Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52]([N:54]1[C@@H:59]([CH3:60])[CH2:58][NH:57][CH2:56][C@H:55]1[CH3:61])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CS(C)=O>[C:47]([O:51][C:52]([N:54]1[C@@H:59]([CH3:60])[CH2:58][N:57]([C:2]2[CH:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[CH:4][N:3]=2)[CH2:56][C@H:55]1[CH3:61])=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C5)cn3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (150 mg, 0.154 mmol) in DMSO (1.5 mL) were added DIPEA (0.143 mL, 0.87 mmol) and (2R,6S)-2,6-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester (124 mg, 0.58 mmol) and the mixture stirred at room temperature for 18 hours. The crude reaction mass was purified by prep-HPLC Method F to afford (3R,5S)-5′-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-3-yl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl}-3,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as an off white solid (80 mg, 40%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([O:23][C:24](=[O:27])[CH2:25][I:26])[CH2:16][C@@:15]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[I:26][CH2:25][C:24]([O:23][C@H:17]1[CH2:16][C@@:15]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[C@H:7]2[C@H:18]1[C@:19]1([CH3:22])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([O:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:21][CH2:20]1)=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11β-iodoacetoxy-5α-pregnan-20-one (20 g) in methylene chloride (400 ml) containing triethylamine (8.4 ml) was cooled to -5° and added dropwise with good stirring to a cooled (-5°) solution of methanesulphonyl chloride (3.77 ml) in methylene chloride (50 ml) at such a rate that the temperature did not exceed +1°. After 30 minutes a further portion of methanesulphonyl chloride (3 ml) and triethylamine (6 ml) was added in a small volume of methylene chloride. After 10 minutes the solution was washed with water, dried and evaporated to give a yellow solid (22.43 g). Crystallization of a small portion afforded an analytical sample of title compound, m.p. 142°-143°, [α]D +83.2°.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.OS(O)(=O)=O.C1C(=O)N([Br:25])C(=O)C1>O>[Br:25][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([CH:2]([F:12])[F:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
1-(Difluoromethyl)-3-nitrobenzene (866 mg, 5.00 mmol) was added to cold conc. H2SO4 and then NBS (890 mg, 5.00 mmol) was added. The mixture was warmed to room temperature for 30 minutes then 50-60° C. for 1 h. The mixture was then poured in water and ice and extracted diethyl ether twice. The organic layer was washed with dilute aqueous NaHCO3 and brine. Purification by chromatography on silica gel (0-15% ethyl acetate in hexanes) yielded 1-bromo-3-(difluoromethyl)-5-nitrobenzene (710 mg, 2.82 mmol, 56.3%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[C:6]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:5]=1>CO.[OH-].[Na+]>[CH2:22]([O:21][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1)[C:3]([OH:32])=[O:2])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)O)c1
Yield: 96.5 %

Procedure:
A solution of 6.0 g (0.013 mol) of 3,5-bis(decyloxy)benzoic acid methyl ester in 300 ml of methanol and 40 ml of 1N sodium hydroxide was stirred at reflux for 3.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 6N HCl. The product was extracted with ethyl acetate and the dried extract was concentrated under reduced pressure to a yellow solid. Recrystallization from methanol-water gave 5.45 g (94% yield, mp 56°-58°) of 3,5-bis(decyloxy)benzoic acid.
Reaction SMILES: N([O-])=O.[Na+].[BrH:5].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([CH3:14])[CH:13]=1)N.CCCCCC>O.[Cu]Br>[Br:5][C:9]1[CH:8]=[C:7]([CH3:6])[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Br
Reactant: Cc1cc(C)cc(N)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(C)cc(Br)c1
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 42 g of sodium nitrite in 150 ml of water is added to a mixture, cooled to −5° C., of 200 ml of 48% HBr and 50 g of 3,5-dimethylaniline. The reaction mixture is stirred for 1 hour at from −5° C. to 0° C. Finally, this reaction mixture is slowly added to a mixture, heated to 80° C., of 88.3 g of copper(I) bromide and 150 ml of 48% HBr. The reaction mixture is stirred for 2 hours at 80° C. and observed by TLC monitoring (silica; hexane). When the reaction is complete, the product is obtained by water-vapour distillation and is purified by column chromatography (silica; hexane). In this manner, 1-bromo-3,5-dimethylbenzene was obtained in a yield of 60% (30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:9]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cn1

Procedure:
A mixture of 10.5 g (0.046 mole) 1-(5-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone, prepared above, and 8.37 g (0.047 mole) N-bromosuccinimide (NBS) in 300 ml. carbon tetrachloride, with stirring, was irradiated and heated with a sunlamp until all of the NBS was consumed (about 45 min.). The reaction mixture was cooled, filtered, and the filtrate washed with aqueous sodium bisulfite and dried. After removal of the solvent, there was obtained a quantitative yield of 1-bromo-1-(5-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone, a light yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl.P([O-])([O-])([O-])=O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CNS(=O)(=O)c1cccc(I)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(CC(N)=O)S(=O)(=O)c1cccc(I)c1
Reaction time: 1.5 h

