Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([CH3:21])[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.[F:22][C:23]([F:35])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH2:33])=[CH:30][N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:35][C:23]([F:22])([CH3:34])[CH2:24][O:25][C:26]1[C:31]([CH2:32][NH:33][C:11]2[N:10]=[C:9]([NH:8][C@H:4]3[CH2:5][CH2:6][CH2:7][C@:2]([OH:1])([CH3:21])[CH2:3]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:30][N:29]=[CH:28][N:27]=1
Reactant: CC(F)(F)COc1ncncc1CN
Reactant: C[C@@]1(O)CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@H]2CCC[C@@](C)(O)C2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A mixture of 4-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (80 mg, crude), (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg 0.246 mmol), and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1 h. The reaction was cooled to room temperature and the mixture was concentrated. The residue was purified by standard methods to give the desired product (26.1 mg, 0.060 mmol, 24% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.69 (s, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 4.73-4.50 (m, 4H), 4.34-4.23 (m, 1H), 1.92-1.08 (m, 14H). MS (ESI) m/z 434.2 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: C#CCCO
Reactant: Cc1ccccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Product: Cc1ccccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 419 (0.40 mmol) and but-3-yn-1-ol (0.40 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 0:100 as the eluent to afford the title compound as light yellow foam.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:22])[S:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)=[O:5])C.[NH2:23][CH2:24][C:25]([O-:27])=[O:26].[Na+]>COCCO>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[C:7](=[O:22])[S:8]2)=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1ccc2c(O)c(C(=O)OCC)c(=O)sc2c1
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCCCOc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc2c1
Yield: 78.7 %

Procedure:
A mixture of 7-butoxy-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (140 mg, 0.434 mmol) and sodium glycinate (420 mg, 4.34 mmol) in 2-methoxyethanol (10 mL) was refluxed overnight (16 h). Reaction mixture was concentrated, and crude residue was dissolved in water, acidified to pH 3 using 1 N HCl to precipitate the product. The precipitate was collected by filtration and dried to provide [(7-butoxy-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (120 mg, 80%). MS ESI(−) m/e: 350.21 (M−1).
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:16]1[C:17]([C:24]([O:26][CH3:27])=[O:25])=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:4]([O:3]/[CH:1]=[CH:2]/[C:16]1[C:17]([C:24]([O:26][CH3:27])=[O:25])=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=1)[CH3:5]
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1nc(SC)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCO/C=C/c1cnc(SC)nc1C(=O)OC
Yield: 62.5 %

Procedure:
A solution of (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 29, 4.34 g, 21.91 mmol), methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (Preparation 30, 3.81 g, 14.48 mmol) and Pd(dppf)Cl2.DCM (505 mg, 0.618 mmol) was dissolved in THF (45 mL) and 2M sodium carbonate in water (15 mL) and heated to 65° C. for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% EtOAc in cyclohexane to give the title compound (2.30 g, 63%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:18](=O)[C:17]3[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:23]>P(Cl)(Cl)(Cl)=O>[Cl:23][C:18]1[C:17]2[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: COc1cccc2c(=O)c(C(=O)C3CCCCC3)c[nH]c12
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(Cl)c(C(=O)C3CCCCC3)cnc12
Yield: 90 %

Procedure:
3-Cyclohexylcarbonyl-8-methoxy-4(1H)-quinolone (5.8 g, 0.02 mol) was heated under reflux in a mixture of chloroform (100 ml) and phosphorus oxychloride (15 ml) for 2.5 hours. The reaction mixture was, partitioned between chloroform, ice and sodium hydrogen carbonate solution (100 g in 1.5 l) and the organic solution was washed with sodium hydrogen carbonate solution and brine. The chloroform solution was dried and evaporated to give 4-chloro-3-cyclohexylcarbonyl-8-methoxy-quinoline (5.5 g, 90%) as an oil.
Reaction SMILES: [N:1]1([C:6]2([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[N:1]1([C:6]2([C:9](=[N:19][OH:20])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 82.6 %

