Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([O:20]C)=O)[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[K].[NH2:23][OH:24].C(O)(=O)C>CO>[CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([NH:23][OH:24])=[O:20])[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCS(=O)(=O)N1CCc2nc(C(=O)OC)ccc2C1
Agent: [K]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)N1CCc2nc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a microwave vial containing methyl 6-(butylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76 mmol, 1.76 M in MeOH). The solution was shaken at rt for 1 h, then acetic acid (0.102 mL, 1.8 mmol) was added to quench excess base. The solvent was then concentrated. To the resulting residue was added DMSO (1.2 mL) and after filtration, the solution underwent purification via prep-HPLC to give 6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide (13.3 mg, 28.3%). LC-MS: (FA) ES+ 314; 1H NMR (Methanol-d4, 300 MHz) δ 7.97 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.9 Hz, 1 H), 4.59 (s, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.13 (m, 4H), 1.77 (m, 2H), 1.47 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]O)[C:6]=2[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:33]I.N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][I:33])[C:6]=2[CH:13]=1
Reactant: II
Reactant: OCCc1coc2ccc(Cl)cc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2occ(CCI)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(5-chloro-1-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid; Yield: 1.2 g (80%); 306 (M+H).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[S-:26][C:27]#[N:28].[Ba+2].[S-]C#N>CC(C)=O.O>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][S:26][C:27]#[N:28])[CH2:12]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: N#C[S-]
Agent: [Ba+2]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSC#N)[C@@]3(C)CC(=O)[C@@H]12
Yield: 96.4 %

Procedure:
A solution of 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (0.75 g.) in acetone (50 ml.) was treated with a solution of barium thiocyanate (2.6 g.) in water (10 ml.). The resulting mixture was refluxed for 4 hr., cooled and then partitioned between water and ether. The organic layer was washed with water, dried (Na2SO4) and evaporated. The residue (720 mg.) was purified by preparative t.l.c. (EtOAc) to afford title compound (685 mg.) as a white foam, [α]D + 67°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=1.[Br:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Br:28][C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:9]=3)[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example A.39) (0.85 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.19 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.97 g, 80%). MS (EI) 544.1 [(M)+]; mp 122° C.
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]Cl)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[C:14]#[N:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCN1CCC(Cc2ccccc2)CC1
Reactant: N#CCc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1cccc2ccccc12

Procedure:
2 g of sodium amide are added in small portions to a solution of naphth-1-ylacetonitrile in 150 ml of anhydrous ether and the mixture is refluxed for 5 hours. 11.8 g of 2-(4-benzylpiperidino)chloroethane are then added and the mixture is refluxed again for 3.5 hours. 200 ml of water are added and the organic phase is decanted and extracted with 300 ml of 10% hydrochloric acid. The aqueous phase is washed with ether, neutralized with 30% sodium hydroxide and extracted with ether. The organic phase is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is then evaporated off to give 16.4 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[C:25]([OH:27])=O)[N:19]([CH3:28])[C:18]=4[CH:29]=3)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1.C([N:35](CC)CC)C.ClC(OCC)=O.N>CC(C)=O>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[C:25]([NH2:35])=[O:27])[N:19]([CH3:28])[C:18]=4[CH:29]=3)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CC(C)=O
Product: Cn1c(C2CC2C(N)=O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (150 mg) and triethylamine (0.139 ml) in acetone (2 ml) was added ethyl chloroformate (0.096 ml) at 0° C. The mixture was stirred at 0° C. for 1 h and then NH3 solution (0.101 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/EtOAc) to give the title compound (125 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH2:12][CH2:11][NH2:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCCN)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3′-Hydroxyacetophenone (1.0 g) and ethylenediamine (1.47 ml) were dissolved in methanol (10 ml), and the solution was stirred at room temperature for 16 hours. The reaction mixture was added with sodium borohydride (277.9 mg), the mixture was stirred at room temperature for 5 hours, and then was added with 1 N hydrochloric acid, and the solvent was evaporated. The resulting residue was added with potassium carbonate and distilled water, and thereby made alkaline, then the mixture was extracted with a 10:1 mixed solvent of chloroform and ethanol, and the organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1 to 5:1:0.1) to obtain the title compound (59.1 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([C:16]2[CH2:17][CH2:18][O:19][CH2:20][CH:21]=2)=[CH:14][N:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[O:19]1[CH2:20][CH:21]=[C:16]([C:15]2[C:14]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[N:13][CH:12]=[N:11][CH:10]=2)[CH2:17][CH2:18]1
Reactant: Clc1ncncc1C1=CCOCC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncncc2C2=CCOCC2)cc1
Temperature: 100 °C

