Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.C([Mg]Cl)(C)C.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>O1CCCC1>[CH2:17]([O:16][C:14]([C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1)=[O:15])[CH3:18]
Reactant: Brc1cscc1Br
Reactant: CCOC(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cscc1Br
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
To a 0° C. solution of 3,4-dibromothiophene (1.0 Kg, 4.13 mol) in tetrahydrofuran (7.4 Kg) was added iPrMgCl (2.0 M solution in tetrahydrofuran, 2.58 Kg, 5.17 mol) keeping the temperature below 5° C. The resulting mixture was stirred at 0-5° C. for 5 hours. To the cooled Grignard solution was added ethyl chloroformate (896 g, 5.17 mol) dropwise keeping the temperature below 10° C. The resulting mixture was warmed to room temperature, and stirred for 16 hours. Water (200 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 10 min. The majority of the tetrahydrofuran was then removed under vacuum and ethyl acetate (4.5 Kg) was added to the mixture followed by 1N aqueous hydrochloric acid. The layers were separated, and the organic layer was washed with 12% brine (5.0 Kg). The solvent was removed under vacuum to give a yellow oil, which was filtered to remove salts to provide 956 g (98% yield) of 4-bromo-thiophene-3-carboxylic acid ethyl ester, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, 1H, J=3.5 Hz), 7.30 (d, 1H, J=3.6 Hz), 4.34 (q, 2H, J=7.10 Hz), 1.38 (t, 3H, J=7.20 Hz); 13C NMR (400 MHz, CDCl3): δ 14.49, 60.95, 110.49, 124.86, 130.93, 133.67, 160.68.
Reaction SMILES: [N:1]([C:4]1[C:13]2[CH:12]=[N:11][C:10]([S:14][CH3:15])=[N:9][C:8]=2[N:7]([CH:16]2[CH2:18][CH2:17]2)[C:6](=[O:19])[CH:5]=1)=[N+]=[N-].C(Cl)Cl.CO>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[C:13]2[CH:12]=[N:11][C:10]([S:14][CH3:15])=[N:9][C:8]=2[N:7]([CH:16]2[CH2:18][CH2:17]2)[C:6](=[O:19])[CH:5]=1
Reactant: CSc1ncc2c(N=[N+]=[N-])cc(=O)n(C3CC3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CSc1ncc2c(N)cc(=O)n(C3CC3)c2n1
Reaction time: 2 h
Yield: 125.2 %

Procedure:
Palladium hydroxide on carbon (10% wt., 150 mg) was added to a solution of 5-azido-8-cyclopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.5 g) in glacial acetic acid (80 mL) and the resulting mixture was stirred under H2 (balloon pressure) for 2 h. A mixture of DCM and MeOH (80/20, 100 mL) was added and the resulting mixture was filtered over a CELITE™ pad and the filter cake was washed with a mixture of DCM and MeOH (80/20, 500 mL). The filtrate was concentrated under reduced pressure to give 1.7 g 5-amino-8-cyclopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a green solid without further purifications. MS=248.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9](=[O:32])[C@H:10]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:11]([N:13]([CH:21]=[O:22])[O:14]C1CCCCO1)[CH3:12])[C:4](=[O:7])[NH:5][CH3:6]>C(O)(=O)C.O>[CH3:33][C:2]([CH3:1])([CH3:34])[C@H:3]([NH:8][C:9](=[O:32])[C@H:10]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:11]([N:13]([CH:21]=[O:22])[OH:14])[CH3:12])[C:4](=[O:7])[NH:5][CH3:6]
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](CCCc1ccccc1)[C@H](C)N(C=O)OC1CCCCO1)C(C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)[C@H](CCCc1ccccc1)[C@H](C)N(O)C=O)C(C)(C)C
Yield: 93 %

Procedure:
A solution of (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)butanoic acid [(1S)-2,2-dimethyl-1-(methylcarbamoyl)-1-propyl]amide (3.0 g, 6.32 mmol) in acetic acid-water (4:1, 10 mL) is heated to 50° C. for 16 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is triturated from hot dichloromethane-diethyl ether to provide (2R,3S)-3-(Formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid [(1S)-2,2-dimethyl-1-(methylcarbamoyl)-1-propyl]amide as a white solid (2.3 g, 93% yield).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>O.O1CCCC1.O1CCOCC1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]([NH:3][CH2:2][CH2:1][NH:4][C:19]([O:22][CH2:23][C:24]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:21])=[O:7])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCN
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NCCNC(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a vigorously shaken solution of 1.39 g of ethylene diamine in 20 ml of water and 20 ml of tetrahydrofuran was added over 45 minutes a solution of 5 g of 4-nitrobenzyl chloroformate in 20 ml of dioxane. The mixture was allowed to warm to room temperature, and 150 ml of ethyl acetate and 200 ml of water were added. The mixture was filtered, and the filtrate dried to afford 2.67 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[C:1](=[N:14]/[OH:15])(\[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]=1)/[CH3:2]
Reactant: CC(=O)c1cc(C(F)(F)F)ccn1
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C/C(=N\O)c1cc(C(F)(F)F)ccn1
Yield: 77.2 %

