Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH:33]1[CH2:38][OH:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH:33]2[CH2:38][OH:39])[NH:12][C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:26]=2)=[N:10]1
Reactant: OCC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CO)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Yield: 43.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.3 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.23 g, 1.5 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.34 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13]C)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(OC)c2ncccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)c2ncccc2c1
Temperature: -25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a −25° C. solution of 3.0 g (15.9 mmol) 6,8-dimethoxyquinoline and 160 mL CH2Cl2 is added 16 mL (15.9 mmol) of 1M BBr3 in CH2Cl2. After stirring for 2 h at −25° C., the reaction mixture is quenched with 300 mL of H2O, the layers separated in a separatory funnel, and the aqueous extracted with CH2Cl2 (2×100 mL). The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2, eluting with 3/1 EtOAc/hexanes containing 10% MeOH, gives 0.96 g (5.48 mmol, a 34% yield) of the title compound as an tan solid. MS (ES) m/z 176 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=[C:12]3[C:11]2=[O:23])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.[Pt]=O>[NH2:20][C:17]1[CH:16]=[C:13]2[C:14](=[O:15])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[C:11](=[O:23])[C:12]2=[CH:19][CH:18]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: Nc1cccc(N2C(=O)c3ccc(N)cc3C2=O)c1

Procedure:
A solution of N-(3-nitrophenyl)-4-nitro phthalimide (5.0 g. ) in tetrahydrofuran (300 ml) was reduced under hydrogen (45 psi) using platinum oxide catalyst (0.2 g.) for 18 hours. The solution was dried (MgSO4), filtered through Celite, and the solvent evaporated under reduced pressure to yield 4-amino-N-(3-aminophenyl)phthalimide; 3.8 g. (93.1%); M.P. 228-231°. Calcd. for C14H11N3O2 : C, 66.4; H, 4.4; N, 16.6. Found: C, 66.9; H, 4.9; N, 16.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[ClH:19]>C(O)C.C(OCC)(=O)C>[ClH:19].[ClH:19].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCC(C(=O)O)CC2)cc1
Reaction time: 8 h

Procedure:
In a 75-mL Parr bottle, 1-(4-nitrophenyl)piperidine-4-carboxylic acid (0.13 g, 0.52 mmol) is dissolved in ethanol/ethyl acetate (1:1, 30 mL). Concentrated hydrochloric acid (0.5 mL) is added. After degassing the mixture with dry ice, palladium on carbon (10%, 30 mg) is added. The reaction mixture is shaken overnight under 50 psi hydrogen, then filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 1-(4-aminophenyl)piperidine-4-carboxylic acid dihydrochloride.
Reaction SMILES: C[N:2](C)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CN.C(N(CC)CC)C.FC(F)(F)C1C=C(C=CC=1)C(Cl)=[O:26]>C1COCC1>[C:3]([NH2:2])(=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(CN)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
As shown in reaction scheme 83, N,N-dimethyl-1-phenylethane-1,2-diamine represented by Formula 101 (439.1 mg, 2.67 mmol, purchased from Alfa Aesar Co.) and triethylamine (0.75 mL, 5.35 mmol) in THF (10 mL) solution were cooled to 0° C. under a nitrogen atmosphere, then, 3-(trifluoromethyl)benzoic acid chloride represented by Formula 153 (613.17 mg, 2.94 mmol, purchased from TCI Co.) in THF (15 mL) solution was slowly added thereto. After agitating the mixture at the same time for 30 minutes, the mixture was left at room temperature for 18 hours. A precipitate generated during the reaction was removed through filtration. The remaining solution was diluted with chloroform and this diluted solution was washed with a potassium carbonate (K2CO3) solution, followed by separation and drying the same with sodium sulfate (Na2SO4). The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 83 as a desired product (VVZ-078; 632.5 mg, 70% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CS(C)=O.[CH3:13][NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:14]([CH3:13])[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CNCC1CCOCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(CC1CCOCC1)c1cncc(Cl)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of 2,6-dichloropyrazine (298 mg, 2.000 mmol), DMSO (6 ml), TEA (0.418 ml, 3.00 mmol) and N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine (264 mg, 2.040 mmol) was stirred at 70° C. for 16 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was let cool to room temperature, diluted with 150 ml of ethyl acetate, washed with 1M NaOH soln. (1×), water (2×), saturated salt soln. (1×), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 475 mg of the title compound as free base, which was used without further purification. LCMS (m/z): 242.0 (MH+), retention time=0.85 min.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:30])[NH:28][CH2:29][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)#[N:4].[CH3:31]I>CN(C)C=O>[C:3]([CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[N:20]([CH3:31])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:30])[NH:28][CH2:29][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)#[N:4]
Reactant: CI
Reactant: N#CCCn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)NC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)CNC3=O
Reaction time: 1 h

