Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18][C:19]([CH3:22])([O-])[CH3:20].[K+]>CN(C=O)C.ClCCCl.C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][C:19]([CH3:22])([CH3:20])[CH3:18])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
A solution of 2-chloro-5-nitrobenzoic acid (10.14 g, 50.3 mmol), thionyl chloride (4.4 mL, 60 mmol) and DMF (4 drops) in 1,2-dichloroethane (150 mL) was stirred at reflux for 14 h, cooled and evaporated. The acid chloride was dissolved in THF (100 mL), cooled to 0° C., and a solution of potassium t-butoxide (5.57 g, 50 mmol) in THF (150 mL) added dropwise over 30 min under nitrogen. The mixture was stirred a further 15 min at 0° C., diluted with aq. NaHCO3, extracted with EtOAc (×2), and the extracts dried (Na2SO4) and evaporated. Crystallisation from petroleum ether gave t-butyl 2-chloro-5-nitrobenzoate as a white crystalline solid (10.1 g, 78%), mp 91.5-92° C. 1H NMR (CDCl3) δ8.59 (d, J=2.8 Hz, 1H, H-6), 8.24 (dd, J=8.8, 2.8 Hz, 1H, H-4), 7.63 (d, J=8.8 Hz, 1H, H-3), 1.65 (s, 9H, t-Bu); 13C NMR (CDCl3) d 163.0 (CO2tBu), 146.1, 140.0, 133.3, (C-1,2,5), 132.0, 126.1, 126.0 (C-3,4,6), 84.0 (CMe3), 28.1 (CH3). Anal. Calculated for C11H12ClNO4 : C, 51.3; H, 4.7; N, 5.4; Cl, 13.8. Found: C, 51.3; H, 4.5; N, 5.6; Cl, 14.0%.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:27][CH:26]=1)=[O:24]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccccc3Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.2 %

Procedure:
To a solution of theophylline (0.90 g) in DMF (20 ml) were added potassium carbonate (0.83 g) and 4-(2-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 13 hours. This reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as needles (1.70 g, 83%). 1H-NMR (CDCl3) δ: 3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.30-7.48(6H,m), 7.63(1H,s), 7.76-7.85(2H,m).
Reaction SMILES: C(CC(O)=O)#N.C([CH:9]1[CH2:14][CH:13]2[C:15]([CH3:17])([CH3:16])[CH:12]2[CH2:11][CH:10]1[CH3:18])=O>>[CH:12]12[C:15]([CH3:17])([CH3:16])[CH:13]1[CH2:14][CH:9]=[C:10]([CH3:18])[CH2:11]2
Reactant: CC1CC2C(CC1C=O)C2(C)C
Agent: N#CCC(=O)O
Product: CC1=CCC2C(C1)C2(C)C

Procedure:
The condensation of cyanoacetic acid and 4-formylcarane obtained via the Prins reaction of 3-carene as described in Annalen 613, p. 43 (1958), was carried out according to the procedure of Example 3A. Yield 73% of the isomeric mixture 3-(3,7,7-trimethylbicyclo [4.1.0]heptylidene-4)propanenitrile and 3-(3,7,7-trimethylbicyclo [4.1.0]heptyl-4)acrylonitrile, b.p. 99°-103° C. at 0.6 mm Hg, nD20 =1.4950, with metallic, woody, rosy odour.
