Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:20][CH:19]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH:18]4[CH2:17]3)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:17][CH:18]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH:19]4[CH2:20]3)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(NC(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
14 mg (0.04 mmol) of cesium carbonate were added to a solution of 35 mg (0.09 mmol) of tert-butyl 5-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 10 μl (0.08 mmol) of benzoyl chloride were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and purified by means of preparative HPLC (acetonitrile/water+0.5% trifluoroacetic acid, gradient: 20/80 to 100/0). 10 mg (22% of the desired compound were obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>C(O)C.CO.ClCCl>[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]3[CH:2]=2)=[C:6]([CH3:16])[CH:7]=1
Reactant: Cc1cc(OCCCCl)ccc1C(=O)CBr
Reactant: Cc1ccnc(N)c1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Cc1ccn2cc(-c3ccc(OCCCCl)cc3C)nc2c1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (6.77 g) and 2-amino-4-picoline (2.4 g) in ethanol (22 mL) was heated at 72° C. for 10 hours. The reaction mixture was cooled to ambient temperature and dissolved in methanol/dichloromethane and treated with Dowex® 550A basic resin until the pH of the mixture was 7. The resin was removed via filtration and the filtrate evaporated. The title compound was precipitated from ethyl acetate upon addition of hexanes and used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:16])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:6]=1.I[CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH3:3][O:4][C:5]1[C:10]([N:11]([CH2:31][CH2:32][CH3:33])[C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:16])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:6]=1
Reactant: CCC(=O)Nc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)CC)c1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
60% NaH (23 mg, 0.58 mmol) is added to a solution of N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propionamide (0.15 g, 0.39 mmol) in DMF (1 ml) at room temperature. After stirring at room temperature for 20 minutes, iodo propane (0.058 ml, 0.58 mmol) is added. The mixture is stirred at room temperature for 3 days. 20 ml of water is added and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography to give N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-N-propyl-propionamide. Rf (hexane/EtOAc=2:1)=0.42.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:43])[NH:22][CH2:23][C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:25]([O:27]N1C(=O)CCC1=O)=O)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)CCCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(OC(C)(C)C)=O)C(ON1C(=O)CCC1=O)=O)(C)(C)C.[NH2:92][CH2:93][C@H:94]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[C:95]([OH:97])=[O:96]>CN(C=O)C>[C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:43])[NH:22][CH2:23][C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[C:25](=[O:27])[NH:92][CH2:93][C@H:94]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[C:95]([OH:97])=[O:96])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NC[C@H](NC(=O)OC(C)(C)C)C(=O)NC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
15-[(S)-2-tert-Butoxycarbonylamino-2-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)ethylcarbamoyl]pentadecanoic acid tert-butyl ester can be prepared in similar fashion as that described for 15-[(S)-5-tert-butoxycarbonylamino-5-(2,5-dioxopyrrolidin-1-yloxycarbonyl)pentylcarbamoyl]pentadecanoic acid tert-butyl ester using (S)-3-amino-2-tert-butoxycarbonylamino propionic acid, and it can be reacted with (S)-3-amino-2-tert-butoxycarbonylamino propionic acid in DMF at RT for 16 h. After concentrating under vacuum, AcOEt can be added the residue and the mixture can be washed with 0.2 N HCl. The organic phase is then dried over MgSO4 and concentrated under vacuum to yield the crude product, 15-[(S)-2-tert-butoxycarbonylamino-2-((S)-2-tert-butoxycarbonylamino-2-carboxyethylcarbamoyl)ethylcarbamoyl]pentadecanoic acid tert-butyl ester. This can either be used without further purification or purified by flash chromatography.
Reaction SMILES: [C:1]([C:3](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:21]([I:30])[CH:20]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=O)#[N:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:16][C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[NH:6][C:4]1[C:24]2[C:19](=[CH:20][C:21]([I:30])=[C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:23]=2)[N:18]=[CH:17][C:3]=1[C:1]#[N:2]
Reactant: COCCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{[3-iodo-4-(2-methoxyethoxy)phenyl]amino}acrylamide (1.0 g, 1.80 mmol) in 35 mL of toluene was heated to reflux and phosphorous oxychloride (1.7 mL, 18.0 mmol) was added dropwise. The mixture was heated at reflux for 2 hours, and an additional 1.7 mL of phosphorous oxychloride was added. The mixture was continued to heat at reflux for 2 hours, and an additional 1.7 mL of phosphorous oxychloride was added and the reaction mixture was heated at reflux overnight. The reaction is then cooled to room temperature and water was added followed by 10 N sodium hydroxide. The mixture was stirred in an ice-bath for 30 minutes and the precipitate was collected by filtration, washed with methylene chloride to give 870 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-iodo-6-(2-methoxyethoxy)-3-quinolinecarbonitrile as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 3.41 (s, 3H), 3.81 (t, 2H), 3.87 (s, 3H), 4.34 (t, 2H), 7.40 (s, 1H), 7.78 (s, 1H), 7.88 (s, 1H), 8.43 (s, 1H), 8.45 (s, 1H), 9.85 (s, 1H); MS (ES) m/z542.1, 544.1 (M−H)−
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[NH:23][N:22]=[N:21][N:20]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].I[CH2:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[N:23]=[N:22][N:21]([CH2:25][C:26]5[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=5[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:20]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3].[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[N:23]([CH2:25][C:26]5[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=5[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:22]=[N:21][N:20]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(-c4nnn[nH]4)ccc3o2)n1
Reactant: CCOC(=O)c1ccccc1CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)c1ccccc1Cn1nnc(-c2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)n1
Product: CCOC(=O)c1ccccc1Cn1nnnc1-c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1

