Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC2OC=CC=2C=1.[CH2:12]([C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=2[CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[CH2:31]([N:33]([CH2:46][CH3:47])[CH2:34][CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH3:32]>>[CH2:12]([C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=2[C:23]=1[C:41](=[O:42])[C:40]1[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][N:33]([CH2:46][CH3:47])[CH2:31][CH3:32])=[CH:45][CH:44]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2oc(Cc3ccccc3)cc2c1
Agent: COc1ccc2occc2c1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccc(OC)cc23)cc1

Procedure:
In like manner, when 5-methoxybenzofuran is used as a starting material in the procedure of Example 34 and the resulting 2-benzyl-5-methoxybenzofuran is acylated with 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride, 2-benzyl-3-[4-(2-diethylaminoethoxy)benzoyl]-5-methoxybenzofuran is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].CCCCCC>C1COCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: c1ccsc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Thiophene (2.0 g, 12 mmol) was dissolved in anhydrous THF (20 mL) and n-BuLi (9.52 mL, 23.8 mmol, 2.5 M in hexane) slowly added at −30° C. under nitrogen flow. After stirring for 1 hour, tributyltin chloride (7.75 mL, 23.8 mmol) was added. After heating to room temperature, followed by stirring for 3 hours, the reaction was terminated. The produced compound was extracted with n-hexane and distilled water, dried with anhydrous MgSO4 and filtered under reduced pressure. The final product tributyl-2-thienylstannane (2.5 g, yield: 46%) was obtained by column chromatography (neutral alumina, n-hexane). The product was used in the next step after removing the solvent.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.[NH2:14][OH:15].Cl.CC([O-])=O.[Na+]>CCO.CCOC(C)=O>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:14][OH:15])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=NO)c2ccccc21
Temperature: 25 °C

Procedure:
4,4-Dimethyl-3,4-dihydro-2H-naphthalen-1-one (2.2 g, 12.6 mmol) was dissolved in EtOH (10 ml) and NH2OH.HCl (1.05 g, 15.2 mmol) and NaOAc (2.0 g, 24 mmol) were added. The mixture was heated to reflux for 2 h upon which a yellow suspension is formed. The suspension is cooled down to RT and diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated to give 4,4-Dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[C:19]2[N:20]([C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=2)[CH:21]=[C:22]([CH3:24])[CH:23]=1>CN(C=O)C>[F:10][C:9]1[C:4]([CH2:3][O:17][C:18]2[C:19]3[N:20]([C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cccnc1CCl
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(C)cn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
15.78 g (86.7 mmol) of 2-(chloromethyl)-3-fluoropyridine hydrochloride (commercially available; additionally described in: U.S. Pat. No. 5,593,993 A1, 1997; WO2007/2181 A2, 2007) and 94.06 g (288.9 mmol) of caesium carbonate were added to 16.92 g (72.2 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 87A in 956 ml of DMF. The reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to RT and filtered, the filtercake was washed with ethyl acetate and the filtrate was concentrated. About 500 ml of water were added to the residue and the precipitated solid was filtered off and dried under high vacuum. This gave 24.1 g (93% of theory) of the target compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[S:22][C:23]([N+:27]([O-])=O)=[CH:24][C:25]=2[CH3:26])=[O:20])=[N:2]1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:27][C:23]1[S:22][C:21]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:20])=[C:25]([CH3:26])[CH:24]=1
Reactant: Cc1cc([N+](=O)[O-])sc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)sc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
(E)-N-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}-3-methyl-5-nitrothiophene-2-carboxamide (90 mg, 0.22 mmol), iron powder (621 mg, 11.13 mmol) and ammonium chloride (59 mg, 1.10 mmol) were added with ethanol (1.0 mL) and water (1.0 mL) at room temperature, stirred at 50° C. for 1 hour and then the reaction mixture was filtered through Celite. The filtrate was extracted with ethyl acetate and the organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain Compound 67 (26 mg, 32%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Br[CH:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]>C1C=CC=CC=1.CN(C)C=O>[O:16]=[C:12]1[CH:11]([N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2=[O:9])[CH2:15][CH2:14][O:13]1
Reactant: O=C1OCCC1Br
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C1OCCC1N1CCCCC1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 107 %