Procedure:
To a 150 mL sealable tube was added 4-aminophenol (388 mg, 3.56 mmol), 4-chloro-5-(3,6-dihydro-2H-pyran-4-yl)pyrimidine (700 mg, 3.56 mmol), and cesium carbonate (1218 mg, 3.74 mmol) with DMSO (23.700 ml). The vessel was sealed and heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water before extracting with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to a dark brown oil that was used without purification. MS (ESI, pos. ion) m/z: 270.0 (M+1).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CO>[C:8]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:12][N:13]([CH3:15])[CH3:14])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CN(C)C=C(C#N)c1ccccc1
Reaction time: 24 h
Yield: 77.9 %

Procedure:
A stirred solution of 5.1 grams (0.044 mole) of benzyl cyanide and 8.7 grams (0.065 mole) of N,N-dimethylformamide dimethyl acetal in 150 mL of methanol was heated at reflux for about 20 hours. After this time gas chromatographic analysis of the reaction mixture indicated that the reaction was not complete. An additional 3.0 mL of the intermediate acetal (total--0.088 mole) was added, and the heating at reflux was continued an additional 24 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was triturated with 25% methylene chloride in petroleum ether, yielding 5.9 grams of 1-cyano-1-phenyl-2-(N,N-dimethylamino)ethene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[CH3:28][NH:29][CH2:30][CH:31]=[C:32]([F:43])[C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:29]([CH3:28])[CH2:30][CH:31]=[C:32]([F:43])[C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38]
Reactant: CNCC=C(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Solvent: CN1CCCC1=O
Product: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 1 h
Yield: 151.6 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one and 2.21 g of methyl-(3,4,4,5,5,6,6,6-octafluoro-hex-2-enyl)-amine are dissolved in 20 ml of N-methylpyrrolidone and stirred for 1 hour at a bath temperature of 80° C. After the reaction solution is cooled to room temperature, the batch is added to saturated common salt solution, extracted with diethyl ether, dried and concentrated by evaporation in a vacuum. 1.69 g of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(3,4,4,5,5,6,6,6-octafluoro-hex-2-enyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without purification in the next stage.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.Cl[CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:19]([O:18][CH2:17][N:5]1[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=[C:4]1[Br:3])[CH2:20][CH2:21][CH3:22]
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Reactant: CCCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOCn1c(Br)nc(C)c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of 293 milligrams (mg) (1.22 mM) of sodium hydride in 30 ml of anhydrous tetrahydrofuran was added, in portions, 3 g (1.22 mM) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate. The resulting suspension was cooled to 0° C. and 1.5 g (1.22 mM) of chloromethyl-n-butyl ether was added dropwise. The reaction mixture was stirred overnight at room temperature. The precipitated sodium chloride was removed by filtration and concentration of the filtrate in vacuo gave 3.6 g (89%) of the desired product, isopropyl N-n-butoxymethyl-2-bromo-4-methyl-5-imidazolecarboxylate as a golden oil (89% yield).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH3:35])[C@H:10]([NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]#[C:29][C@@H:30]3[CH2:32][C@H:31]3[CH2:33][OH:34])[CH:24]=2)[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:8][C:9]([CH3:36])([CH3:35])[C@H:10]([NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]#[C:29][C@@H:30]3[CH2:32][C@H:31]3[CH2:33][OH:34])[CH:24]=2)[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1)C(C)(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirring solution of (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (64) in methanol (10 mL) was added 4N HCl in dioxane (10 mL) and the reaction mixture was stirred at rt for 2 hr, then at 4° C. overnight. The mixture was concentrated under reduced pressure to give a residue, which was partitioned between water and MTBE. The aqueous layer was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.5, 1.2 g, 3.0 mmol, 79%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=C1N=C(N[C@H]2CCCC[C@@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@H]2CCCC[C@@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (823 mg) in 2-propanol (15 mL) were added 4-{[(1S,2S)-2-hydroxycyclohexyl]amino}thiazol-2(5H)-one (780 mg) and piperidinium acetate (360 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/heptane to give the title compound (645 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH2:23][OH:24])[C:15]1=[O:25].N1C=CC=CC=1>ClCCl>[C:1]([O:24][CH2:23][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH2:13][CH2:12][CH2:11][Cl:10])[C:15]1=[O:25])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: O=c1n(CO)c2ccccc2n1CCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCC(=O)OCn1c(=O)n(CCCCl)c2ccccc21
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Heptanoyl chloride (0.64 mL, 4.15 mmol) was added dropwise at 0° C. to 1-(3-chloropropyl)-3-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-one (1.00 g, 4.15 mmol) and pyridine (0.50 mL, 6.23 mmol) in dichloromethane (20 mL) and then allowed to warm to room temperature. The mixture was washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (30% ethyl acetate/hexanes) to give product as an oil (1.35 g, 92%); NMR (DMSO-d6); δ0.80 (t, J=6.8 Hz, 3H); 1.15-1.19 (m, 6H); 1.46-1.49 (m, 2H); 2.08-2.12 (m, 2H); 2.30 (t, J=7.2 Hz, 2H); 3.67 (t, J=6.4 Hz, 2H); 3.97 (t, J=6.8 Hz, 2H); 5.88 (s, 2H); 7.10-7.16 (m, 2H); 7.24-7.29 (m, 2H); MS for C18H25ClN2O3 m/z 353 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=1>CC#N>[Cl:9][C:10]1[C:15]([Cl:1])=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
N-chloro-succinimide (NCS, 79.45 g, 0.6 mol) was added to a solution of compound 7 (25.8 g, 0.12 mol) in dry CH3CN (300 mL). The resulting suspension was heated at reflux for 2 hours and then cooled to room temperature. After washing with 10% aqueous NaOH (2×150 mL), then water (2×200 mL), the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid. This solid was recrystallized from EtOH to give 28.7 g (95%) of compound 8 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][O:17]C(=O)CC)[CH2:10][O:11][C:12](=[O:15])[CH2:13][CH3:14].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:22])([CH2:10][O:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:16][OH:17]
Reactant: CCC(=O)OCC(O)(COC(=O)CC)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CCC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Yield: 62.8 %