Procedure:
A solution of 2-acetyl-4-trifluoromethylpyridine (1.2 g), hydroxylamine (0.495 g) and sodium acetate (2.2 g) in a mixture of ethanol:water (20:10 ml) was heated under reflux for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (×2). The combined extracts were washed with water, dried and concentrated to give a solid which was washed with hexane to give (E)-2-acetyl-4-trifluoromethylpyridine oxime (1.0 g, 77% yield) as a pale pink solid; 1H NMR (270 MHz): δ2.39(3H,s), 7.47(1H,d), 7.89(1H,brs), 8.12(1H,s), 8.12(1H,s), 8.78(1H,d); ppm.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[NH:17]1[CH:21]=[CH:20][N:19]=[N:18]1>CN(C=O)C>[CH3:16][C:15]1[C:8]([N:18]2[N:19]=[CH:20][CH:21]=[N:17]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: Cc1cccc(C#N)c1F
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C#N)c1-n1nccn1
Temperature: 120 °C

Procedure:
K2CO3 (8.18 g, 59.2 mmol) was added to a RT solution of 2-fluoro-3-methylbenzonitrile (4.0 g, 29.6 mmol) and 1H-1,2,3-triazole (1.72 mL, 29.6 mmol) in DMF (80 mL) and the resulting suspension was heated to 120° C. for 4 h. The reaction mixture was cooled to RT and quenched with water before being extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 33% to 50% EtOAc in hexane) to give 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile as a white solid. LC-MS B: tR=0.62 min; [M+H]+=185.16.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=[CH2:38])[CH2:31][CH2:30]1.C(N(CC)CC)C.[OH:46][N:47]=[C:48](Cl)[CH3:49]>C(Cl)Cl>[CH3:49][C:48]1[CH2:38][CH:37]([CH2:36][O:35][C@H:32]2[CH2:31][CH2:30][C@H:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:46][N:47]=1
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Reactant: CC(Cl)=NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution (40 mL) of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (2.7 g) and triethylamine (7.5 mL) in methylene chloride was added N-hydroxyethanimidoyl chloride (5 g) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 28%).
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].[NH2:12][C:13]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:16]([CH2:27][CH3:28])=[N:15][C:14]=1C#N>C(Cl)(Cl)Cl>[C:13]([C:14]1[N:15]=[C:16]([CH2:27][CH3:28])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[C:10]=1[I:11])#[N:12]
Reactant: CCc1nc(C#N)c(N)n1CCCCNS(C)(=O)=O
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCc1nc(C#N)c(I)n1CCCCNS(C)(=O)=O
Temperature: 80 °C
Yield: 57 %

Procedure:
A solution of isoamylnitrite (0.30 g, 2.6 mmol), diiodomethane (2 mL), and chloroform (3 mL) was heated at 85° C. A mixture of N-[4-(5-amino-4-cyano-2-ethyl-1H-imidazol-1-yl)butyl]methanesulfonamide (0.2 g, 0.7 mmol) and chloroform (8 mL) was added over a period of 15 minutes. The reaction was stirred and heated at 80° C. for an additional 10 minutes, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified through a layer of silica gel (15 g, eluting sequentially with chloroform, 2% methanol in chloroform, 4% methanol in chloroform, 8% methanol in chloroform, and 10% methanol in chloroform) to provide 0.16 g (57%) of N-[4-(4-cyano-2-ethyl-5-iodo-1H-imidazol-1-yl)butyl]methanesulfonamide as an amber syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To 6-formyl-indole-1-carboxylic acid tert-butyl ester (1.2 g) in methanol (5 mL) in an ice bath was added sodium borohydride (0.27 mg) portion wise. The reaction was allowed to warm to room temperature over 1.5 hr. The reaction diluted with ethyl acetate (200 mL) washed with water (200 mL), brine (100 mL), dried over sodium sulfate, concentrated, adsorbed onto silica gel and purified by flash chromatography with a gradient from 5-40% ethyl acetate in hexanes to yield 6-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester as a clear viscous oil (0.91 g, 78%) LC-MS (ES) calculated for C14H17NO3, 247.1; found m/z 246 [M−H]−.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[Cl-].[Li+].[CH2:14]1[O:17][CH:15]1[CH3:16].S(=O)(=O)(O)O>CN(C)C=O>[OH:17][CH:15]([CH3:14])[CH2:16][N:7]1[C:3]([CH2:1][CH3:2])([CH2:10][CH3:11])[C:4](=[O:9])[N:5]([CH2:14][CH:15]([OH:17])[CH3:16])[C:6]1=[O:8]
Reactant: CC1CO1
Reactant: CCC1(CC)NC(=O)NC1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(CC(C)O)C(=O)N1CC(C)O
Reaction time: 5 h

