Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cccc(C2(O)CCC(=O)CC2)c1
Product: Cc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-m-tolyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>CC(C)=O.C(N(CC)CC)C>[CH:13]1([NH:18][C:19]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C=NC1CCCC1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(NCCc1c[nH]c2ccccc12)NC1CCCC1
Yield: 34.7 %

Procedure:
Tryptamine (1.04 g, 6.5 mmol) was dissolved in a mixture of acetone (20 ml) and triethylamine (1 ml) under a nitrogen atmosphere. Cyclopentyl isocyanate (795 mg, 7.15 mmol, 0.81 ml) was swiftly added dropwise at 0° C. and the mixture was then subsequently stirred for 2H, while cooling with ice, and at RT overnight. A white solid had precipitated out of the solution, and was filtered off with suction and rinsed with acetone. It was 641 mg of pure product. The filtrate was concentrated i. vac. and the residue was then stirred thoroughly with acetone (10 ml). The undissolved white solid was filtered off with suction and rinsed with acetone, and a further 612 mg of pure product were obtained in this way.
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:20]=[CH:21][C:14]=23)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)[N:20]=[CH:21][C:14]=23)[CH2:11]1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CN(Cc5ccccc5)C4)ncnc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CNC4)ncnc32)cc1
Yield: 318.5 %

Procedure:
4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.01 mmol, 46 mg) was dissolved in a mixture of ethyl acetate (5 mL) and methanol (5 mL). Palladium catalyst (30 mg, 65% by wt) was added to the reaction. The mixture was exposed to hydrogen gas for 60. minutes at room temperature and atmospheric pressure. The mixture was passed through celite to remove palladium catalyst. Removal of organic solvents in vacuo and purification by flash chromatography provided 4-(azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (11 mg, 5%). 1H NMR (400MHz, MeOH-d4) δ (ppm): 8.45 (m, 2H); 8.37 (d, 2H); 8.05 (d, 2H); 4.54 (m, 1H); 4.35 (dd, 2H); 3.69 (m, 2H); 3.09 (s, 3H). LCMS (ESI), m/z 346.2 (M+H+, 100%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide (Intermediate 19, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNC(=O)C(C)(C)C)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (60 mg, 0.155 mmol), triethylamine (17 mg, 24 μL, 0.170 mmol), pivaloyl chloride (19 mg, 19 μL, 0.155 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-29 (65 mg, 89%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 7.65 (t, J=6.2 Hz, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 6.39 (br s, 2H), 5.90 (s, 2H), 4.26 (t, J=6.0 Hz, 2H), 3.04 (q, J=6.0 Hz, 2H), 2.68 (s, 6H), 1.83-1.87 (m, 2H), 1.27 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 178.8, 154.9, 152.9, 151.9, 148.3, 147.5, 146.6, 144.7, 119.8, 119.7, 109.5, 102.5, 101.7, 45.3, 40.3, 38.8, 34.8, 28.9, 27.7; (ESI) m/z [M+H]+ calcd. for C22H30N7O3S, 472.2131. found 472.2128.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH:43]=1)OC1C=CC=CC=1)#[N:27]>>[C:26]([NH:28][C:29]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:23])=[N:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]2[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]2)[CH:43]=1)#[N:27]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.54 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,5-pentanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. %]) =643 ([M+H]+, 7), 229 (54), 154 ([m-NO2 -benzylOH] 100); IR (KBr): 2165 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt which forms a dry foam under reduced pressure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10](CO)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([S:24]([CH3:23])(=[O:26])=[O:25])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC12CC1CN(Cc1ccccc1)C2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C12CC1CN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyl-1-hydroxymethyl-3-azabicyclo[3.1.0]hexane in ethyl acetate were added triethylamine (2.15 gm, 0.02125 mole) and methane sulphonylchloride (1.947 gm, 0.017 mole). The mixture was stirred at 0° C. for 1 hour. The reaction was quenched by the addition of saturated NaHCO3. The separated organic layer was washed with water, brine, dried and evaporated to give the crude product, which was used as such for further reaction.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cncn2)nc1
Reaction time: 0.5 h

Procedure:
2-fluoro-5-nitropyridine (0.5 g, 3.38 mmol), 1,2,4-triazole (0.22 g, 3.22 mmol) were added in DMF (6.4 mL), then cesium carbonate (3.14 g, 9.65 mmol) was added. The reaction was run at room temperature for 30 minutes. Water (50 mL) was added and product fell out of the solution. The solution was filtered and the solid was rinsed with ethyl acetate/water (1:1, 20 mL×2), hot hexane (20 mL) to give the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH2:9]([CH:11]1[O:13][CH2:12]1)[Cl:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:13][CH:11]([CH2:9][Cl:10])[CH2:12][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1nccn1CC(O)CCl

