Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH:8]1[C:21]2[CH:20](O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(O)(C(F)(F)F)=O>[CH:8]1[C:21]2[CH:20]([S:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: OC1c2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CSC1c2ccccc2Oc2ccccc21)C(=O)O
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A sample of 0.61 g of cysteine (5 mmole) was suspended in 100 ml of 1,2-dimethoxyethane and 2 ml of TFA. The suspension was stirred under nitrogen gas at room temperature until the solution became clear. To this clear solution was added 1 g of 9H-xanthen-9-ol (5.1 mmole) in one portion. The reaction mixture was stirred at room temperature for 30 minutes and was then neutralized to pH 7 by the addition of a saturated aqueous Na2CO3 solution. The mixture was then concentrated by rotary evaporation. The residue was diluted with 50 ml of water. The aqueous solution was treated with 10% aqueous citric acid solution to adjust the pH to 6. The mixture was stirred at room temperature for 1 hr. The resultant white solid was collected by filtration and was washed with 3×10 ml of water and 3×10 ml of ethyl acetate. The product was dried to yield 1.30 g of product.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1.[OH:19][CH2:20][CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[H-].[Na+]>>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][CH2:20][OH:19])[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ICCCc1cccc(OCc2ccccc2)c1
Reactant: OCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Product: OCCc1nccn1CCCc1cccc(OCc2ccccc2)c1
Yield: 78.9 %

Procedure:
Using benzyl 3-(3-iodopropyl)phenyl ether (3.53 g), 2-(2-hydroxyethyl)imidazole (1.46 g) and 65% oily sodium hydride (0.48 g), the same reaction as Reference Example 11-(iv) was carried out to yield the titled compound (2.66 g) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1cccc(OCCCCl)c1
Reaction time: 24 h
Yield: 95.1 %

Procedure:
Methyl 3-hydroxyphenylacetate (87 g, 0.52 mol) was dissolved in acetone (500 mL). 1-Bromo-3-chloropropane (55 mL, 0.56 mol) was added, followed by potassium carbonate (73 g, 0.53 mol) and acetone (100 mL). The reaction was heated at reflux. After 24 hours, more 1-bromo-3-chloropropane (5 mL, 50 mmol) was added and the reaction refluxed for a further 24 hours. The mixture was cooled, filtered and rotary evaporated. The product was purified by passage over a short column of silica gel (650 g: 135 mm diameter column) eluted with hexane, and 30% ethyl acetate in hexane, to afford methyl 3-(3-chloro-propoxy)-phenylacetate (120 g, 95%) as an oil. 1H NMR (CDCl3) δ 7.25 (1H, dd), 6.93-6.85 (3H, m), 4.16 (2H, t), 3.79 (2H, t), 3.73 (3H, s), 3.62 (2H, s), 2.28 (2H, m).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:12][C:13]([N:15]2[C@@H:23]3[C@@H:18]([C:19]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=4[CH2:21][CH2:22]3)[CH2:17][CH2:16]2)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].[ClH:32]>C1COCC1.C(O)C.O.C1COCC1.O>[ClH:32].[CH:7]1([CH2:12][CH2:13][N:15]2[C@@H:23]3[C@@H:18]([C:19]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=4[CH2:21][CH2:22]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1C(=O)CC1CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCC1
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
1.02 g (0.0269 mol) of lithium aluminum hydride were suspended in 30 ml of THF under argon. A solution of 6.5 g (0.0207 mol) of rac-cis-3-(cyclopentyl-acetyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole in 80 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 1 hour. 10 ml of THF/water 9:1, 2 ml of a 4N aqueous NaOH solution and 2 ml of water were cautiously added dropwise thereto in succession, whereupon the mixture was boiled under reflux for 15 minutes until a complete white precipitate had resulted. After filtration and concentration there was obtained an oil which was dissolved in 100 ml of ethanol. 5.1 ml (0.0245 mol) of 4.78N ethanolic HCl solution were added dropwise thereto, the mixture was stirred for 15 minutes and concentrated. The residue crystallized from 100 ml of hot ethyl acetate. There were obtained 5.87 g (86%) of rac-cis-3-(2-cyclopentyl-ethyl)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole hydrochloride as white crystals with m.p. 185°-187° (dec.).
Reaction SMILES: [Cl-].[Br:2][C:3]1[C:15]2[C:14]3[CH2:13][CH2:12][NH2+:11][CH2:10][C:9]=3[CH:8]=[N:7][C:6]=2[NH:5][N:4]=1.CCN(C(C)C)C(C)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Br:2][C:3]1[C:15]2[C:14]3[CH2:13][CH2:12][N:11]([C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:33])[CH2:10][C:9]=3[CH:8]=[N:7][C:6]=2[NH:5][N:4]=1
Reactant: Brc1n[nH]c2ncc3c(c12)CC[NH2+]C3
Reactant: O=C=Nc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Reaction time: 0.17 h
Yield: 293.1 %