Reaction SMILES: CN(OC)[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH:13]([Mg]Br)=[CH2:14].[NH4+].[Cl-]>C1COCC1>[CH:5]1([C:3](=[O:4])[CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the stirring solution of N-methyl-N-methoxy-cyclohexanecarboxamide (0.05 mol, 8.5 g) in 150 ml anhydrous THF at −10-0° C. (ice-NaCl bath) the solution of vinyl magnesium bromide (1M in THF, 0.1 mol, 100 ml) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h (white solid formed), then at rt for 4 h (the solid dissolved). The resulting solution was added slowly by cannula into a well-cooled Erlenmeyer flask equipped with magnetic stirrer and thermometer, containing 0.5 L saturated aqueous NH4Cl, with such speed that the temperature stays between 0° C. and +10° C., at vigorous stirring. At higher temperatures oligomerization of the product occurs. The phases were separated; the aqueous one extracted with EtOAc (3×100 ml), and the combined organic extracts were washed with sat. aq. NH4Cl until pH<7 (5×50 ml, carefully removing all the N,O-dimethylhydroxylamine product), then washed with brine (100 ml), dried with Na2SO4, and concentrated under vacuum >80 mbar (taking care not to evaporate the volatile product). Yield 11.8 g of yellow oil containing pure vinylcyclohexylketone. Used in the next reaction without purification as 0.05 mol. 1H NMR (400 MHz, CDCl3) δ 6.41 (dd, 1H, 17.5 Hz, 10.3 Hz, Z—H—CH═C), 6.25 (dd, 1H, 17.5 Hz, 1.4 Hz, E-H—CH═C), 5.74 (dd, 1H, 10.3 Hz, 1.4 Hz, CO—CH═C), 2.60 (m, 1H, cyclohexyl CH—CO), 1.9-1.7 (m, 3H, cyclohexyl), 1.7-1.5 (m, 2H, cyclohexyl), 1.4-1.2 (m, 5H, cyclohexyl).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][O:57][C:58]1[C:63]([C:64]([O:66][CH3:67])=[O:65])=[C:62]([OH:68])[C:61]([Br:69])=[CH:60][CH:59]=1)=[O:51])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:33])[C:14](=[O:25])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[C:9]([CH2:48][CH3:49])[CH:8]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl.[OH-].[Na+]>C1COCC1.CO>[C:1]([NH:4][C@H:5]([C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][O:57][C:58]1[C:63]([C:64]([O:66][CH3:67])=[O:65])=[C:62]([OH:68])[C:61]([Br:69])=[CH:60][CH:59]=1)=[O:51])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:14]([C:15]([OH:17])=[O:16])=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([OH:34])=[O:33])=[C:9]([CH2:48][CH3:49])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(C[C@H](NC(C)=O)C(=O)NCCCCOc2ccc(Br)c(O)c2C(=O)OC)ccc1N(C(=O)C(=O)OCc1ccccc1)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(C[C@H](NC(C)=O)C(=O)NCCCCOc2ccc(Br)c(O)c2C(=O)OC)ccc1N(C(=O)C(=O)O)c1ccccc1C(=O)O
Reaction time: 3 h

Procedure:
Methyl 6-{4-[(N-acetyl-4-{{2-[(benzhydryloxy)carbonyl]phenyl}[(benzyloxy)(oxo)acetyl]amino}-3-ethylphenylalanyl)amino]butoxy}-3-bromo-2-hydroxybenzoate was treated with trifluoroacetic acid (500 μL)/methylene chloride (500 μL) at ambient temperature for 4 hours, concentrated under reduced pressure and co-evaporated with acetonitrile (2×10 mL). The residue was taken up in 1N NaOH (3 eq.)/methanol (250 μL)/THF (250 μL), stirred for 3 hours and concentrated under reduced pressure to provide the titled compound. MS (ESI (+)) m/e 742, 743 (M+H)+; 1H NMR (500 MHz, DMSO-d6) 8.08-7.92 (m, 2H), 7.45-6.94 (m, 7H), 6.64 (d, 2H), 4.43-4.38 (m, 1H), 3.90-3.86 (m, 2H), 3.78 (s, 3H), 3.10-3.05 (m, 2H), 2.90-2.85 (m, 1H), 2.75-2.62(m, 3H), 1.76(s, 3H), 1.64-1.58 (m, 2H), 1.52-1.45 (m, 2H), 1.18 (t, 3H).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1)=[O:10].[C:20]([C:22]1[CH:39]=[CH:38][C:25]([O:26][CH2:27][CH:28]([NH:30][C:31](=[O:37])[C@H:32]([CH:34]([CH3:36])[CH3:35])[NH2:33])[CH3:29])=[CH:24][CH:23]=1)#[N:21].O>C(Cl)Cl>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH:28]([NH:30][C:31](=[O:37])[C@H:32]([CH:34]([CH3:35])[CH3:36])[NH:33][C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)=[O:10])[CH3:29])=[CH:38][CH:39]=1)#[N:21]
Reactant: Cc1ccc(OC(=O)Cl)cc1C
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc(OC(=O)N[C@H](C(=O)NC(C)COc2ccc(C#N)cc2)C(C)C)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
0.6 g of N-methylmorpholine, and subsequently 1.2 g of 3,4-dimethylphenyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.7 g of the desired product in the form of a white crystal (yield: 74%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>C(O)C.C(O)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:15][N:14]([CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)N(C)C
Reactant: CN(N)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CON=C(C(=O)N(C)C)C(C)=NN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