Procedure:
2-Nitroimidazole (1 molar equivalent) in acetone was mixed with epichlorohydrin (1.1 molar equivalent) and potassium carbonate (0.001 molar equivalent). The mixture was refluxed overnight and taken to dryness in vacuo to give 1-(2-hydroxy-3-chloropropyl)-2-nitroimidazole. 1-(2-Hydroxy-3-chloropropyl)-2-nitroimidazole is taken up in ethyl acetate and mixed with an equal volume of 10% aqueous sodium hydroxide with vigorous stirring for 1 hour at room temperature. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and taken to dryness to give 1-(2,3-epoxypropyl)-2-nitroimidazole. 1-(2,3-epoxypropyl)-2-nitroimidazole (1 molar equivalent) dissolved in acetone was mixed with N′-1,1,1,3,3,3-hexafluoroisopropylpiperazine (1.1 molar equivalent) and the solution refluxed overnight. The reaction solution was taken to dryness in vacuo to give 1-(2-hydroxy-3-(N′-1,1,1,3,3,3-hexafluoroisopropylpiperazino)-2-nitroimidazole (XVI) that was recrystallized from ethanol. The chemical intermediate, N′-1,1,1,3,3,3-hexafluoroisopropylpiperazine, was prepared by heating 1,1,1,3,3,3-hexafluoroisopropyl bromide (1.0 molar equivalent) and piperazine (1.1 molar equivalent) at reflux in ethanol overnight. The chemical intermediate 1,1,1,3,3,3-hexafluoroisopropyl bromide was prepared by reacting commercially available 1,1,1,3,3,3-hexafluoroisopropyl alcohol (1 molar equivalent) with phosphorus tribromide (0.33 molar equivalent) in ethyl ether overnight at room temperature.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Br:17][C:13]1[C:12]([O:18][CH3:19])=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1c(Br)cccc1-c1ccccc1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of phenylboronic acid (3.4 g, 28.7 mmol), 2,6-dibromoanisole (22.3 g, 83.8 mmol, 3 equiv.) and palladium tetrakistriphenylphosphine (0.6 g) in ethylene glycol dimethyl ether (50 mL) and a solution of potassium carbonate (10.8 g, 0.078 mol) in water (50 mL) were kept at reflux under nitrogen with good stirring overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (800 mL) and water (400 mL). The organic phase was washed with water (2×400 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the residue was chromatographed on silica (360 g) with heptane (5 L) to afford 6.55 g of pure product (87%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O:18][C:19](=[O:26])[NH:20][CH2:21][CH:22]1[CH2:25][NH:24][CH2:23]1)([CH3:17])([CH3:16])[CH3:15]>C(O)CCCC>[C:14]([O:18][C:19](=[O:26])[NH:20][CH2:21][CH:22]1[CH2:23][N:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:25]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Reactant: COc1ccc2nccc(Br)c2n1
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CC(CNC(=O)OC(C)(C)C)C3)c2n1
Temperature: 80 °C
Yield: 42.1 %