Procedure:
To a solution of 1-bromo-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium chloride (0.16 g, 0.55 mmol) in dichloromethane (5 mL), Hunig's Base (0.59 mL, 3.3 mmol) was added and stirred under inert atmosphere. After 10 minutes, phenyl isocyanate (0.06 mL, 0.57 mmol) was added and the reaction was allowed to stir at room temperature for 2 hours. The mixture was diluted with dichloromethane (10 mL) and washed with water (2×5 mL), dried over anhydrous sodium sulfate, filtered and dried in vacuo. The resulting pale brown solid was purified by flash column chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product as light pink solid (0.6 g, 30%). M.p.=249-250° C., 400 MHz 1H NMR (DMSO-d6) δ: 10.64 (s, 1H), 9.66 (s, 1H), 8.82 (s, 1H), 8.25 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.2 (d, J=8.8 Hz, 2H), 7.07 (t, J=7.2 Hz, 1H), 6.95 (d, J=6.4 Hz, 1H), 4.25 (t, J=5.2 Hz, 2H), 3.24 (s, 2H), 2.96 (t, J=6 Hz, 2H), 2.2-2.14 (m, 2H); LCMS [M+H]: 350.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:24]([N:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(Cl)Cl>[C:24]([N:31]1[CH2:36][CH2:35][CH:34]([O:37][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OC2CCCCO2)CC1

Procedure:
With stirring, 8.16 ml (0.09 mol) of 3,4-dihydro-2H-pyran and 1.5 g (0.006 mol) of pyridinium-(toluene-4-sulfonate) are added to a solution of 12.08 g (0.06 mol) of N-BOC-4-hydroxypiperidine (cf. EP 0 278 621) in 300 ml of methylene chloride. The reaction mixture is stirred for 2.5 hours at room temperature, then washed with 2×50 ml of brine:water (1:1) mixture, dried over sodium sulfate and concentrated under vacuum, giving the title compound in the form of a colourless oil; Rf =0.58 (silica gel/ethyl acetate:hexane (2:1), which gradually solidifies in crystalline form at 0° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Cl:16].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[Cl:16]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(Cl)c(Oc2ccncc2Br)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccncc2Br)cc1F
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a cold (−10° C.) solution of 3-bromo-4-(2-chloro-5-fluorophenoxy)pyridine (1.98 g, 6.54 mmol) in conc. sulfuric acid (5 ml) was added nitric acid (0.55 ml, 8.69 mmol). The resultant mixture was stirred at the same temp for 20 minutes and was then allowed to warm to ambient temp for 30 min. The reaction mixture was treated with crushed ice, stirred, filtered, washed and dried to provide 3-bromo-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine, (2.08 g, 91% yield) as orange yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.62 (m, 2H), 7.81 (d, J=8 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H); MS (ESI) m/z: 348.9 (M+1H+).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]([CH3:35])([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:24][OH:25].C(OCC)C>C(Cl)Cl>[CH3:22][C:23]([CH3:35])([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:24]=[O:25]
Reactant: CC(C)(CO)COCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C=O)COCc1ccccc1