1.0 g (5.8 mmol) of 2-methoxyimino-N,N-dimethylacetoacetamide was dissolved in 15 ml of ethanol and 0.5 ml of acetic acid, and 0.78 g (6.4 mmol) of N-methyl-N-phenylhydrazine was added and the mixture was stirred for 24 hours at room temperature. After distilling the solvent of water was added and the mixture was extracted three times with 20 ml of diethylether. After washing with a dilute hydrochloric acid, water and a saturated aqueous sodium chloride, the mixture was dried over with anhydrous magnesium sulfate, and the solvent was distilled of, and finally the residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 1.38 g (yield: 86%) of 2-methoxyimino-N,N-dimethy-3-(N-methyl-N-phenylhydrazono)butyramide as a yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(-n2cccn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Yield: 0.1 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (15 mL). This was followed by dropwise addition of a 4-(1H-pyrazol-1-yl)benzonitrile (250 mg, 1.48 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) with stirring at 0° C. To this was added LiAlH4 (337 mg, 8.87 mmol, 6.00 equiv). The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of NaOH (15%, aq). The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was obtained as 0.251 mg of a white crude solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][O:28][C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)=[O:30].CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:29]([O:28][CH3:27])=[O:30])[CH:36]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)c1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3-methoxycarbonylphenylboronic acid (0.158 g) in ethanol (1 ml). The mixture was heated under reflux for 2 hours, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from ether/hexane gave the title compound as an light brown solid, m.p. 214-6° C.
Reaction SMILES: [Br:1][C:2]([F:9])([F:8])[C:3](OCC)=[O:4].[NH:10]([CH3:12])[CH3:11]>C1COCC1>[Br:1][C:2]([F:9])([F:8])[C:3]([N:10]([CH3:12])[CH3:11])=[O:4]
Reactant: CNC
Reactant: CCOC(=O)C(F)(F)Br
Solvent: C1CCOC1
Product: CN(C)C(=O)C(F)(F)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of ethyl bromodifluoroacetate (370 g, 1.82 mol) in 1000 mL of THF was added a solution of Me2NH in THF (2.0 M, 1000 mL, 2.0 mol). A slightly exothermic reaction occurred. The solution was stirred at room temperature overnight. The solvent was then carefully removed by distillation and the residue purified by rectification. The product was obtained as a colorless liquid (343 g, >99% pure by GC, 1.7 mol, 93% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26].[CH2:27]1[O:29][CH2:28]1>C1COCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH2:28][OH:29]
Reactant: Cc1ccncc1Br
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: OCCCc1ccncc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
Diisopropylamine (7.1 g, 70 mmol) is dissolved in THF (100 ml), and thereto is added a solution of n-butyl lithium in hexane (35.7 ml, 60 mmol) at −70° C., and the mixture is stirred for 15 minutes. Then, to the mixture is added a solution of 3-bromo-4-methylpyridine (8.6 g, 50 mmol) in THF (30 ml). Ten minutes thereafter, to the mixture is added ethylene oxide (2.6 g, 60 mmol), and the mixture is warmed to 0° C. over a period of time for one hour. The reaction is quenched with a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (150 ml×2). The organic layer is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (8.5 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[S:40]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:42]3[CH:43]=[CH:44][S:40][CH:41]=3)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(C)=O)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 93.6 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-acetyl-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (303 mg, 0.5 mmol), 3-thiopheneboronic acid (128 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (326 mg, 1.0 mmol) to obtain 4-[3-[6-(3-acetyl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (285 mg, 94%) as a light brown oil: ES(+)-HRMS m/e calcd for C35H44O7S (M+Na)+ 631.2700. found 631.2704.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.P(Cl)(Cl)([Cl:23])=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1
Reactant: CCCCc1ccc2nc(C(=O)OCC)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCc1ccc2nc(C(=O)OCC)cc(Cl)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