Procedure:
A mixture of 8-bromo-2-methoxy-[1,5]naphthyridine (495 mg, 2.07 mmol, prepared as in WO 2006/032466) and tert-butyl-[(azetidin-3-yl)methyl]carbamate (405 mg, 1.05 eq) in pentanol (2 mL) was heated at 80° C. overnight. The majority of the solvent was removed in vacuo at elevated temperature (50-60° C.). The residue was triturated with ether to form the desired intermediate as beige solid (300 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([OH:12])[C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cnc2c(c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.97 Gram of 7,8-dihydro-3-methylquinolin-5(6H)-one was dissolved in 20 ml of methanol, then to this solution was added 0.23 g of sodium borohydride under ice-cooled condition, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, then methanol was removed by evaporation, next extracted with chloroform, and the chloroform extract was dried with anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain 0.98 g of 3-methyl-5-hydroxy-5,6,7,8-tetrahydroquinoline in the form of colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[N:11]1.[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1.CO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)[C:12]([NH:17][C:18](=[O:39])[CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])=[CH:25][C:24]=2[C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])[CH2:20][CH3:21])=[N:11]1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Reactant: c1c[nH]cn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1n1ccnc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
66 g (0.1 mol) of 1-(2,4,6-trichlorophenyl)-3-[α-(2,4-di-tert-amylphenoxy)butyramido]-4-bromo-5-oxo-2-pyrazoline and 27.2 g (0.4 mol) of imidazole were well mixed with each other in a mortar, then stirred for 2 hours under heating to 100° C. To the reaction mixture was added 200 ml of methanol to prepare a solution. Then 1 liter of ethyl acetate was added thereto, followed by washing several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate, and concentrated. Upon crystallization of the residue from acetonitrile-ethyl acetate (volume ratio:20.1), 48 g of pure Coupler (1) was obtained. The melting point of the coupler was 185°-187° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][NH:17][C:16]2=[O:20])=[CH:11][CH:10]=1)[CH:5]([F:7])[F:6].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]1([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@H:32]([CH3:33])[O:31]1>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]([OH:31])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:32]([N:17]1[CH:18]=[CH:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]([F:3])([F:21])[CH:5]([F:6])[F:7])=[CH:10][CH:11]=2)[C:16]1=[O:20])[CH3:33]
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
60% Sodium hydride in oil (2.4 g) was added portionwise to a stirred solution of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (16.6 g) and the resulting mixture was stirred for 30 minutes at room temperature. (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (10 g) was added and the mixture was stirred at 80° C. for 20 hours. After cooling, the mixture was concentrated into a volume of about 50 ml under reduced pressure and diluted ice-water (400 ml) and ethyl acetate (500 ml). The ethyl acetate layer was separated, washed with a 10% aqueous phosphoric acid solution (400 ml) and an aqueous solution of sodium chloride (400 ml×2) successively and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to 2/1) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (7.56 g) as an oily substance, which was identical with the compound obtained in the Reference Example 47.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CI>O>[CH3:3][N:24]([C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:14]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(C(=O)c1ccncc1)c1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Sodium hydride (60% (w/w) oil mixture) (200 mg, 0.500 mmol) was added at 0° C. to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 5 N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (121 mg, 0.496 mmol), obtained as described in Referential example 1-3. The resulting mixture was stirred for one hour, and an N,N-dimethylformamide (DMF) solution of methyl iodide (0.8 M, 0.62 ml, 0.496 mmol) was added thereto at 0° C. The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g, hexane/ethyl acetate=1/1). Thus, N-methyl-N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0614) (65.9 mg, 51.5%) was yielded as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].B(F)(F)F.CCOCC.[CH:19]([O:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([N:29]2[CH2:34][CH2:33][C:32](=[CH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][C:24]=1[CH3:41])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]1[CH:9]=[C:6]([CH:7]([OH:8])[CH2:37][C:36](=[O:38])[CH:35]=[C:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[C:26]3[CH:39]=[CH:40][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[C:24]([CH3:41])[CH:25]=3)[CH2:30][CH2:31]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)C=C1CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Reactant: O=Cc1cncc(F)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC(=CC(=O)CC(O)c3cncc(F)c3)CC2)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-fluoronicotinaldehyde (51 mg, 0.41 mmol) in dichloromethane (1.7 mL) was cooled to −78° C. and boron trifluoride diethyl etherate (164 μL, 0.82 mmol) was added. The mixture was stirred at −78° C. for 5 min. The solution from step 1 was added. The mixture was stirred at −78° C. for 5 min, quenched with a buffer solution of pH=7. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to afford 4-(5-fluoro-3-pyridyl)-4-hydroxy-1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butan-2-one (105 mg). 1H NMR (400 MHz, CDCl3) δ 8.46-8.31 (m, 2H), 7.53-7.49 (m, 1H), 7.24-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H), 6.09 (s, 1H), 5.26 (dd, J=8.9, 5.9 Hz, 1H), 4.62-4.53 (m, 1H), 4.13-4.12 (m, 1H), 3.69 (br d, 4H), 3.00 (br s, 2H), 2.88 (d, J=6.2 Hz, 2H), 2.37 (br s, 2H), 2.21 (s, 3H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 440.21, found 441.4 (M+1)+; Retention time: 1.65 minutes (3 min run).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2NC=N[C:7]=2[CH:6]=1)[NH2:4].C(C1C=C2C([CH2:20][CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)=CC=1)#N>>[NH2:4][C:3](=[N:2][OH:1])[C:5]1[CH:6]=[C:7]2[C:8]([CH2:20][CH2:21][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:23]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2C1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(N)=NO)cc2C1
Yield: 80 %

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from tert-butyl 7-cyano-3,4-dihydroisoquinoline-2(1H)-carboxylate obtained in step 1 (1.50 g; 5.81 mmol). The solvent was evaporated in vacuo and further freeze dried to give the title compound as an off-white solid (1.35 g, 80%). 1H NMR (DMSO-d6) δ 9.54 (s, 1H), 7.46 (m, 2H), 7.14 (d, J=8 Hz, 1H), 5.74 (bs, 2H), 4.49 (s, 2H), 3.54 (t, J=5.9 Hz, 2H), 2.76 (t, J=5.9 Hz, 2H), 1.49 (s, 9H). HPLC (Method A), Rt 2.40 min (Purity: 99.4%). LC/MS (Method B): 292.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 2,5-dimethyl-4-nitrobenzoic acid (480 mg, 2.4 mmol) in dry methanol (8.2 mL) at 0° C. under dry nitrogen was added thionyl chloride (0.538 mL, 7.38 mmol). The resulting mixture as allowed to warm to room temperature and stirred for about 7 hours. Additional thionyl chloride (0.300 mL) was added and stirring was continued at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide methyl 2,5-dimethyl-4-nitrobenzoate (578 mg) as a pale yellow solid. HPLC (10-70) Rt=4.61; NMR (300 MHz, CDCl3) δ 2.57 (s, 3H), 2.61 (s, 3H), 3.94 (s, 3H), 7.82 (s, 1H), 7.87 (s, 1H).