Procedure:
A 200 ml reaction vessel was charged with 3 g of 2-(2,4-difluorophenyl)-1,3-dipropionyloxy-2-propanol, 200 mg of Lipase D made by Amano Pharmaceutical Co., Ltd. (derived from Rhizpus delemer, Enzyme No. 6), 100 ml of 50 mM acetate buffer (pH 5) and 10 ml of cyclohexane. The resulting mixture was stirred at 30° C. to react for 18 hours. After the reaction liquid was extracted three times with 50 ml of ethylacetate, the organic layers were combined and the combined organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed trader reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 1.55 g of oily (R)-2-(2,4-difluorophenyl)-3-propionyloxy-1,2-propanediol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 16.7 minutes ((R)-form) and 13.5 minutes ((S)-form)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Cl:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:14])([F:15])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2
Reactant: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a solution of 6-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (31 mg, 0.12 mmol) in concentrated H2SO4 (0.3 mL) at 0° C. was added KNO3 (14 mg, 0.14 1 mmol, Baker). The mixture was stirred at 0° C. for 0.5 h and then at room temperature for 20 h and it was poured into ice water (2 g). The precipitate was collected by filtration, giving 31 mg of crude title compound. The sample was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl to give a yellow precipitate which was collected by filtration and then dried in air at 50° C. for 4 h to give the title compound (29 mg, 80%) as a yellow powder. Crystallization from DMSO/H2O gave pure compound (18 mg) as yellow microcrystals. mp: 342°-5° C., IR (KBr, cm-1): 3394, 3301, 3248, 3209, 1761, 1701, 1628, 1542. 1H NMR (DMSO-d6): δ7.618 (s, 1H), 12.351 (s, 1H), 12.552 (s, 1H). HRMS: calcd for C9H3ClF3N3O4 (M+) m/z: 308.9763, found: 308.9759.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of 4-trifluoromethyl-2-nitrophenol(1.0 g, 4.8 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol(150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(708 mg, 83%). 1H NMR (CD3OD): δ 6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])(=[O:19])[CH3:18]
Reactant: COc1ccccc1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(C)=O
Temperature: 2.5 °C
Reaction time: 0.3 h

Procedure:
Ortho anisidine (0.67 moles, 82 g.) was taken in a 1 L round bottom flask equipped with a liquid addition funnel and a guard tube; triethylamine (1.0 mole, 100 g) was added to it in one lot. Above mixture was cooled to 0-5° C. and acetyl chloride was added drop-wise maintaining temperature below 10° C. After addition of acetyl chloride cooling was removed and the reaction mixture was stirred at 25-28° C. for 0.3 hours. After the completion of reaction (TLC), the reaction mixture was poured on ice-water, and aqueous layer was extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 96.5 g. of solid.