Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1.[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:42](=[O:44])[CH3:43])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1
Reactant: CCc1cc(NCCCCCCO)nc(Cl)n1
Reactant: CC(=O)Cl
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(NCCCCCCOC(C)=O)nc(Cl)n1
Yield: 65.4 %

Procedure:
In 10 ml of dichloromethane were dissolved 1.00 g of dl-5-chloro-6-ethyl-4-(6-hydroxyhexyl)aminopyrimidine and 0.40 g of acetyl chloride, and under stirring, 0.50 g of triethylamine was added to the solution and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=4:1) to give 0.70 g of the title compound as pale yellow oily product. nD19.6 1.5228.
Reaction SMILES: [C:1]([C:9]1C([N+]([O-])=O)=CC(C(OCC)=O)=CC=1O)(=O)[C:2]1C=CC=C[CH:3]=1.C(I)C.[Cl:27][C:28]1[CH:50]=[CH:49][C:31]([C:32]([C:34]2[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][C:35]=2[OH:48])=[O:33])=[CH:30][CH:29]=1.C(I)CCC>>[CH2:9]([O:48][C:35]1[CH:36]=[C:37]([CH:43]=[C:44]([N+:45]([O-:47])=[O:46])[C:34]=1[C:32](=[O:33])[C:31]1[CH:49]=[CH:50][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:38]([OH:40])=[O:39])[CH2:1][CH2:2][CH3:3]
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Solvent: CCI
Solvent: CCCCI
Product: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(Cl)cc1

Procedure:
By replacing in Example 6, step B, ethyl 4-benzoyl-3-hydroxy-5-nitrobenzoate and ethyl iodide with equimolar amounts of ethyl 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoate and n-butyl iodide respectively and following the procedure described, 3-n-butoxy-4-(4'-chlorobenzoyl)-5-nitrobenzoic acid is obtained with a melting point of 180°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+].Cl.O>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=C[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
p-Methoxybenzaldehyde (11.19 g, 82.2 mmol) and nitromethane (5.0 g, 82.2 mmol) were dissolved in methanol (20 mL) in a two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel. NaOH (4.27 g, 0.107 mol) in ice/water (10 mL) was added dropwise to the solution keeping the temperature below 15° C. A fine slurry formed during addition and additional methanol was added to allow efficient stirring. After the addition the reaction mixture was diluted with ice/water and the resulting clear solution was added dropwise to a solution of HCl/H2O (40 mL/60 mL); a yellow precipitate formed during the addition. The precipitate was filtered on a buchner funnel and crystallized from methanol obtaining 4-methoxy-β-nitrostirene (10.66 g, 72%). Yellow needles. M.p. 57-58° C. ESI-MS: 180 (MH+); (Calc. for C9H9NO3: 179 u.m.a.).
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:48](=O)([O:56]C1C=CC([N+]([O-])=O)=CC=1)[O:49][CH:50]([O:52][C:53](=[O:55])[CH3:54])[CH3:51].O>CN(C)C=O>[C:53]([O:52][CH:50]([O:49][C:48]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:56])[CH3:51])(=[O:55])[CH3:54]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(C)OC(C)=O)CC3)CC2=O)cc1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
To a suspension of 107 mg of ethyl 4-[[2-oxo-4-(piperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 2 ml of N,N-dimethylformamide were added 110 mg of proton sponge and 85.7 mg of 1-acetoxyethyl 4-nitrophenyl carbonate with stirring at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 ml of water and extracted three times with 4 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was removed by distillation. The residue thus obtained was purified by chromatography on an LH-20 column (chloroform:methanol=1:1) to give 119 mg of the title compound (100%).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]4([OH:18])[CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]4([O:18][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C3(O)CC3)ccc12
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)CC1
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Step 2 A solution of 4-bromo-7-(1-hydroxycyclopropyl)-9H-carbazole-1-carboxamide (0.151 g, 0.436 mmol), tert-butylchlorodimethylsilane (0.079 g, 0.524 mmol) and imidazole (0.074 g, 1.091 mmol) in DMF (2.2 mL) was stirred at rt for 18 h. Additional tert-butylchlorodimethylsilane (0.079 g, 0.524 mmol) and imidazole (0.074 g, 1.091 mmol) were added and stirring was continued for 1 h. The mixture was diluted with EtOAc (75 mL) and washed seven times with brine. The organic layer was dried and concentrated and the residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to give 4-bromo-7-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-9H-carbazole-1-carboxamide (0.144 g, 67%).
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:9])[CH3:8])(=O)C.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=O.C(O)(=O)C1C=CC=CC=1>>[CH3:10][C:11](=[CH:12][CH2:13][CH2:9][C:7](=[CH:6][CH:5]=[O:4])[CH3:8])[CH3:15]
Reactant: CC(=O)OCC=C(C)C
Reactant: CC(C)=CC=O
Agent: O=C(O)c1ccccc1
Product: CC(C)=CCCC(C)=CC=O
Yield: 48 %

