(=O)(=O)OCc1cccc(C(F)(F)F)c1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(Cc2cccc(C(F)(F)F)c2)c2ccccc12
Yield: 95.2 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.68 g of (3-trifluoromethylbenzyl) methanesulfonate and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.98 g of 1-(3-trifluoromethylbenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 95%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][CH:22]=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O.S([O-])(O)(=O)=O.[K+].O1CCC[CH2:34]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][CH:22]([OH:23])[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC=O
Reactant: C1CCOC1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC(O)C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 1.6M methyllithium-ether solution (5.5 ml, 8.8 mmol) in tetrahydrofuran (20 ml) was added (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(formylmethyl)pyrrolidine (1.67 g, 4.86 mmol) under a nitrogen atmosphere at -70° C., and the mixture was stirred for 2 h at the same temperature. To the mixture was added saturated aqueous ammonium chloride (3 ml) below -70° C., and then the mixture was warmed at room temperature. The reaction mixture was poured into a mixture of water (200 ml) and 1N aqueous potassium hydrogensulfate (20 ml), and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was subjected to silica gel column chromatography (heptane-ethyl acetate) to give (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-hydroxypropyl)pyrrolidine diastereomer A (890 mg, yield: 51%) and diastereomer B (350 mg, yield: 20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:15])[CH2:9][C:10]([O:12]CC)=[O:11].C(O)C.[OH-].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:15])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CC(C)c1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CC(=O)O)c1ccccc1Br
Reaction time: 8 h
Yield: 105.5 %

Procedure:
To a solution of ethyl 3-(2-bromophenyl)-3-methylpropionate (28.04 g, 109.1 mmole) in the mixture of ethanol (200 ml) and water (100 ml) was added potassium hydroxide (12.2 g, 218.2 mmole). The solution was heated under reflux for 5 hours, left standing overnight as it was, the solvent was removed to about half of its original amount, and dilute hydrochloric acid was added to the concentrate. To this mixture was added dichloromethane followed by an aqueous ammonium chloride solution, the layers were separated, and the organic layer was dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure to give 3-(2-bromophenyl)-3-methylpropionic acid (27.97 g, quant.).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:12]1=[O:28].[OH-].[Na+]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[C:12]2=[O:28])=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(Cl)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)n(Cc2ccc(Cl)cc2)c2ccccc21

Procedure:
The product is produced as described in example 22 from 4 g. 8-[3-(4-chlorobenzyl)-2-oxo-benzimidazolin-1-yl]-caprylic acid methyl ester and 0.8 g. of NaOH.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:20][N:21]([CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[CH2:27][S:28][CH2:29][CH2:30]N)[CH3:22]>C(O)C>[CH3:20][N:21]([CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)[CH3:22]
Reactant: CN(C)Cc1cccc(CSCCN)c1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: Cc1ccc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)cn1

Procedure:
A mixture of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (1.0 g),2-[3-(dimethylaminomethyl)benzylthio]ethylamine (1.30 g, 1.5 equivalents) and ethanol (3 ml) was heated under reflux for 29 hours and evaporated to dryness. The residue was dissolved in water and the solution was adjusted to pH13 and extracted with ether (which was discarded). The aqueous phase was adjusted to pH 10.5 with hydrochloric acid and the solution was extracted with ether and chloroform. The combined organic extracts were evaporated to dryness and the residue was crystallised from acetonitrile to give 2-[2-[3-(dimethylaminomethyl)benzylthio]ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone m.p. 122°-125°. Treatment with hydrogen chloride in ethanol gives the trihydrochloride salt and treatment with hydrogen bromide in ethanol gives the trihydrobromide salt.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:13][OH:14]
Reactant: C=O
Reactant: Cc1ccc2nccc(O)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2ncc(CO)c(O)c2c1