Procedure:
A mixture of 5-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-1H-tetrazole (1.55 g), ethyl 2-iodomethylbenzoate (1.67 g) and potassium carbonate (1.80 g) in 2-butanone (15 ml) was stirred under reflux for 5 hours. After being cooled, the resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 5-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-[2-(ethoxycarbonyl)phenylmethyl]-2H-tetrazole (2.05 g) and 5-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-1-[2-(ethoxycarbonyl)phenylmethyl]-1H-tetrazole (0.24 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCc2ccccc2C1
Solvent: CCOCC
Product: Fc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of p-fluorophenyl magnesium bromide, and 200 ml. of diethyl ether is stirred for four hours and then refluxed for one hour. The mixture is acidified with the addition of 200 ml. of 1N hydrochloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated. The residue, containing 2-p-fluorophenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5% palladium-on-charcoal catalyst; the resulting mixture is heated to 200°C for six hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2-p-fluorophenylnaphthalene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([Cl:24])[CH:26]=3)=[CH:16][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a solution of 1.65 g (4.83 mmol) of (3′-amino-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (100 mL) is added 0.64 mL (5.0 mmol) of 3-chlorobenzoyl chloride. After stirring at room temperature overnight the mixture is concentrated under reduced pressure. The residue is diluted with water and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash silica gel chromatography to provide 1.40 g (60.4%) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a white foam.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([CH3:21])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15](Cl)[N:14]=1.[C:22]1([CH:29]=[CH:28][CH:27]=[C:25]([OH:26])[CH:24]=1)[OH:23].Cl>S1(CCCC1)(=O)=O>[C:5]1([CH3:21])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[N:18]=[C:17]([C:27]2[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=2[OH:26])[N:16]=[C:15]([C:27]2[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=2[OH:26])[N:14]=1
Reactant: Cc1cc(C)c(-c2nc(Cl)nc(Cl)n2)c(C)c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(C)c(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reaction time: 14 h
Yield: 84.6 %

Procedure:
148.7 g (1.21 mol) of anhydrous aluminium trichloride (purity 98%) are added with stirring to a suspension of 130.0 g (0.485 mol) of 2-mesityl-4,6-dichloro-1,3,5-triazine (i) in 300 ml of petroleum ether with a boiling range of 110°-140° C. and 385 ml of sulfolane. During this addition, the mixture warms to 45° C. A solution of 133.5 e (1.21 mol) of resorcinol (purity 98%) in 155 ml of sulfolane is added to the mixture over the course of 45 minutes. The mixture is warmed at 80°-85° C. for 5 hours 30 minutes with evolution of HCl. The upper phase (petroleum ether) is removed, and the lower, viscous phase is transferred while still hot into a stirred mixture of 2.11 of methanol and 2.11 of water. After the mixture has been stirred for 14 hours, the solid is filtered off, stirred in 2.2 l of 1 molar HCl for 1 hour and re-filtered. The filter cake is suspended in 1000 ml of water, stirred for 30 minutes and re-filtered. This operation is repeated twice. The filter cake is dried for 24 hours at 80° C. and a pressure of 60 mmHg (8000 Pa), giving 170.5 g of the title product (ii) of the formula ##STR62## of m.p. 230°-234° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1.C([Mg]Br)C.Br[C:18]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[C:19]=1[Br:25].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[Br:25][C:19]1[C:20]([NH:22][C:23](=[O:24])[C:18]=1[C:6]1[C:5]2[C:9](=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[NH:8][CH:7]=1)=[O:21]
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2c[nH]c3cc4c(cc23)OCO4)=C1Br
Yield: 56.8 %