Procedure:
N2-[(3-Iodophenyl)sulfonyl]glycinamide (0.14 g) was stirred with sodium hydride (60% oil dispersion, 0.02 g) in DMF (2 ml) at 21° under nitrogen for 15 min. 2-Trimethylsilylethoxymethyl chloride (0.08 ml) was added and stirring was continued for 1.5 h. The mixture was poured into pH 6.4 phosphate buffer and the product was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), concentrated and applied to a silica Bond Elut Cartridge (5 g) in dichloromethane containing methanol. The cartridge was eluted with dichloromethane, diethyl ether and ethyl acetate to give the title compound (0.16 g), LCMS RT=3.49 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2NCCNC2=O)cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(C2C(=O)NCCN2C(C)=O)cc1OC

Procedure:
23.6 l g (0.1 mol) of the 3-(3,4-dimethoxyphenyl)-piperazin-2-one prepared in accordance with Example 1 are introduced into 100 ml of acetic anhydride.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2([CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[N:37]#CBr>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2([CH2:23][CH2:22][N:21]([C:24]#[N:37])[CH2:20][CH2:19]2)[CH2:17]1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Reactant: N#CBr
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To 1.0 g of 1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] of Example 17 in 16 ml of dry chloroform is added 2.4 g of anhydrous potassium carbonate and 0.73 g of cyanogen bromide. The reaction is stirred 7 hours at room temperature and then is filtered through paper. Approximately one ml of methanol is added and the solution is rotary evaporated to a glass. The glass is chromatographed on 80 cc of silica gel with 1:1, ether:dichloromethane to give a crystalline solid. The solid is recrystallized thrice from acetone-hexane to give a solid of 1-(2-chlorophenyl)-1'-cyanospiro(indoline3,4'-piperidine), mp 157.5°-159.5° C.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13]O>>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: CO
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(CN)cc1

Procedure:
Hydrogen chloride gas was blown into methanol (250 ml) on ice with stirring to prepare a methanol solution of hydrogen chloride (44.4 g). To the solution, 4-aminomethylbenzoic acid (25.70 g) was added at room temperature and the mixture was heated under reflux with stirring for 28 hours to obtain an almost homogeneous solution. The solvent was evaporated under reduced pressure from the solution to obtain methyl 4-aminomethylbenzoate hydrochloride (33.11 g) as a colorless solid.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10].CC([O-])(C)C.[K+].O>O1CCCC1>[CH3:13][C:8]1([C:9]([O:11][CH3:12])=[O:10])[C:1]2([CH2:5][CH2:4][CH2:3][CH2:2]2)[O:6]1
Reactant: COC(=O)C(C)Cl
Reactant: O=C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C)OC12CCCC2
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
9.3 g (0.11 mol) of cyclopentanone and 13.5 g (0.11 mol) of methyl 2-chloropropionate are cooled to 0 to 2° C.; at this temperature, 13.6 g (0.12 mol) of potassium tert-butylate suspended in 200 ml of tetrahydrofuran are added slowly dropwise with stirring over a period of about 90 minutes, after which the mixture is stirred for a further 60 minutes without cooling. A little water is added to the reaction mixture, which is subjected to extraction with diethyl ether; the organic phase is dried over sodium sulfate, the drying agent is filtered off, and evaporation of the solvent gives 10.6 g of methyl 2-methyl-1-oxaspiro[2.4]heptane-2-carboxylate, which can be employed without further purification in the subsequent stage (see b).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18]2[CH:19]=[C:20]([CH2:22]/[CH:23]=[CH:24]/[OH:25])[O:21][C:17]=2[CH:16]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18]2[CH:19]=[C:20](/[CH:22]=[CH:23]/[CH:24]=[O:25])[O:21][C:17]=2[CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C/C=C/O)oc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(/C=C/C=O)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A mixture of (E)-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]propen-1-ol (3.85 g), activated manganese dioxide (8.00 g) and dichloromethane (150 ml ) was stirred at room temperature for 2 hours. After the insoluble portion was filtered off, the filtrate was concentrated to yield crystals of (E)-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]acrolein (3.40 g, 89%), which was then recrystallized from dichloromethane-isopropyl ether to yield colorless prisms having a melting point of 132° to 133° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.5 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (37 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:17]([C@H:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]3[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:12]2)=[O:19])=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Reactant: NCc1ccc(F)cc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(F)cc3C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.264 mmol) in N,N-Dimethylformamide (DMF) (4 ml) was added ({[4-fluoro-2-(trifluoromethyl)phenyl]methyl}amine (0.051 g, 0.264 mmol) followed by diisopropylethylamine (0.101 ml, 0.580 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.128 g, 0.290 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (82 mg, 0.148 mmol, 56%). MS (ES) m/e 441 [M+H]+. 1H NMR (400 MHz, DMSO-D6) □ 7.6 (bs, 1H), 6.8 (m, 1H), 6.7 (m, 1H), 6.5 (m, 1H), 3.8 (m, 2H), 3.3 (m, 1H), 2.2 (s, 3H), 2.2-2.1 (m, 1H), 1.7-1.6 (bm, 1H), 1.5 (s, 3H), 1.3-1.1 (bm, 4H), 0.8-0.5 (bm, 4H)
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH3:18]
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: CCO
Product: CCOC1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 25 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was refluxed in 25 ml dry ethanol for 7 hours. The mixture was evaporated to few ml and the precipitate was filtered off, washed with ethanol and dried to give 0.229 g of the crude compound, which was recrystallized from acetic acid-water to yield 0.131 g (25%) of the title compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 1.1 (t, 3H), 3.25 (dq, 1H), 3.43 (dq, 1H), 5.22 (s, 1H), 7.17 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.51 (d, 1H), 12.1 (s, 1H), 12,31 (s, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[C:13]([N:16]1[C:22]([CH2:24][CH3:25])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[S:18])(=[O:15])[CH3:14]>>[C:13]([N:16]1[C:22]([CH2:24][CH3:25])([CH3:23])[C:20](=[O:21])[N:19]=[C:17]1[S:18][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:3]([CH3:12])[CH3:2])(=[O:15])[CH3:14]
Reactant: CCC1(C)C(=O)NC(=S)N1C(C)=O
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Product: CCC1(C)C(=O)N=C(SCc2ccccc2N(C)C)N1C(C)=O