Procedure:
24.8 g (0.1 mol) of 4-chlorophenyl 1-(1, 2, 4-triazol-1-yl)-cyclopropyl ketone were refluxed for 4 hours with 10.4 g of hydroxylamine hydrochloride, 10.6 g of sodium acetate in 200 ml of ethanol and 100 ml of water, the solvent was removed in vacuo, and the crystal slurry obtained was triturated with water. 21.7 g (83%) of the title compound were obtained as colorless crystals of melting point 186°-218° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.C1(C)C=CC=CC=1.[C@:39]12([CH2:49][S:50]([OH:53])(=[O:52])=[O:51])[C:46]([CH3:48])([CH3:47])[CH:43]([CH2:44][CH2:45]1)[CH2:42][C:40]2=[O:41]>O>[CH3:47][C:46]1([CH3:48])[C@@H:43]2[CH2:44][CH2:45][C@@:39]1([CH2:49][S:50]([OH:53])(=[O:52])=[O:51])[C:40](=[O:41])[CH2:42]2.[CH3:23][N:20]1[CH2:19][CH2:18][N:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: CN1CCN([C@@H]2CCC[C@H](NC(=O)OCc3ccccc3)C2)CC1
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of (cis)-benzyl-3-(4-methylpiperazin-1-yl)cyclohexylcarbamate (2.0 g, 6.04 mmol, 1.0 eq.), isopropyl acetate (12 ml) and toluene (2.5 ml) was heated for 15 minutes at 65° C. (1S)-(+) Camphorsulfonic acid (700 mg, 3.02 mmol, 0.5 eq.) and water (0.1 ml) were added at RT and the mixture was heated for 3 hours at 75° C. Stirring was then carried out for 3 hours at RT and the mixture was subsequently allowed to stand overnight at RT for crystallization. The resulting precipitate was filtered off and washed with isopropyl acetate (20 ml). For purification, the desired product was recrystallized from ethanol/isopropyl acetate. Yield: 14% (500 mg, 0.888 mmol)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH3:10])=[O:4].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH2:10][Br:12])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1scc(Br)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1scc(Br)c1CBr
Yield: 56.7 %

Procedure:
4-Bromo-3-methyl-thiophene-2-carboxylic acid methyl ester (3.0 g, 12.8 mmol), example 31-a, N-bromosuccinimide (2.33 g, 13.1 mmol), and benzoyl peroxide (310 mg, 1.28 mmol) were suspended in 32 mL of benzene and heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-40% ethyl acetate in hexanes to produce 2.28 g of a yellow solid. 1H NMR (CDCl3, 200 MHz): δ=7.48 (s, 1H), 4.91 (s, 2H), and 3.94 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.NC1C=CC=CC=1NC(=O)C1C=CC(CN2CC3C(=CC(OC)=C(OC)C=3Br)C2=O)=CC=1.B(O)(O)[C:62]1[CH:67]=[N:66][CH:65]=[N:64][CH:63]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:62]3[CH:63]=[N:64][CH:65]=[N:66][CH:67]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Agent: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3cncnc3)C2=O)cc1
Yield: 68 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and pyrimidin-5-yl-5-boronic acid instead of phenyl boronic acid to obtain the title compound (68%).
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:18]3)=[CH:9][CH:8]=1)=[O:4].[OH-]>O1CCCC1.CO>[C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:18]3)=[CH:9][CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)COc1ccc(-c2c3ccc(OCC(=O)OC)cc3cc3sc4ccccc4c23)cc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2c3ccc(OCC(=O)O)cc3cc3sc4ccccc4c23)cc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of [11-(4-methoxycarbonylmethoxy-phenyl)-benzo [b]naphtho[2,3-d]thiophen-8-yloxy]-acetic acid, methyl ester (0.268 g, 0.551 mmol) in tetrahydrofuran (8 mL) and methanol (5 mL) was added an aqueous solution of potassuim hydroxide (1 N, 2.2 mL, 2.2 mmol) dropwise at room temperature. After stirring 2 hours an addition of potassuim hydroxide (1 N, 1 mL, 1 mmol) was introduced. After stirring another 14 hours the solvents were removed and the residue was disolved in water (50 mL) and was acidified with 10% aqueous hydrochloric acid, and the organics were extracted with diethyl ether. The solvent was removed and chased with benzene and petroleum ether and dried at 53° C. to give the title compound as a white solid (0.18 g, 43%): mp 245-246° C.; NMR (DMSO-d6); δ13.08 (broad s, 2 H), 8.44 (s, 1 H), 7.93 (d, J=8 Hz, 1 H), 7.45 - 7.35 (m, 3 H), 7.31 (d, J=9 Hz, 2 H), 7.22 (d, J=9 Hz, 2 H), 7.17 (dd, J=3,9 Hz, 1 H), 7.10 (ddd, J=9, 9, 1 Hz, 1 H), 6.67 (d, J=8 Hz, 1 H), 4.84 (d, J=7 Hz, 4 H); MS (EI): [M+] 458; Anal. Calc. for C26 H18O6S: C, 68.11, H, 3.96, N, 0.00. Found: C, 66.41, H, 3.95, N, 0.05.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14](OCC)=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[NH4+:23].[OH-]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([NH2:23])=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1
Reactant: CCOC(=O)Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Yield: 66 %