Procedure:
1.25 g (0.05 mol) of sodium hydride (2.5 g of a 50% commercial suspension in paraffin, previously washed twice with benzene) are suspended in 50 ml of anhydrous N,N-dimethylformamide. A solution of 4.95 g (0.05 mol) of 2-piperidinone in 20 ml of N,N-dimethylformamide is added dropwise to the suspension. The mixture is then heated to 60° C. until no more gas is evolved, whereafter it is cooled. A solution of 8.25 g (0.05 mol) of 3-bromodihydro-2(3H)-furanone in 20 ml of anhydrous N,N-dimethylformamide is added dropwise while keeping the temperature at 5° to 10° C. The mixture is then stirred at 60° C. for 5 hours. N,N-Dimethylformamide is evaporated off under reduced pressure. The residue is taken up in chloroform and the insoluble matter filtered off on Norit. The filtrate is again evaporated and 9.8 g of a heavy syrup are obtained. Mass spectrum: M+. at 183 m/e.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]([O:26]CC)=[O:25])=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7].[OH-].[Na+].Cl>C1COCC1.O.CO>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24]([OH:26])=[O:25])=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: CCOC(=O)c1n[nH]c2cc(-c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc3c(C(=O)O)n[nH]c3c2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 127 %

Procedure:
To a stirred solution of ethyl 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate (12 mg, 25 μmol) in THF/water/methanol (10/1/1, 2.5 Ml), was added 1N aqueous sodium hydroxide solution (1.3 Ml). The mixture was stirred at 70° C. for 12 h and cooled to room temperature. The pH of solution was adjusted to 4-5 with 1N hydrochloric acid aqueous solution. The aqueous solution was extracted with ethyl acetate and the combined organic layer was washed with water, dried over magnesium sulfated, and concentrated under reduced pressure to give 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylic acid (13.5 mg), which was used in next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:6][CH:7]=1)(=[O:34])=[O:33]
Reactant: Nc1ccc(C2=NCC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: O=C1CN=C(c2ccc(NS(=O)(=O)Cc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 40.8 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-e][1,4]diazepin-2(3H)-one (30 mg, 0.1 mmol) obtained in Example 64, (1), and (2-chlorophenyl)methanesulfonyl chloride (34 mg, 0.15 mmol), the title compound (20 mg, yield 27%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5](C(=O)C(F)(F)F)[CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(O)=O>O1CCOCC1.O.CO>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1cc([N+](=O)[O-])ccc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c3c(ccc2c1)NCC3CCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
A solution of 131 (1.00 g, 2.79 mmol) in dioxane (30 mL) was treated with a solution of Cs2CO3 (3.26 g, 10 mmol) in water (3 mL) and MeOH (17 mL), and the mixture was stirred vigorously at room temperature for 15 min. The resulting solution was treated with AcOH (1.2 mL), then concentrated to a small volume under reduced pressure and partitioned between water and CH2Cl2. The organic phase was washed with water (×2), dried, and filtered through a column of silica gel. Evaporation and trituration with petroleum ether/iPr2O gave 1-(chloromethyl)-7-nitro-1,2-dihydro-3H-benzo[e]indole (134) (702 mg, 96%) as an orange-red solid: mp (CH2Cl2/petroleum ether) 121-122° C.; 1H NMR [(CD3)2SO] δ 8.76 (d, J=2.2 Hz, 1H), 8.05 (dd, J=9.3, 2.3 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.76 (d, J=9.3 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.79 (s, 1H), 4.17-4.04 (m, 1H), 3.95-3.78 (m, 2H, 3.76-3.63 (m, 2H). Anal. (C13H11ClN2O2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)[C:9]2[C:10]([C:18]([OH:20])=O)=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH:15]4[CH2:17][CH2:16]4)[C:13]=3[CH3:14])[C:18](=[O:20])[N:21]2[C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)nn(C3CC3)c2C)cn(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2C(=O)c3nn(C4CC4)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylic acid (Step 20.4). tR: 4.06 min (HPLC 1); tR: 0.92 min (LC-MS 2); ESI-MS: 409.2 [M+H]+ (LC-MS 2); Rf=0.39 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.17 (m, 4H) 1.91 (s, 3H) 2.13 (s, 3H) 3.34 (s, 3H) 3.60-3.67 (m, 1H) 6.09 (s, 1H) 7.20-7.26 (m, 2H) 7.32-7.43 (m, 3H) 7.70 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]3)[CH:21]=2)[CH:16]=1)[CH2:9][CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:36].[Cl-].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:36][C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][C@H:26]3[CH2:27][CH2:28][C@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][CH2:31]3)[CH:21]=2)[CH:16]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCC(N)=O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
The mixture of 3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoic acid (483 mg, 1.0 mmol), NH4Cl (215 mg, 5.0 mmol, 5.0 equiv), Et3N (510 mg, 5.0 mmol, 5.0 equiv) and HATU (760 mg, 2.0 mmol, 2.0 equiv) in anhydrous THF (20 mL) was stirred at 45° C. for 15 min. The reaction mixture was concentrated in vacuum and the residue was purified by chromatography with silica gel (DCM/MeOH=20/1) to give compound the title compound as a white solid (337 mg, yield: 70%). ESI-MS (M+H+): 483.3. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (d, 2H), 7.60 (s, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 7.12 (dd, 1H), 4.49 (s, 2H), 4.38-4.31 (m, 1H), 3.30 (t, 2H), 2.30 (t, 2H), 2.19 (d, 2H), 1.81 (d, 2H), 1.45-1.33 (m, 11H), 1.23-1.16 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:25][C:26]1[C:31](O)=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:31]3[C:30]([F:33])=[C:29]([F:34])[C:28]([F:35])=[C:27]([F:36])[C:26]=3[F:25])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