Procedure:
In a dry three-neck flask equipped with a mechanical stirrer and an addition funnel was placed 78.8 g (0.21 moles) of pyridinium dichromate, Aldrich Chemical, see Tetrahedron Lett., 399 (1979), ibid., 731, (1980) and 200 ml of dry CH2Cl2. The mixture was vigorously stirred and a solution of 26.8 g (0.138 mole) of 2,2-dimethyl-3-(phenylmethoxy)propanol, the product of Example 1a, in 50 ml of CH2Cl2 was added in one portion. The reaction was followed by gas liquid chromatography (GC) and required four days stirring at room temperature. The black brown reaction mixture was poured into 200 ml ethyl ether and the mixture was filtered through a dry silica gel column to obtain a colorless solution. Removal of solvent gave a residue which was distilled through a vigreux column to obtain the title compound, a colorless liquid, bp 72°-75°/0.02 mmHg.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[H][H]>[Pd].CCO>[CH2:6]([O:5][P:4]([C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccc(N)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A mixture of diethyl(4-nitrophenyl)phosphonate (150 mg, 0.58 mmol), EtOH (40 ml) and 10% Pd/C (30 mg) was hydrogenated under 50 psi of hydrogen pressure at 40° C. for 6 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate concentrated in vacuo to afford 130 mg of desired diethyl(4-aminophenyl)phosphonate (yield: 98%), which was used directly in further chemistries without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([CH:13]=[N:14][OH:15])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[Cl:26]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([Cl:26])=[N:14][OH:15])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(C=NO)c(I)cc1OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(Cl)=NO)c(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-benzyloxy-2-iodo-5-methoxy-benzaldehyde oxime (reference example 2-1) (12.8 g) and N,N-dimethylformamide (110 mL) was added N-chlorosuccinimide (4.9 g) at room temperature. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the mixture under ice-bath cooling. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzimidoylchloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]1([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: BrCCCCCc1ccccc1
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2O)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(CN(CCc2ccccc2OCCCCCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
1.78 g (4.63 mmol) of methyl 4-{[(tert-butoxycarbonyl)-(2-hydroxyphenethyl)-amino]methyl}benzoate from Ex. V.2, 1.05 g (4.63 mmol) of 5-phenyl-1-bromopentane and 0.77 g (5.55 mmol) of potassium carbonate in 15 ml of acetonitrile are heated at reflux for 18 hours. The reaction mixture is poured into water, extracted with ethyl acetate and dried over magnesium sulphate and the solvent is distilled off under reduced pressure. A solid is obtained which is reacted further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1.C(OCC)C>C(Cl)(Cl)Cl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: O=C1CCC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51929.6 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.14 g) obtained in Example 1d) in chloroform (10 ml) was added succinic anhydride (0.06 mg), and the mixture was stirred at room temperature for 3 days. Diethyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound as a pale-brown powder (0.12 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])C=O.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13]>>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Br:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(Cl)c(Br)c1
Product: COC(OC)c1ccc(Cl)c(Br)c1

Procedure:
A solution of 6.8 g of 3-bromo-4-chlorobenzaldehyde in 17 ml of trimethyl orthoformate was stirred with 6.9 g of Amberlyst 15 resin at room temperature overnight. The mixture was filtered and the filtrate was evaporated to give 4.5 g of 3-bromo-4-chlorobenzaldehyde dimethyl acetal as a colourless oil, mass spectrum (EI) m/e 266 [M+].
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:50])[CH2:33][NH:34][C:35]([CH2:37][NH:38][CH2:39][C:40]([NH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41])=[O:36])=[CH:28][CH:27]=1.CN1CCOCC1>CN(C=O)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:50])[CH2:33][NH:34][C:35](=[O:36])[CH2:37][N:38]2[CH2:39][C:40](=[O:41])[NH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44]2=[O:45])=[CH:28][CH:27]=1
Reactant: CC(C)C(NC(=O)CNCC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C1NC(=O)CN(CC(=O)NCC(=O)c2ccc(Br)cc2)C1=O
Yield: 58.5 %