Procedure:
A solution of ethyl 2-(3-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetate (3 g, 9.58 mmol) in conc. NH4OH (40 mL) was heated at reflux for 2 h. After removal of the solvent, the residue was purified by column chromatography to afford 2-(3-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide (1.8 mg, 66% yield). 1H NMR (300 MHz, DMSO-d6): 7.48-7.42 (m, 4H), 7.30 (s, 1H), 6.91 (s, 1H), 5.77 (s, 1H), 5.73-5.72 (m, 2H), 4.44 (s, 2H). MS (ESI) m/z: 285 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=3[S:9][C:5]=2[C:4]([NH2:15])=[N:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1>[CH3:1][N:2]1[C:6]2[C:7]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=3[S:9][C:5]=2[C:4]([NH:15][C:16](=[O:18])[CH3:17])=[N:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(c1)sc1c(N)nn(C)c12
Solvent: C1CCOC1
Product: CC(=O)Nc1nn(C)c2c1sc1cc(C)ccc12
Temperature: 20 °C

Procedure:
A solution of 0.1 mole of 1,6-dimethyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-amine and 30.0 g. of acetic anhydride in 180 ml. of tetrahydrofuran was heated under reflux for 1 hour. The reaction mixture was then cooled to 20° C. and the precipitate which formed was collected by filtration. Recrystallization from N,N-dimethyl formamide/water gave N-(1,6-dimethyl-1H-(1)benzothieno-[3,2-c]pyrazol-3-yl)acetamide, m.p. 253°-255° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[O:13][C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[O:16][C:17]=2[C:18]([NH2:20])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[C:6]1([C:12]2[O:13][C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[O:16][C:17]=2[C:18]#[N:20])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C1=C(c2ccccc2)Oc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC1=C(c2ccccc2)Oc2ccccc2O1