Procedure:
60 parts of prenyl acetate, 40 parts of 3,3-dimethylacrolein and 2parts of benzoic acid are heated together for five hours thirty minutes at 140°C and the product is worked up. 11.1 parts of citral is obtained having a boiling point of 104°C at 12 mm in a yield of 48% at a conversion of 32% (based on 3,3-dimethylacrolein).
Reaction SMILES: [CH3:1][CH:2]([C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C-:14]#[N:15].[K+]>CCO.O>[C:14]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([CH3:1])[C:11]([OH:13])=[O:12])=[CH:4][CH:5]=1)#[N:15]
Reactant: [C-]#N
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(CC#N)cc1
Temperature: 80 °C

Procedure:
A suspension of 2-(4-bromomethyl)phenylpropionic acid (2.0 g, 8.2 mmol) and potassium cyanide (1.6 g, 24.7 mmol) in EtOH (10 mL) and water (2 mL) was heated at 80° C. in a sealed tube for 1 h. The mixture was cooled to room temperature, diluted with water (10 mL) and the EtOH was removed under reduced pressure. The remaining aqueous mixture was extracted once with EtOAc then acidified carefully with 2N HCl until pH˜3 is reached. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over MgSO4, filtered, and concentrated to give 2-[4-(cyanomethyl)phenyl]propionic acid in ˜90% purity. This material was used directly in the next step. A mixture of 2-[4-(cyanomethyl)phenyl]propionic acid (1.4 g, 7.4 mmol) in MeOH (8 mL) and aqueous NaOH (5N, 8 mL, 40 mmol) was heated at 85° C. in a sealed tube for 1.5 h. The mixture was cooled to room temperature, the MeOH was removed under reduced pressure, and the remaining aqueous was extracted with once ether. The aqueous layer was acidified with 2N HCl until pH˜2 to generate a precipitate that was filtered and dried under vacuum to afford 2-[4-(carboxymethyl)phenyl]propionic acid (1.1 g, 71%) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.27 (br s, 1H), 7.15-7.22 (m, 4H), 3.61 (q, J=6.8 Hz, 1H), 3.50 (s, 2H), 1.30 (d, J=7.2 Hz, 3H); MS (Electrospray): m/z 163.1 (M−CO2H). To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethanamine bis-HCl (0.39 g, 1.3 mmol), 2-[4-(carboxymethyl)phenyl]propionic acid (0.35 g, 1.7 mmol), EDC (0.35 g, 1.8 mmol), and 1-hydroxy-7-azabenzotriazole (0.25 g, 1.8 mmol) in DMF (5 mL) was added diisopropylethylamine (1.2 mL, 6.7 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (20 mL) and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude oil that was purified by preparative reversed-phase HPLC to give 2-{4-[2-oxo-2-(((1R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethyl)amino)ethyl]phenyl}propionic acid mono-TFA salt as a foam; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.6 Hz, 1H), 8.33 (d, J=2.8 Hz, 1H), 7.49 (dd, J=2.8 and 8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.19 (s, 4H), 4.88-4.93 (m, 1H), 4.85 (q, J=8.8 Hz, 2H), 3.62 (q, J=7.2 Hz, 1H), 3.44 (s, 2H), 1.35 (d, J=8.0 Hz, 3H), 1.33 (d, J=7.6 Hz, 3H); MS (Electrospray): m/z 411.4 (M+H).
Reaction SMILES: Cl.C([O:6][C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])=[O:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.3 %