Procedure:
In the present Example, 2.27 g of 2-dimethylaminobenzylchloride hydrochloride and 2.0 g of 1-N-acetyl-5-ethyl-5-methyl-2-thiohydantoin were reacted following the procedure of Example 33. The desired compound was obtained in the form of needle-like crystal. The yield of this compound was 1.37 g with a yield ratio of 41.1%, and the melting point was 83°-85° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br>C(Cl)Cl>[Br:15][C:8]1[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: BrBr
Reactant: CCc1ccccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-ethyl-benzaldehyde (5.00 g, 37.3 mmol) in CH2Cl2 (23 mL) was carefully added AlCl3 (8.70 g, 65.2 mmol). The mixture was cooled to 0° C. and a solution of bromine (1.9 mL, 37.2 mmol) in CH2Cl2 (23 mL) was added over 6 hours. The reaction mixture was stirred at room temperature overnight. The mixture was poured onto an ice/water mixture and stirred for 10 minutes. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with 2 M HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 35.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:8]([C:28]([F:31])([F:30])[F:29])=[N:9][N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:21]=1.Cl[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1.O>[CH:22]1([N:10]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]4[O:20][CH2:19][CH2:18][CH2:17][C:16]=4[CH:21]=3)=[C:7]([C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:28]([F:31])([F:30])[F:29])=[N:9]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: FC(F)(F)c1nn(C2CCCCC2)c(-c2ccc3c(c2)CCCO3)c1Br
Reactant: CCOC(=O)C(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(C2CCCCC2)c1-c1ccc2c(c1)CCCO2
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
Under nitrogen, isopropyl magnesium chloride 2M in tetrahydrofuran (0.47 mL, 0.94 mmol) was dropwise added to a solution of 4-bromo-1-cyclohexyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (54b) (134 mg, 0.31 mmol) in anhydrous tetrahydrofuran (1.0 mL), previously cooled to −20° C. After 90 minutes stirring at the same temperature, ethyl chlorooxoacetate (70 μL, 0.62 mmol) was added dropwise. The mixture was stirred at −20° C. for 40 minutes before being poured in water (2 mL). The mixture was extracted with ethyl acetate (2×3 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 75/25) to provide the desired keto-ester (54c) (104 mg, 0.23 mmol, 74%).
Reaction SMILES: C([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:16]([Cl:24])=[CH:17][C:18]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[Cl:25])[C:6]1=[O:26])C=C>FC(F)(F)C(O)=O>[Cl:24][C:16]1[C:13]2[C:14](=[O:15])[N:5]([OH:4])[C:6](=[O:26])[C:7]3=[CH:8][CH:9]=[C:10]([Cl:25])[C:11]([C:12]=23)=[C:18]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:17]=1
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(N4CCCC4)cc(Cl)c(c23)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccc(Cl)c3c(N4CCCC4)cc(Cl)c(c23)C(=O)N1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.8 %

Procedure:
A solution of 2-allyloxy-4,7-dichloro-6-(pyrrolidin-1-yl)benzo[de]isoquinoline-1,3-dione (0.5 g, 1.3 mmol, from Example J4) in trifluoroacetic acid (10 mL) was treated with boron tristrifluoroacetate (6 mL, 6.0 mmol, 1.0 M in trifluoroacetic acid). The reaction mixture was stirred at room temperature for 4 hours and evaporated in vacuo. The residue was chased with dichloro methane and redissolved in methanol which was also evaporated. The residue was partitioned between dichloromethane/water, separated, the organic layer dried, and evaporated in vacuo. The residue was triturated with petroleum ether, the solid removed by filtration, and dried in vacuo to give 0.2 g of the title compound, mp 243-245° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CC(C)=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)=CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 28.7 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.1 g of 1-bromo-3-methyl-2-butene were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.50 g of 2-(3-methyl-2-butenyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (78)).