Procedure:
36 mg (1.2 mmole) sodium hydride (80% in mineral oil) are suspended under an atmosphere of nitrogen in 50 mL dry dimethylformamide and 365 mg (1 mmole) 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole added portionwise thereto at ambient temperature. After subsidence of the gas evolution, stirring is continued for 1 hour at 20° C. 0.08 mL (1.25 mmole) methyl iodide is then added thereto and stirring continued for 16 hours at ambient temperature. The solvent is distilled off in a vacuum and the residue is chromatographed on silica gel with toluene/ethanol (95:5 v/v). The fraction with an Rf of 0.3 in dichloromethane/methanol (95:5 v/v) is isolated and recrystallized from tetrahydrofuran. 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of pale yellow crystals which decompose above 270° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:37]([O:38][CH3:39])=[CH:36][C:27]2[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[C:37]([O:38][CH3:39])=[CH:36][C:27]3[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccc(OC)cc4-n4cccn4)n3)c(OC)cc21

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (30%); 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.47 (bs, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.79 (m, 2H), 7.56 (s, 1H), 7.23 (s, 1H), 7.01-6.95 (m, 2H), 6.51 (s, 1H), 3.84 (bs, 8H), 2.36 (bs, 2H), 2.05 (bs, 2H), 1.9 (bs, 2H), 1.03 (m, 3H); MS (m/e) 534.48 (M+H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:2]=[N-:3].C(N([CH2:18][CH3:19])CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[N:1]([CH2:4][C@H:5]([O:12][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:18][CH3:19])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:2]=[N-:3]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C[C@@H](O)CN=[N+]=[N-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)O[C@@H](CN=[N+]=[N-])CC(=O)OCC
Temperature: 0 °C
Reaction time: 5 h
Yield: 186.4 %

Procedure:
In a 100 ml four-necked flask were charged 6.0 g (34.6 mmol) of ethyl (R)-4-azido-3-hydroxybutyrate, 4.2 g (41.5 mmol) of triethylamine, 0.12 g (1.04 mmol) of 4-dimethylaminopyridine, and 60 ml of tetrahydrofuran and the mixture was cooled to 0° C. 5.10 g (38.1 mmol) of hexanoyl chlrodie was slowly added thereto dropwise in a nitrogen stream. After the addition, the reaction mixture was stirred at a room temperature for 5 hours, and then 14 ml of 5% HCL was added thereto. After the liquid separation, the mixture was washed thrice with 30 ml of 5% aqueous solution of sodium chloride and then concentrated to give 8.75 g (93%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25]Br>>[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[C:13]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: CN(CCc1ccccc1)C(=O)CBr
Product: COC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(=O)N(C)CCc1ccccc1

Procedure:
Following the procedure of Example 10, 5-benzyloxy-2-carbomethoxyindole is alkylated with N-methyl-N-phenethyl-2-bromoacetamide to give N-methyl-N-phenethyl-2-(5-benzyloxy-2-carbomethoxyindol-1-yl)acetamide. (m.p. 155°-156° C.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[N+:25]([O-:27])=[O:26])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and 1,3,5-Trifluoro-2-nitro-benzene (0.57 ml, 4.87 mmol) are dissolved in 10 ml of dimethylformamide. After addition of potassium carbonate (1.3 g, 9.74 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:21]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22]1>C(O)(C)C.CCOC(C)=O.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:22]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C1CCN(C2CCNC2)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Brc1ccc(N2CCC(N3CCCCC3)C2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
283 mg (1.00 mmol) 4-bromo-iodobenzene, 10 mg (0.05 mmol) CuI, 124 mg (2.00 mmol) ethyleneglycol and 424 mg (2.00 mmol) potassium phosphate are added to a reaction vessel, which is evacuated and rinsed with argon several times. Then 154 mg (1.00 mmol) 1-pyrrolidin-3-yl-piperidine in 1 mL isopropanol are added and the reaction is shaken for 15 h at 80° C. The reaction solution is diluted with EtOAc and extracted twice with 5% ammonia solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][OH:23])=[CH:4][C:3]=1[F:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][C@H:9]2[CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][C:3]=1[F:24]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (4.50 g) in THF (41.7 mL) were added triethylamine (3.49 mL) and methanesulfonyl chloride (1.94 mL) under ice-cooling, and the mixture was stirred for 3 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.01 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[C:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)(=O)[CH3:14]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:12])[CH:14]=[CH:13][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccc2ccccc2c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 2-naphthaldehyde and 2-acetylnaphthalene, 1,3-di-(2-naphthalenyl)prop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: C(OC([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:7]1=[O:19])=O)C.O>[N+](C)([O-])=O>[CH:13]1([N:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:6][C:7]2=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1C(=O)CCN(C2CCCCC2)C1=O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=C1CCN(C2CCCCC2)C(=O)C1