Procedure:
In dichloromethane (50 ml), 1-[2-tert-butoxycarbonyl-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (250 g) was dissolved, followed by the dropwise addition of trifluoroacetic acid (50 ml) under ice cooling. After stirring at room temperature for 5 hours, the solvent was distilled off. The residue was dissolved in methanol and the resulting solution was allowed to stand in a refrigerator for one day. The colorless solid so precipitated was collected by filtration and dried, whereby the title compound (550 mg, 28%) was obtained as a colorless solid.
Reaction SMILES: [Na].Cl.C(O[C:6](=[NH:8])[CH3:7])C.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1>C(O)C>[NH:8]=[C:6]([N:16]([C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:19][CH:18]=1)[NH2:17])[CH3:7]
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(=N)N(N)C(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
1.65 g (72 mmol) sodium are dissolved in 80 mL ethanol. 8.89 g (72 mmol) ethylacetimidate hydrochloride in 160 mL ethanol are added at ambient temperature and the precipitated sodium chloride is filtered off. The filtrate is combined with 6.00 g (40 mmol) 4-methyl-benzoic acid hydrazide and stirred overnight. The reaction mixture is evaporated down and cooled. The precipitated solid is filtered off and washed with cold ethanol and diethyl ether (5.7 g white solid). A further 1.2 g of solid are obtained from the filtrate after distillation of the solvent and recrystallisation from ethanol.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[O:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:25]=3[N:24]=2)=[CH:19][CH:18]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(NC(C)C)(C)C>CN(C)C=O>[NH2:16][C:14]1[O:15][C:11]([CH:2]([NH:1][C:32]([C:30]2[CH:29]=[CH:28][C:26]3[NH:27][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[N:24][C:25]=3[CH:31]=2)=[O:33])[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:12][N:13]=1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccncc3)nc2c1
Reactant: Nc1nnc(C(N)CCc2ccccc2)o1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Nc1nnc(C(CCc2ccccc2)NC(=O)c2ccc3[nH]c(-c4ccncc4)nc3c2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.18 g of 5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-ylamine was dissolved in 10 ml of dry dimethylformamide at RT, treated with 200 mg of 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, 270 mg of TOTU, and 0.12 ml of diisopropylamine, and stirred at RT for 4 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed successively with water, saturated sodium hydrogencarbonate solution, water, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was stirred with methyl tert-butyl ether, filtered off, and dried under high vacuum. 2-Pyridin4-yl-1H-benzimidazole-5-carboxylic acid [1-(5-amino-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]amide, which melts at 160° C. with decomposition, is obtained.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.[CH3:32][NH:33][C:34]([C:36]1[CH:46]=[CH:45][C:39]([CH:40]=[CH:41][C:42](O)=[O:43])=[CH:38][CH:37]=1)=[O:35].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:42](=[O:43])[CH:41]=[CH:40][C:39]3[CH:45]=[CH:46][C:36]([C:34](=[O:35])[NH:33][CH3:32])=[CH:37][CH:38]=3)[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCNCC4)c3Cl)c2n1
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)N2CCN(C(=O)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)CC2)cc1
Reaction time: 3 h
Yield: 116.1 %

Procedure:
To a solution of 8-[2,6-dichloro-3-(piperazine-1-carbonyl)benzyloxy]-2-methylquinoline dihydrochloride (60 mg), 4-(methylcarbamoyl)cinnamic acid (20.9 mg) and 1-hydroxybenzotriazole (22.6 mg) in N,N-dimethylformamide (0.6 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (27.4 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[4-[4-(methylcarbamoyl)cinnamoyl]piperazine-1-carbonyl]benzyloxy]-2-methylquinoline (73 mg) as colorless amorphous.
Reaction SMILES: N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.[F:24][C:25]([F:42])([F:41])[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=2)[CH2:29]1)=[O:27]>C(Cl)(Cl)Cl>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][S:37]([C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[CH2:29][N:28]([C:26](=[O:27])[C:25]([F:42])([F:24])[F:41])[CH2:36]3)(=[O:38])=[O:39])=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.7 %