Procedure:
4-Hydroxy-6-methylquinoline was reacted with formaldehyde in aqueous sodium hydroxide at 40°-45° for 60 hours to give the novel compound 4-hydroxy-3-hydroxymethyl-6-methylquinoline, m.p. 188°-189° (dec.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Na+].[I-].Cl.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:22].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:32][CH2:31]1)[CH3:22]
Reactant: CCOc1ccccc1N1CCCNCC1
Reactant: O=c1ccc2ccc(OCCCCBr)cc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CCOc1ccccc1N1CCCN(CCCCOc2ccc3ccc(=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of intermediate 15 (150 mg, 0.51 mmol) and NaI (150 mg, 1.0 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 31 (130 mg, 0.51 mmol) and anhydrous K2CO3 (282 mg, 2.04 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=50:1) to give 7-(4-(4-(2-ethoxyphenyl)-1,4-diazepan-1-yl)butoxy)quinolin-2(1H)-one (compound 14) (50 mg, 24%). 1H NMR (300 MHz, CDCl3) δ 10.89 (bs, 1H), 7.69 (d, J=9.6 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 6.92-6.78 (m, 5H), 6.71 (d, J=2.7 Hz, 1H), 6.51 (d, J=9.6 Hz, 1H), 4.10-4.01 (m, 4H), 3.36-3.30 (m, 4H), 2.89-2.79 (m, 4H), 2.62-2.59 (m, 4H), 2.02-2.01 (m, 2H), 1.89-1.82 (m, 2H), 1.45 (t, J=6.9 Hz, 3H). HPLC: 99%, RT 2.375 min. MS (ESI) m/z 436.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:19])[C:10]([NH:12][C:13]([NH:15][C:16]([NH2:18])=[O:17])=[O:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C>O>[CH2:1]([O:8][CH:9]([C:10]1[NH:12][C:13](=[O:14])[NH:15][C:16](=[O:17])[N:18]=1)[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OCc1ccccc1)C(=O)NC(=O)NC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(OCc1ccccc1)c1nc(=O)[nH]c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To an ice-cold suspension of 2-benzyloxy-N-ureidocarbonyl-propionamide (9.4 mmol, 2.5 g) in water (15 mL) was added KOH (28 mmol, 1.6 g) in water (10 mL). The reaction temperature was slowly raised to room temperature, and the reaction was allowed to stir for 1 h. Sufficient acetic acid was added to adjust the pH of the reaction to 5, and the resulting cloudy solution was extracted with chloroform (3×20 mL). The chloroform layer was collected, dried, filtered and the filtrate was concentrated to obtain a residue, which was triturated with isopropyl ether to obtain 6-(1-benzyloxy-ethyl)-1H-[1,3,5]triazine-2,4-dione (74%, 1.72 g); NMR 1.4 (d, 3H), 4.2 (t, 1H), 4.6 (dd, 2H), 7.4 (m, 5H), 11.2 (s, 1H), 12.1 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH3:11])[N:7]=[C:6]([NH2:12])[N:5]=1)[CH3:2].[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH:10][CH3:11])[N:7]=[C:6]([NH:12][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH3:13])=[O:16])(=[O:24])=[O:25])=[O:28])[N:5]=1)[CH3:2]
Reactant: CCOc1nc(N)nc(NC)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CCOc1nc(NC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)n1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a suspension of 0.8 g of 4-ethoxy-6-methylamino-1,3,5-triazin-2-amine in 25 ml of methylene chloride was added 1.14 g of 2-(methoxycarbonyl)benzenesulfonyl isocyanate. Dissolution of the suspension occurred, followed by precipitation of a solid. After 1 hour at ambient temperature, the solid was collected and dried giving 0.9 g of the title compound, m.p. 204°-206° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][CH:38]=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1.CO>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][C:38]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[C:8]5[O:15][C:14]6[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=6[C:9]=5[N:10]=[CH:11][N:12]=4)[CH2:2][CH2:3]3)=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: c1ccc2c(c1)oc1c(N3CCNCC3)ncnc12
Reactant: S=CNCc1ccc2c(c1)OCO2
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: S=C(NCc1ccc2c(c1)OCO2)N1CCN(c2ncnc3c2oc2ccccc23)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinobenzofurano[3,2-d]pyrimidine (200 mg, 0.79 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1c in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 150 mg (37%).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:37]([Si:41]([CH3:58])([CH3:57])[O:42][CH:43]([C:45]1[O:46][C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)=[CH:48][N:49]=1)[CH3:44])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:37]([Si:41]([CH3:58])([CH3:57])[O:42][CH:43]([C:45]1[O:46][C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[O:11])[CH:53]=[N:52]2)=[CH:48][N:49]=1)[CH3:44])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid (44 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.25 min, [M+H]+=593.58.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19](C(=O)C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)[C@@H:18]([CH3:42])[CH2:17]1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:7])(=O)C.[OH-].[K+].Cl>C(O)C.O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C@@H:18]([CH3:42])[CH2:17]2)[C:6](=[O:7])[CH2:5][OH:4])=[CH:14][CH:13]=1
Reactant: CC(=O)OCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H]1C[C@@H](N(C(=O)CO)c2ccc(Cl)cc2)c2ccccc2N1
Temperature: 70 °C