Procedure:
3.59 ml (30 mmol) of phosphorus oxychloride are slowly added to a solution of 1.52 g (6 mmol) of the amide obtained in Step A in 15 ml of anhydrous pyridine. The medium is then heated at reflux for 2 hours under argon and then allowed to cool. After evaporation of the solvent in vacuo, the residue obtained is diluted with dichloromethane; the organic phase is then hydrolysed with a saturated solution of sodium hydrogen carbonate. The aqueous phase is extracted with dichloromethane; the organic phase is then dried over magnesium sulphate. The solvent is then evaporated under reduced pressure. Chromatography on a silica column (eluant:AcOEt/PE:40/60) allows the title nitrile to be obtained in the form of a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].[CH3:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21](Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[CH3:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][N:1]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: [N-]=[N+]=NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCc1ncc(-c2ccc([N+](=O)[O-])cc2)o1
Temperature: 85 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
To a mixture of crude 2-azido-1-(4-nitrophenyl)-ethanone (8.2 mmol) and 1,2,-dichloroethane (80 ml) was added 3-chlorocarbonyl-propionic acid methyl ester (1.1 ml, 9.0 mmol) and triphenylphosphine (2.4 g, 9.0 mmol). The mixture was stirred at 85° C. for 12 hours. After cooling to room temperature, the mixture was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4 followed by 1:1) to give 3-[5-(4-nitro-phenyl)-oxazol-2-yl]-propionic acid methyl ester (520 mg, 23% yield for 2 steps). 1H NMR (acetone-d6) δ 2.92 (t, 2H, J=7.1 Hz, CH2), 3.19 (t, 2H, J=7.1 Hz, CH2), 3.68 (s, 3H, CH3), 7.74 (s, 1H, Ar), 7.98 (d, 2H, J=9.0 Hz, Ar), 8.34 (d, 2H, J=9.0 Hz, Ar).
Reaction SMILES: [OH:1][C:2]1[C@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1C(OCC)=O.C(O)C.O.C(=O)=O.[Cl-].[Na+]>C(OCC)(=O)C>[CH3:9][CH:8]([CH3:10])[CH2:7][C@@H:6]1[NH:5][C:4](=[O:11])[CH2:3][C:2]1=[O:1]
Reactant: CCOC(=O)C1=C(O)[C@H](CC(C)C)NC1=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)C[C@@H]1NC(=O)CC1=O
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
Approximately 150 mmol of (S)-2,5-dihydro-4-hydroxy-5-(2-methylpropyl)-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester is added as rapidly as possible to 1 L of boiling ethanol-water (1:1, pot temperature 85-87° C.) in a 3 L beaker with vigorous stirring. Complete solution occurs rapidly and vigorous effervescence is observed. Refluxing is continued 20 minutes until the CO2 evolution ceases. The beaker is plunged into an ice bath to rapidly cool the solution, 120 g of sodium chloride and 500 ml of ethyl acetate are added and the organic layer is separated. The aqueous layer is extracted with 2×500 ml of ethyl acetate and the organic fractions combined, dried over magnesium sulfate and evaporated to a solid. The solid is slurried in 200 ml of diethyl ether, diluted with 200 ml of ethyl acetate, and stirred approximately 15 minutes until most of the solid dissolves. The insoluble material is filtered off and the filtrate evaporated to afford 15.9 g of (S)-5-(2-methylpropyl)-2,4-pyrrolidinedione as an off-white solid; mp 94°-95° C. [α]D23 =-80° (C=1%, chloroform). TLC (ethyl acetate, silica gel, ultra violet (uv)) Rf =0.4.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[OH:15])([O-])=O>[Pd].[Rh].O>[NH2:3][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[OH:15]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Rh]
Solvent: O
Product: Nc1ccc(O)c(N)c1
Temperature: 116 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
Onto the bottom of a cylindrical reactor a chamber is placed which is made of a 100μ-thick foil having the working surface area of 50 cm2. The foil is manufactured of an alloy consisting of 95% by mass of palladium and 5% by mass of rhodium. Hydrogen is continuously fed inside the chamber under the pressure 2.5 atm at the rate of 10 ml/min. Outside the chamber in the reactor there are placed 22 g of 2,4-dinitrophenol, whereafter 250 ml of distilled water are added thereto. The reactor is heated to the temperature of 116° C., pressure inside the reactor is increased to 4 atm; under these conditions the process of hydrogenation is conducted under stirring for 3 hours. Then the reactor is cooled and the precipitated crystals are filtered-off to give 15.2 g of 2,4-diaminophenol. The product is recrystallized from acetone to give 10.3 g of 2,4-diaminophenol with the melting point of 80° C. The yield of 2,4-diaminophenol is 71.6% of the theoretical (i.e. as calculated for the initial 2,4-dinitrophenol).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[N:15]([CH2:22][CH2:23][CH:24]2[CH2:26][O:25]2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.O>[Cl:13][C:14]1[N:15]([CH2:22][CH2:23][CH:24]([OH:25])[CH2:26][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(OC(F)(F)F)cc2)c(Cl)n1
Temperature: 81 °C
Reaction time: 12 h
Yield: 67.2 %

Procedure:
4-Trifluoromethoxyphenol (0.375 mL, 2.89 mmol) was added to a mixture of epoxide 129 (250 mg, 1.15 mmol) and powdered K2CO3 (558 mg, 4.04 mmol) in anhydrous 2-butanone (3 mL) under N2, and the mixture was stirred at 81° C. for 12 h. The resulting cooled mixture was diluted with water (50 mL) and extracted with CH2Cl2 (4×50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-25% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 25-33% EtOAc/petroleum ether gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-[4-(trifluoromethoxy)phenoxy]-2-butanol (130) (306 mg, 67%) as a pale yellow oil; 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.16 (br dd, J=9.1, 0.8 Hz, 2H), 6.88 (dt, J=9.2, 3.0 Hz, 2H), 4.37-4.24 (m, 2H), 4.02-3.93 (m, 2H), 3.86 (dd, J=10.0, 7.8 Hz, 1H), 2.47 (dd, J=4.2, 1.1 Hz, 1H), 2.13-1.98 (m, 2H); HRESIMS calcd for C14H14ClF3N3O3 m/z [M+H]+ 398.0540, 396.0569. found 398.0538, 396.0567.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:10]([C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:12])[C@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Product: C[C@H]1CCCN(C(=O)c2ccccc2Oc2ccccc2)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 2-phenoxybenzoic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 470, [M+1]+.