Procedure:
A solution of 125.0 g of 5,5-diethylhydantoin (0.8 mol), 300.0 g of dimethylformamide and 2.00 g of lithium chloride is stirred at 52° C. 128 g of propene oxide (2.2 mols) are added dropwise over the course of 21/2 hours. Stirring is then continued for 5 hours at 85°-90° C. The reaction mixture is adjusted to pH = 7 with 2-3 drops of 25% strength sulphuric acid, and is filtered. The clear solution is concentrated on a rotational evaporator at 80° C. bath temperature, under a waterpump vacuum, and is subsequently treated under a high vacuum (0.2 mm Hg) at 80° C. until constant weight is reached.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: FC(F)(F)CN1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(4-bromophenyl)piperazine (1.24 g, 5.16 mmol) in DCM were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.20 mL, 7.22 mmol) and cesium carbonate (5.04 g, 15.0 mmol). The resulting mixture was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer was collected and concentrated in vacuo. Purification by chromatography on silica gel (0 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 324.8 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J=9.1 Hz, 2 H),6.78 (d, J=9.0 Hz, 2 H),3.19-3.16 (m, 4 H),3.03 (q, J=9.5 Hz, 2 H),2.84-2.81 (m, 4 H).
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].CS(O[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O.O>CN(C)C=O>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5]1=[O:13])=[CH2:1]
Reactant: CC(C)(C)OC(=O)NCCCCCCOS(C)(=O)=O
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)n1c(=O)n(CCCCCCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
5.9 g (135 mmol) of a 55% sodium hydride dispersion in mineral oil are washed oil-free with hexane and subsequently covered with 100 ml of dimethylformamide. To this suspension are added dropwise at room temperature 22.3 g (128 mmol) of 1-(1-methylvinyl)benzimidazolin-2-one in 100 ml of dimethylformamide. After stirring at room temperature for 2 hours 55.0 g of tert.-butyl [6-[(methylsulphonyl)oxy]hexyl]carbamate in 100 ml of dimethylformamide are added dropwise and the reaction mixture is stirred at room temperature for 18 hours. Thereafter. the reaction mixture is poured into 1 l of water and extracted with 750 ml of methylene chloride. The organic extract is washed with water, dried over potassium carbonate and evaporated. The thus-obtained residue is chromatographed on 950 g of silica gel with methylene chloride/hexane, methylene chloride and a 95:5 mixture of methylene chloride and isopropanol as the elution agent, whereby there are obtained 45.3 g of tert.-butyl [6-[3-(1-methylvinyl)-2-oxo-1-benzimidazolinyl]hexyl]carbamate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:16]=[C:15]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=O)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCCCOCCCC>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:16]=[C:15]([C:17]2([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[S:28][CH2:25][CH2:26][S:27]2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccco2)c1
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCCCOCCCC
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C2(c3ccco3)SCCS2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Dissolve 5-(furan-2-carbonyl)-N-methyl-N-propyl-isophthalamic acid methyl ester (290 mg, 0.88 mmol) in dichloromethane (2 mL). Cool to 0° C., add a solution of ethane-1,2-dithiol (0.22 mL, 2.2 mmol) and then add a solution of boron trifluoride dibutyl etherate (0.66 mL, 5.2 mmol) in dichloromethane (5 mL). Warm the mixture to room temperature and stir overnight. Quench with water and dilute with dichloromethane. Wash the organic layer by saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 30:70 ethyl acetate:hexanes) to give the title compound (38%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:17][C:18]1[C:23]([NH2:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.[H-].[Na+].C(Cl)(Cl)Cl>CN(C=O)C.O>[N+:25]([C:21]1[CH:22]=[C:23]([NH:24][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:8]=[CH:7][N:6]=2)[C:18]([CH3:17])=[N:19][CH:20]=1)([O-:27])=[O:26]
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2)n1
Reactant: Cc1ncc([N+](=O)[O-])cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-methylsulfonyl-4-(pyridin-3-yl)pyrimidine (3.0 g) and 2-methyl-3-amino-5-nitropyridine (5.0 g) in DMF (50 mL) at 0-5° C. was added sodium hydride (60%, 2.3 g). The reaction mixture was naturally warmed to room temperature and stirred for 6 hours. Chloroform (50 mL) and water (50 mL) were added to the reaction and the phases were separated, the aqueous phase was extracted with Chloroform (2×100 mL). The organic extracts were combined, dried, filtered, concentrated and the residue was purified by chromatography to provide_N-(5-nitro-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (5.2 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]=[C:17]1[CH2:22][C:21](=O)[CH2:20][CH2:19][NH:18]1>C1C=CC=CC=1.C(#N)C.CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH:10][C:21]2[CH2:20][CH2:19][NH:18][C:17](=[O:16])[CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C1CCNC(=O)C1
Solvent: CO
Solvent: c1ccccc1
Solvent: CC#N
Product: COc1ccc(NC2=CC(=O)NCC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
0.60 g (2.89 mmole) of the 3-cyclopentyloxy-4-methoxyaniline produced in Example 1(2) and 0.33 g (2.89 mmole) of 2, 4-dioxopiperidine were dissolved in solution of 15 ml of benzene, 4 ml of acetonitrile, and 1 ml of methanol and the mixture was stirred at room temperature for 24 hours. After the reaction, the solvent was removed in vacuo and the residue was triturated with ether. The precipitated brown crystal was collected by filtration, then dried in vacuo to obtain the title compound 0.88 g (yield 100%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[Br:16]Br.Cl>O.C(OCC)C>[Br:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][C:5]2=[O:15]
Reactant: O=C1CCCc2ccccc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: O=C1CCCc2c(Br)cccc21
Temperature: 80 °C