Procedure:
1-Cyclohexyl-2,4-dioxo-piperidine-3-carboxylic acid ethyl ester (3.1 g, 11.6 mmol) was heated with water (0.25 ml, 13.9 mmol) in nitromethane (30 ml) at 95° C. for 1 hour. The solution was concentrated to give an off-white solid weighing 2.3 g (93%). A sample was recrystallised from toluene.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2c1OCCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At 0° C., boron tribromide (5.6 cm3) is added slowly to a solution of 5-methoxy-1,4-benzodioxane (5 g, 30.1 mmol) in 25 cm3 of CH2Cl2. The mixture is stirred at 0° C. for 15 min, the solution is then hydrolysed with 10 cm3 of water and the product is extracted with CH2Cl2. Purification on a silica column (eluent: 100% CH2Cl2) enables 4.49 g of a colorless oil to be obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][NH:12][C:13]3[CH:17]=[CH:16][NH:15][C:14]=3[C:18]([O:20]CC)=O)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:23].C([N:32]=[C:33]=[S:34])(=O)C1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][N:12]3[C:13]4[CH:17]=[CH:16][NH:15][C:14]=4[C:18](=[O:20])[NH:32][C:33]3=[S:34])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:23]
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2c(C)c(C)ccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: Cc1ccc2[nH]c(Cn3c(=S)[nH]c(=O)c4[nH]ccc43)nc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
Ethyl 3-{[(4,5-dimethyl-1H-benzimidazol-2-yl)methyl]amino}-1H-pyrrole-2-carboxylate (0.043 g, 0.14 mmol) was dissolved in CH2Cl2 (1.5 mL) and benzoyl isothiocyanate (0.026 g, 0.16 mmol) was added. After stirring at r.t. for 1 h the solvent was removed in vacuo. The residue was dissolved in ammonia (7N in methanol) and heated to 70° C. for 2 h in a sealed vessel. The solvent was removed in vacuo and the residue was purified by preparative HPLC, obtaining a white solid, 0.008 g (18%) of the title compound, as a tautomeric mixture (1:1).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:3]([CH:2]([CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH3:5]
Reactant: CCCCC(=O)OCC
Reactant: O=Cc1ccccc1
Product: CCCC(C(=O)OCC)C(O)c1ccccc1

Procedure:
A 100 milligram sample of the prepared hydroxy-ester is pyrolyzed in a sealed tube at 240°-245° C. for 1 hour. Examination of the pyrolyzate by liquid chromatography indicates that it consists of 60% of unreacted hydroxy-ester and 40% of a 1:1 mixture of ethyl valerate and benzaldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22](C)(C)[CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16].S(=O)(=O)(O)O.C(O)C>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a solution of di-tert-butyl (3-fluoro-4-nitrophenyl)malonate (5.11 g, 14.4 mmol) in methylene chloride (50 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to yield a colorless solid substance. To the solid substance were added concentrated sulfuric acid (1 ml) and ethanol (50 ml) and the mixture was heated and refluxed for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ice water (100 ml) was poured in the residue, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby ethyl 3-fluoro-4-nitrophenylacetate (3.15 g, 96%) was obtained as a yellow oil.
Reaction SMILES: Br[CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5]CC)=O.[CH2:11]([NH2:14])[CH2:12][NH2:13].[O-]CC.[Na+]>C(O)C>[CH:8]([CH:2]1[NH:14][CH2:11][CH2:12][NH:13][C:3]1=[O:5])([CH3:9])[CH3:10]
Reactant: NCCN
Reactant: CCOC(=O)C(Br)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)C1NCCNC1=O

Procedure:
Ethyl 2-bromo-3-methylbutanoate (2.2 g, 10.52 mmol) in ethanol (15 mL) was added dropwise over a period of 2.5 hours to a stirred refluxing solution of ethane-1,2-diamine (13.2 mL, 197 mmol) in ethanol (60 mL). The mixture was heated for another 2.5 hours, and sodium ethoxide in ethanol (21% by wt) (4.0 mL, 10.80 mmol) was added and the mixture was heated for another 90 minutes. The reaction was then cooled and concentrated. After trituration with ether, the title compound was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[N+:23]([O-])=O)(=[O:14])=[O:13])[C:3]1=[O:26].CO>[Ni].C1COCC1>[NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[NH2:23])(=[O:14])=[O:13])[C:3]1=[O:26]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(N)c1
Reaction time: 1 h
Yield: 14 %

Procedure:
A mixture of 2.4 g of the compound obtained in EXAMPLE 105, 1 g of Raney® nickel, 50 ml of MeOH and 50 ml of THF is hydrogenated at atmospheric pressure for 1 hour at RT. The catalyst is filtered off on C elite® and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.316 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=160°-166° C.