Procedure:
6.44 g (40 mmol) 5,6-methylenedioxyindole are dissolved in 300 ml anhydrous toluene and mixed dropwise at 60° C. with 20 ml of a 2M solution of ethyl magnesium bromide in tetrahydrofuran (Aldrich). After completion of the addition, there is added dropwise thereto a solution of 1.7 g (6.67 mmol) dibromomaleinimide in 50 ml toluene, with the addition of the minimum amount of tetrahydrofuran required for solution, and then heated under reflux for 18 hours. After cooling, the reaction mixture is mixed with a saturated aqueous solution of ammonium chloride, the organic phase is separated off and the aqueous phase is extracted three times with toluene and once with ethyl acetate. The combined organic phases are dried, rotary evaporated and chromatographed in silica gel (elution agent: dichloromethane/ethyl acetate 30:1 v/v). There is obtained 1.27 g (56% of theory) 2-bromo-3-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide; m.p. about 185° C. (decomp.); RF=0.50 (dichloromethane/ethyl acetate 3:1 v/v); and 0.63 g (22.5% of theory) 2,3-bis-(5,6-methylenedioxy-1H-indol-3-yl)-maleinimide in the form of red crystals; m.p, about 270° C. (decomp.), after recrystallisation from propanol; RF=0.36 (dichloromethane/ethyl acetate 3:1 v/v).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)C.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([CH2:16][C:17]#[N:18])=[O:15].[CH2:19]([N:26]1CCC(=O)CC1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:5][C:4]2[CH2:1][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:6][CH2:7][C:8]=2[C:16]=1[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1cccs1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N#CCC(=O)c1cccs1
Agent: [S]
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1cccs1)CCN(Cc1ccccc1)C2
Yield: 78 %

Procedure:
The procedure of Example 1 was followed except that 2-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-2-carbonyl)acetonitrile (Steps A and B). 1-Benzyl-4-piperidone (van der Klein et al., (1999), J. Med. Chem. 42: 3629–3635), 2-(thiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 78%; IR (KBr) cm−1: 3412, 2928, 1570, 1419, 1355, 1265, 1119, 700; 1H NMR (CDCl3):δ 2.35 (t, 2H, J=5.2 Hz), 2.59 (t, 2H, J=5.6 Hz), 3.47 (s, 2H), 3.67 (s, 2H), 6.26 (bs, 2H), 7.05 (m, 1H), 7.30 (d, 1H, J=5.2 Hz), 7.35 (m, 5H), 7.53 (d, 1H, J=4 Hz); yellow solid, mp: 122–123° C. (petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:20]=[CH:19]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(N)nc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 99.7 %

Procedure:
To a solution of 2-amino-5-bromopyridine (300 mg, 1.73 mmol) in DMF (1.5 mL) and proprionitrile (3.5 mL) under Argon were added DIPEA (613 μL, 3.71 mmol), tert-butyl acrylate (1.02 mL, 7.06 mmol), tri(o-tolyl)phosphine (106 mg, 0.35 mmol) and palladium acetate (39 mg, 0.17 mmol). The mixture was stirred at 100° C. for 20 h, then allowed to come back to room temperature, filtered through Celite pad and rinsed with EtOAc. The residue obtained after concentration was purified by flash chromatography (eluent: 95/5 DCM/MeOH) to give the title compound as an orange solid (380 mg, quantitative).
Reaction SMILES: Cl.[CH:2]1([CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.C(Cl)Cl.[OH:24][CH:25]([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>CCOCC>[CH:2]1([CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16]([O:24][CH:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:30][CH3:31])=[O:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: CCC(O)C(=O)OC
Reactant: O=C(Cl)CCc1ccc(NCC2CC=CCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(OC(=O)CCc1ccc(NCC2CC=CCC2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-(cyclohex-3-enylmethylamino)hydrocinnamoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl 2-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-(cyclohex-3-enylmethylamino)hydrocinnamate as a white solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[O:9]=[C:10]1[NH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])[C:12](=[O:27])[N:11]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1>CN(C=O)C>[O:9]=[C:10]1[N:14]([CH3:1])[C:13]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)([CH2:15][O:16][CH2:17][CH:18]=[CH2:19])[C:12](=[O:27])[N:11]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:38])([F:39])[F:37])[CH:29]=1
Reactant: C=CCOCC1(c2ccc(F)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2ccc(F)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
325 mg of potassium carbonate and 0.25 mL of iodomethane are added to a solution of 0.85 g of 4-[2,5-dioxo-4-(4-fluorophenyl)-4-[(2-prop enyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in step 4, dissolved in 3 mL of DMF. The mixture is stirred at rt for 4 hours under argon atmosphere, evaporated to dryness, diluted with water and brine and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58][CH2:59][CH2:60]CO)=[C:54]([CH3:63])[CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:60][CH2:59][S:58][C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][C:54]=2[CH3:63])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: Cc1cc(Cl)ccc1SCCCO
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCSc4ccc(Cl)cc4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 61.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (82 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[4-chloro-2-methylphenyl]sulfanyl-1-propanol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 58%).