126 parts of ethyl 4-hydroxy-6-n-butylquinoline-2-carboxylate, prepared as described in Example 2, and 213 parts of phosphorus oxychloride were stirred together. After the exothermic reaction had subsided the dark-coloured mixture was stored for 1 hour at room temperature then cooled to 0°C, diluted with 75 parts of ethanol to improve its mobility and subsequently added dropwise to 500 parts of ice and 1500 parts of water. The aqueous mixture was neutralised to pH 7 - 8 by addition of sodium carbonate when 133.2 parts of a light brown coloured crystalline solid separated out and were collected by filtration and dried. This material was purified by recrystillisation from about 380 parts of acetone (with carbon treatment) and yielded 100.8 gm. of ethyl 4-chloro-6-n-butylquinoline-2-carboxylate which was isolated as pale grey needles, m.pt. 58°- 58.5°C. An additional 27.5 parts of less pure product, m.pt. 54.5°-56°C, was obtained by dilution of the acetone mother-liquor with water.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN1CCOCC1>CN1C(=O)CCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of 3-fluoro-5-amino-6-nitrotoluene (10 g, 58.79 mmol) in anhydrous NMP (160 mL) under nitrogen was added BOC-piperazine (39 g, 209.4 mmol) and 4-methylmorpholine (25.9 mL). The resulting dark solution was heated to reflux for 72 h, cooled to room temperature and diluted with ethyl acetate (4000 mL). The organic layer was washed with water (8×1500 mL), brine (1×1500 mL), dried over sodium sulfate and evaporated in vacuo. The resulting dark oil was dissolved in boiling absolute ethanol (800 mL) and concentrated to a total volume of 400 mL and left to stand overnight at room temperature. The solution was further cooled to −20° C. for 5 h and the resulting solid was filtered off and dried in vacuo to give 16.3 g (83%) of a light yellow solid. 1H NMR (500 MHz, CDCl3) δ 6.16 (brs, 1H), 6.04 (brs, 1H), 3.70–3.60 (m,4H), 3.38–3.25 (m, 4H), 2.53 (s, 3H), 1.48 (s, 9H); LCMS (M+H)+ m/z 337.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][NH2:5]
Reactant: Cc1cc(Cl)cc(Cl)c1C#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Cl)cc(Cl)c1CN

Procedure:
The preparation takes place in analogy to Example 6A from 2,4-dichloro-6-methylbenzonitrile with subsequent treatment with 4N hydrochloric acid in dioxane.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[C:12]2[CH:20]=[O:21])C1C=CC=CC=1.CO>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[C:12]2[CH:20]=[O:21]
Reactant: COc1cc2[nH]cc(C=O)c2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2[nH]cc(C=O)c2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
5-Benzyloxy-6-methoxyindole-3-carboxaldehyde (0.75 g) was suspended in a mixed solvent of methanol (60 ml) and ethyl acetate (20 ml), and 10% palladium on carbon (85 mg) was added thereto, followed by stirring at room temperature for one hour under an atmosphere of hydrogen. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 5-hydroxy-6-methoxyindole-3-carboxaldehyde (0.51 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[O:9][CH2:10][C:4]=2[C:3]=1[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].[C:25](=O)([O:41]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][O:33][N+:34]([O-:36])=[O:35]>CN(C=O)C.O>[C:25](=[O:41])([O:18][C:3]1[C:4]2[CH2:10][O:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:5]=2[CH:6]=[N:7][C:2]=1[CH3:1])[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][O:33][N+:34]([O-:36])=[O:35]
Reactant: Cc1ncc2c(c1O)COC2c1ccc(Cl)cc1
Reactant: O=C(OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc2c(c1OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])COC2c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of cicletanine (120 mg, 0.55 mmol) in DMF (10 mL) was added Cs2CO3 (373 mg, 1.15 mmol) and followed by 5,6-bis(nitrooxy)hexyl 4-nitrophenyl carbonate (210 mg, 0.54 mmol). The mixture was stirred at rt over night and diluted with H2O, extracted with CH2Cl2 and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column 25M; TLC method: n-hexane/ethyl acetate 5/5; Rf=0.35), affording product. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.36-7.27 (m, 4H), 6.21 (s, 1H), 5.34 (m, 1H), 5.26 (m, 1H), 5.13 (m, 1H), 4.77 (m, 1H), 4.48 (m, 1H), 4.32 (m, 2H), 2.51 (s, 3H), 1.84 (m, 4H), 1.69-1.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[C:33]([NH:37][C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][C:38]([NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:46])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-tert-butyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-tert-butyl-acetamide in an analogous manner as described in example 1. LR-MS: 642.3 [(M+H)+]