Procedure:
HATU (3.70 g, 9.7 mmol) was added to a solution of 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-amino)-acetylamino]-3-methyl-butyric acid (2.78 g, 6.5 mmol), and 4-methylmorpholine (3.57 mL, 32.5 mmol) in DMF (100 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (150 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2×50 mL), saturated sodium bicarbonate (50 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield N-[2-(4-bromo-phenyl)-2-oxo-ethyl]-2-(3-isopropyl-2,5-dioxo-piperazin-1-yl)-acetamide (1.56 g, 3.8 mmol, 60%). C17H20BrN3O4 calculated 409.1 observed [M+1]+ 410.1; rt=2.00 min.
Reaction SMILES: [C:1](=[O:5])(OC)[NH2:2].[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]>CCCCCCCCCCN(CCCCCCCCCC)C.CO>[NH2:6][C:1]([NH2:2])=[O:5].[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]
Reactant: COC(N)=O
Agent: CCCCCCCCCCN(C)CCCCCCCCCC
Agent: O=C1CCCN1
Solvent: CO
Product: NC(N)=O
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
A mixture containing 50 g (0.67 mole) of methyl carbamate, 272 g (3.20 moles) of pyrrolidone, 2.4 g of TK-1 tin catalyst, and 2.4 g of DAMA-10 was heated at 140° C. under 40-50 mm Hg pressure for 3.5 hours. The methanol produced by the reaction was collected in a dry ice-acetone trap during the reaction. The reaction mixture was then analyzed with GLC (internal standard method). The results indicated that the yield of pyrrolidone urea was 85% based on methyl carbamate charged, and 10% of the starting methyl carbamate still remained in the reaction mixture. The reaction mixture was then distilled under reduced pressure to remove excess pyrrolidone and the remaining methyl carbamate. The residue was stirred with 200 ml of toluene for 15 minutes and filtered. The collected solid was washed with toluene and air-dried to afford 46 g (54%) of the desired product; mp 142°-144° C. (lit. mp 142°-143° C.); IR (cm−1): 3360, 1710, 1660, 1590, 1370, 1250; 1H-NMR (CDCl3): δ8.2 (s, 1 H), 5.9 (s, 1 H), 3.9 (t, 2 H), 2.6 (t, 2 H), 2.1 (t, 2 H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1CCCC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Cl)c(C[C@H](CC=O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c(Cl)c1
Yield: 49 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)-2-(4-methoxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (6.65 g, 14.87 mmol), tetrahydrofuran (140 mL) and water (45 mL) with 2.5% osmium tetroxide in t-butanol (378 mL, 1.487 mmol). Add sodium periodate (9.55 g, 44.63 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 3.35 g (49%) of desired product. MS (m/z): 451 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccno3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]([CH:4]([CH3:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].[ClH:14]>[Pd].CO>[ClH:14].[NH2:1][CH:4]([CH3:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(N=[N+]=[N-])C(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.7 %

Procedure:
Palladium on carbon (1.069 g, 1.005 mmol) was added to the solution of 2-azido-1-phenyl-1-propanone (1.76 g, 10.05 mmol) and hydrochloric acid (6.69 mL, 80 mmol) in CH3OH (50 mL) under nitrogen, and the reaction mixture was stirred under hydrogen overnight at 25° C. The mixture was filtered, washing with CH2Cl2 (50 mL) and CH3OH (100 mL), and concentrated. Water (100 mL) was added, and the resulting mixture was lyophilized to yield an HCl salt of the title compound (1.9 g) as a brown solid. LC-MS (ES) m/z=150 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][CH:17]=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:17]1[S:16][C:14]2[C:13]([N:18]=1)=[CH:12][CH:11]=[C:10]([C:7]1([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]1)[N:15]=2)[C:24]#[N:25]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: c1ccc(C2(c3ccc4ncsc4n3)CC2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 190 °C

Procedure:
A mixture of 5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (48.3 mg, 191 μmol), 4-bromo-3-methylbenzonitrile (45.0 mg, 230 μmol), PdCl2(AmPhos)2 (6.78 mg, 9.57 μmol), and cesium carbonate (187 mg, 574 μmol) in DMF (1.6 mL) was heated (microwave) under argon at 190° C. for 40 min. The reaction mixture was then partitioned between EtOAc (40 mL) and water (15 mL). The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/hexanes) furnished 3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile as a light-yellow solid. MS (ESI) m/z: Calculated: 367.1; Observed: 368.1 (M++1).