Procedure:
2.21 g of AlCl3 are placed in a round-bottomed flask, to which 0.91 ml of 3,4-dihydro-2H-naphth-1-one is added over 10 min and 0.41 ml of Br2 is added over 5 min, and the mixture is heated at 80° C. for 10 min. It is allowed to return to ambient temperature and a solution comprising 20 g of ice and 2.7 ml of concentrated hydrochloric acid is added thereto. The mixture is then diluted with water and diethyl ether. The organic phase is subsequently separated, dried and concentrated under reduced pressure. The residue is purified by reverse phase preparative chromatography. 172 mg of compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([CH3:17])[C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([CH3:17])[C:7]=1[CH2:18][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(CBr)n(C)c2c(Br)cc(Br)cc12
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c2cc(Br)cc(Br)c2n1C)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 5,7-dibromo-2-bromomethyl-1-methyl-1H-indole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.36 (s, 1H), 7.62 (s, 1H), 5.18 (s, 2H), 4.4-3.79 (m, 8H), 1.6-1.0 (m, 15H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.NO.[N:20]1C=CC=CC=1>C(O)C>[CH3:15][C:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[C:11]([CH3:12])[O:13][N:20]=1
Reactant: CC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Cc1noc(C)c1-c1ccc([N+](=O)[O-])cc1
Yield: 91.7 %

Procedure:
A mixture of 3-(4-nitrophenyl)-pentane-2,4-dione (50 mg, 0.22 mmol), hydroxylamine hydrochloride (15 mg, 0.22 mmol) and pyridine (17 mg, 0.22 mmol) in ethanol (10 ml) was heated to reflux overnight. Evaporation of the solvent gave a residue which was partitioned between water and ethyl acetate. The organic layer was separated, washed with water, then brine and dried. Evaporation to dryness yielded 3,5-dimethyl-4-(4-nitrophenyl)-isoxazole (44 mg, 90%) as solid.
Reaction SMILES: [SH:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16](Cl)=[O:17])([O-:12])=[O:11].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[SH:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][O:5][C:16](=[O:17])[C:15]1[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: CCCC(C)(S)CCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(C)(S)CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 84.2 %

Procedure:
To a solution of 5.0 g (34 mmol) of (rac)-3-mercapto-3-methyl-hexan-1-ol in 20 ml of CCl4 was added in portions 8.6 g (37 mmol) of 3,5-dinitrobenzoyl chloride. The mixture was stirred for 72 h, then 10 ml of a saturated NaHCO3 solution was added, the organic layer was separated, washed with 15 ml of brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash-chromatography (silicagel, hexane/EtOAc 4:1) and gave 9.8 g (84%) of (rac)-3,5-dinitro-benzoic acid 3-mercapto-3-methyl-hexyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:21][CH:20]([OH:22])[C:19]2[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(C2CO2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(O)CNCCc2ccc(OC)c(OC)c2)cc1
Reaction time: 8 h

Procedure:
A mixture of 16 g. (88 mmol) of 3,4-dimethyoxyphenylethylamine and 13.5 g. (88 mmol) of p-methoxystyrene oxide is heated with stirring under argon on a steam bath overnight. A sample is withdrawn from the reaction mixture and chromatographed on a silica column, eluting with benzene ethyl acetate to isolate the pure product in crystalline form. To the remainder of the reaction mixture is added 100 ml. of ethyl acetate-hexane (1:1) and seeded with the crystalline product, with stirring and chilling. Filtration furnishes the product N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-methoxyphenyl)ethylamine, m.p. 92° C.