100 g of 4-octyloxybiphenyl-4′carboxylic acid and 62 g of pentafluorophenol are introduced into 1 liter of dichloromethane. Agitation is carried out for 15 minutes and 69.6 g of N,N′-dicyclohexylcarbodiimide in solution in 500 ml of dichloromethane is added over 15 minutes. The dark beige suspension is agitated for 20 hours at ambient temperature. The dicyclohexylurea is filtered and the filtrate is concentrated. Distillation to constant volume is carried out by the regular addition of ethanol up to the vapour temperature of 74° C. The reaction medium is cooled down to ambient temperature, followed by agitating for one hour, filtering then washing with ethanol. After drying, 145.7 g of sought product is obtained in the form of crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH2:16]([C:23]1[O:27][C:26]([NH2:28])=[N:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[O:27][C:26]([NH:28][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:4]([O:14][CH3:15])[CH:3]=2)=[N:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ncc(Cc2ccccc2)o1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2ncc(Cc3ccccc3)o2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 5-benzyl-oxazol-2-ylamine. The title compound was obtained as a yellow solid (Yield=22%). MS ISP (m/e): 361.3 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]([F:42])([O:21][C:22]([F:41])([F:40])[C:23]([F:39])([O:28][C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:24]([F:27])([F:26])[F:25])[C:3]([F:20])([F:19])[O:4][C:5]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[K+].Cl>O>[Cl:1][C:2]([F:42])([O:21][C:22]([F:40])([F:41])[C:23]([F:39])([O:28][C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:24]([F:25])([F:26])[F:27])[C:3]([F:19])([F:20])[O:4][C:5]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(C(=O)OC)c(OC(F)(F)C(F)(Cl)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(OC(F)(F)C(F)(Cl)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Dimethyl 2-(2-chloro-1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)terephthalate as prepared in Example 3 (10.00 g, 0.0148 mol) was added to a solution of water (100 mL) and potassium hydroxide (KOH, 8.0 g) in a reaction flask. The resulting solution in the reaction flask was heated to reflux overnight, cooled to room temperature (about 25° C.) and then acidified by adding concentrated HCl to the reaction flask to achieve a pH of ˜1, determined by the formation of a precipitate in the reaction flask. The resulting precipitate was filtered and dried under vacuum. NMRs of this precipitate showed the desired material, 2-(2-chloro-1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)terephthalic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[CH:17]([Br:21])[CH2:18][CH2:19]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([Br:21])[C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C(Br)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C1C(Br)CCN1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
6.1 g (14.3 mmol) (RS)—N-(4-benzyloxy-phenyl)-2,4-dibromo-butyramide and 0.1 g of Dowex 2×10 are suspended in 50 ml dichloromethane. 7 ml of a 50% aqueous sodium hydroxide solution is slowly added under vigorous stirring. The resulting reaction mixture is stirred overnight at RT, then poured into 25 ml of cold water. The organic phase is separated, dried and evaporated. The crude material is recrystallised from ethyl acetate to yield 1.72 g (35%) of a brownish solid. Mp=125–126° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl.[C:6]([Cl:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>O.C(Cl)(Cl)Cl>[ClH:11].[C:6]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCN
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCCN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethylenediamine (15 mmol, 10.1 cm3) in water (150 cm3) at 0° C. was adjusted to pH 8.5 with 3N HCl. To this, was added a solution of methacryloyl chloride (16.5 mmol, 16.1 cm3) in chloroform (100 cm3), dropwise, over 2 h. After the addition was complete, the reaction mixture was stirred at 0° C. for a further 2 h. The organic and aqueous layers were then separated, and the aqueous layer extracted with chloroform (3×50 cm3). The aqueous layer was then collected and conc. in vacuo (freeze-dryer) to give a white solid. The residue was subjected to repeated fractional recrystallization from room temperature methanol, and the filtrate concentrated to give N-methacryloyl-ethylenediamine monohydrochloride as a clear, yellow oil (14.32 g. 58%). N-methacryloyl-ethylenediamine monohydrochloride (16 mmol, 20.0 g) was stirred in 2M NaOH (60 cm3) for 10 min. This solution was subsequently diluted to a volume of 160 cm3 with water, and stirred at 0° C. To this mixture was added a solution of acryloyl chloride (17.6 mmol, 14.3 cm3) in chloroform (300 cm3), dropwise, over 3 h. After the addition was complete, the reaction mixture was then stirred at 0° C. for a further 2 h. The organic and aqueous layers were separated, and the aqueous portion extracted with chloroform (3×100 cm3). The organic extracts were combined and concentrated to give the crude product as a white solid. Recrystallization from acetonitrile then gave N-acryloyl, N′-methacryloyl-ethylenediamine as colorless needles (10.70 g, 37%), m.p. 140-142/C. δH (400 MHz; CDCl3) 6.84 (1H, br s), NH; 6.74 (1H, br m), NH; 6.27 (1H, dd, J 16.9, 1.5 Hz), HC═CHaHb; 6.13 (1H, dd, J 17.0, 10.2), HC═CHaHb; 5.74 (1H, s), (H3C)C═CHcHd; 5.65 (1H, dd, J 10.3, 1.6 Hz), HC═CHaHb; 5.34 (1H, br m), (H3C)C═CHcHd; 3.49 (4H, m), 2×CH2; 1.95 (3H, s), CH3. δC (75.4 MHZ:CDCl3) 169.4, NHOC(H3C)C═CH2; 167.0, NHOCHC═CH2; 139.2, (H3C)C═CH2; 130.7, HC═CH2; 126.2, HC═CH2; 120.1, (H3C)C═CH2; 40.4 CH2CH2; 39.5, CH2CH2; 18.4, CH3. Found: M+. 182.1059.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12](C(O)=O)O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[CH:12][N:19]([C:20]2[CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:23]=[CH:24][CH:25]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1ccn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Temperature: 250 °C
Reaction time: 0.17 h