Procedure:
To a solution of 2-[{(2S,4R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}(4-chlorophenyl)amino]-2-oxoethyl acetate (500 mg, 0.82 mmol, 1 equ.) in ethanol (6 mL) and water (1 mL) was added potassium hydroxide (229 mg, 4.1 mmol, 5 equ.). The mixture was heated to 70° C. for 4 h. The mixture was neutralized with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and twice with brine, dried over sodium sulfate, filtered and concentrated to give crude N-(4-chlorophenyl)-2-hydroxy-N-[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide used as such in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=[N+:11]([CH2:13]C1C=CC=CC=1)[O-:12].Cl.C(NO)C1C=CC=CC=1.CN1C([N+]([O-])=O)=CN=C1C=O>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=[N+:11]([CH3:13])[O-:12]
Reactant: Cn1c([N+](=O)[O-])cnc1C=[N+]([O-])Cc1ccccc1
Agent: Cl
Agent: Cn1c([N+](=O)[O-])cnc1C=O
Agent: ONCc1ccccc1
Product: Cn1c([N+](=O)[O-])cnc1C=[N+](C)[O-]

Procedure:
The corresponding α-(1-methyl-5-nitroimidazol-2-yl)-N-benzylnitrone can also be prepared using N-benzylhydroxylamine hydrochloride in the above reaction with 1-methyl-2-formyl-5-nitroimidazole.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][CH2:20][CH2:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:23][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:22]2[O:21][CH2:20][CH2:19][C:18]=2[CH:17]=1
Reactant: Fc1cc2c(c(N3CCN(Cc4ccccc4)CC3)c1)OCC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1cc2c(c(N3CCNCC3)c1)OCC2
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 1-benzyl-4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazine (2.06 g, 6.6 mmol), 10% palladium on carbon (0.6 g) and ammonium formate (0.83 g, 13 mmol) in ethanol (20 ml) was allowed to refux for 2 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromatography (10-30% methanol-methylene chloride plus ammonium hydroxide) afforded 1.10 g (75%) of product as a yellow oil; MS EI m/e 222 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].Cl[C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2OC)s1
Yield: 97.5 %

Procedure:
A mixture of 2,4-dimethoxybenzylamine (58.7 mmol, 8.81 ml, 9.81 g), methyl 5-chloro-4-nitrothiophene-2-carboxylate (45.1 mmol, 10 g) and potassium carbonate (180 mmol, 24.94 g) were stirred at rt in Acetonitrile (226 mL) for 1 h. Reaction was quenched with water and the resulting precipitate was collected to give methyl 5-(2,4-dimethoxybenzylamino)-4-nitrothiophene-2-carboxylate 86 (15.5 g, 97%). NMR (400 MHz, CDCl3) 3.82 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 4.45 (d, J=5.9 Hz, 2H), 6.46 (dd, J=8.2 Hz and 2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.99 (s, 1H), 8.89 (br s, 1). (m/z)=353 (M+H)+.