Procedure:
Pyridine (2.57 mL, 31.9 mmol) and dimethylaminopyridine (195 mg, 1.59 mmol) were added to a solution of 4-fluoroaniline (1.86 g, 16.7 mmol) in chloroform (46 mL) at room temperature and the mixture was cooled in ice. 2-(Trifluoroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride (5.00 g, 15.9 mmol) was added thereto and the mixture was warmed to room temperature and stirred for 15 hr. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed with 1 mol/L hydrochloric acid and brine, the organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was powdered with diethyl ether and collected by filtration to afford the title compound as a pale pink powder (5.85 g).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=1[NH2:26]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][C:25]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=1[F:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(F)c(F)c1C
Yield: 87.1 %

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (1.0 g) and 2,4-difluoroaniline (0.5 g), the procedure of Reference Example 8 is repeated to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate (1.1 g).
Reaction SMILES: C(#N)C.[CH3:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[CH2:6]([N:5]([CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])[CH3:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)C(=O)OC
Reactant: CNCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C(C(=O)OC)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To an acetonitrile (60 mL) solution of N-methylbenzylamine (15 mL), an acetonitrile (10 mL) solution of dimethyl bromomalonate (12 g) was added dropwise at room temperature, and the mixture was stirred for 6 hours at room temperature. Toluene (0.20 L) was added, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. To the residue, toluene (0.10 L) and OH type silica gel (6.0 g) were added, and the mixture was stirred for 20 minutes at room temperature and then filtered. The filtrate was concentrated under reduced pressure to obtain dimethyl [benzyl(methyl)amino]propanedioate (pale yellow oil) (14 g, 96%).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.[CH3:16][CH2:17][Mg+].[Br-].O>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2([NH2:13])[CH2:17][CH2:16]2)[N:9]=[CH:8]1
Reactant: CC[Mg+]
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(C2(N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a round bottom flask was added 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (310 mg, 3.19 mmol) in THF (10 ml), followed by the addition Ti(OiPr)4 (0.9 ml, 3.05 mmol) Next, EtMgBr (3.0 M in ether) (1.85 ml, 5.55 mmol) was added slowly. The clear solution changed to dark and gas evolved was found. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was added with water (10 ml). The solid precipitate was filtered through celite. The filter cake was washed with THF (10 ml), EtOAc (10 ml). The combined solvent was concentrated to afford 400 mg of 1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-cyclopropylamine, m/z 254.6 [M+1]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccc(F)cc2)CC1

Procedure:
4-(fluoro)phenyl chloroformate (5.00 g, 28.6 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.90 g, 21.9 mmol) according to general procedure 1. Yield=5.54 g, 99%. m/z MH+=262.03. HPLC rt=10.6 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](C2C=CC=C(C)C=2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([N:30]1[CH:34]=[CH:33]N=C1)(N1C=CN=C1)=[O:24]>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:30]([C:34]3[CH:33]=[CH:4][CH:3]=[C:2]([CH3:7])[CH:1]=3)[C:23](=[O:24])[NH:15][CH2:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(C2(CN)CCN(Cc3ccccc3)CC2)c1
Solvent: ClCCl
Product: Cc1cccc(N2C(=O)NCC23CCN(Cc2ccccc2)CC3)c1
Reaction time: 72 h

Procedure:
A mixture of 1-benzyl-4-(3-methylphenyl)-4-aminomethyl-piperidine (0.52 g, 1.67 mmol) and 1,1′-carbonyldiimidazole (0.41 g, 2.5 mmol) in dichloromethane (2 mL) was stirred at room temp. for 3 days. The resultant solution was concentrated and the residue subjected to column chromatography on silica gel eluting with a 1:1 mixture of chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the title compound. FAB MS m/e 336 (M+1)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([N:21]=[C:22]=[S:23])[CH:20]=1>C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([NH:21][C:22](=[S:23])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:20]=1
Reactant: NCC(N)=O
Reactant: COc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of glycinamide hydrochloride (5.5 g), triethyl amine (5.05 g), 5-chloro-2-methoxyphenyl-isothiocyanate (9.95 g), and chloroform (500 mL) were heated at reflux for 3 hours. The mixture was then cooled to ambient temperature and washed with water (300 mL). The organic phase was separated. Precipitate formed upon standing. The solid was collected by filtration, washed with water, then with diethyl ether and air dried to give 2-[3-(5-chloro-2-methoxyphenyl)-thioureido]acetamide (12.8 g), m.p. 166°-169° C. (dec.). This compound was used without further purification for the preparation of the title compound.