Procedure:
5-(Benzyloxy)-4-oxo-4H˜pyran-2-carboxylic acid (36.9 g, 150 mmol) and 3-aminobiphenyl (25.35 g, 150 mmol) were combined in diphenyl ether (110 ml). The mixture was heated to 250° C. (pre-heated block) in an open flask. After 10 min, the mixture was cooled to room temperature. The residue was purified by silica gel chromatography to provide 3-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one. ′H NMR S (400 MHz, d6-DMSO): 7.55 (d, J=7.6 Hz, 1H), 7.46 (m, 4H), 7.44-7.31 (m, 5H), 7.29-7.11 (m, 4H), 6.51 (d, J=7.2 Hz, 1H), 5.17 (s, 2H). MS (M+H)+354.
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:20](=[O:23])[CH2:21][CH3:22])[C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH:15]([C:20](=[O:23])[CH2:21][CH3:22])[C:16](=[O:19])[CH2:17][CH3:18])[CH2:12][CH2:13]2)=[CH:24][CH:25]=1
Reactant: CCC(=O)C(CC1CCC(Cc2ccc(OC)cc2)CC1)C(=O)CC
Agent: BrB(Br)Br
Product: CCC(=O)C(CC1CCC(Cc2ccc(O)cc2)CC1)C(=O)CC

Procedure:
It is further contemplated that 4-[4-(4-methoxybenzyl)-cyclohexylmethyl]heptane-3,5-dione can be demethylated with boron tribromide according to the procedure of Example 2 to give 4-[4-(4-hydroxybenzyl)cyclohexylmethyl]heptane-3,5-dione [II; Ar is 4-HOC6H4, Y' is CH2, R is C2H5 ].
Reaction SMILES: [N:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O-:9].[Na+]>CO>[N:1]1([C:6](=[NH:7])[O:9][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CN1CCCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCCC1

Procedure:
In the manner given in Example 2, 1-pyrrolidinecarbonitrile is treated with sodium methoxide in methanol to give methyl 1-pyrrolidinecarboximidate.