Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)=[CH2:2].[O:22]1[C:26](=O)[CH2:25][NH:24]C1=O.Cl.N>C(Cl)Cl.O>[ClH:21].[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:24][CH2:25][C:26]1=[O:22])=[CH2:2]
Reactant: C=COCCNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C1CNC(=O)O1
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: C=COCCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
To a solution of 0.3g of 2-(β-vinyloxyethyl)amino-5-chlorobenzophenone in 20 ml of dry methylene chloride is added 0.27g of oxazolidin-2,5-dione. To the mixture is added 20 ml of etheral hydrogen chloride under cooling. The mixture is allowed to stand at room temperature with occasional stirring. The reaction mixture is poured into water, basified with aqueous ammonia and extracted with methylene chloride. The extracts are combined and dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is dissolved in ether and treated with ethanolic hydrogen chloride to give 1-(β-vinyloxyethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one hydrochloride, m.p. 213° - 215° C (dec). Recrystallization from isopropanolchloroform gives colorless prisms, m.p. 216° - 218° C (dec.).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[CH:5][C:6]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8](OC)=[O:9])#[N:2].[NH2:18][NH2:19]>CCO>[C:1]([C:3]1[C:4]([CH3:17])=[CH:5][C:6]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([NH:18][NH2:19])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)c(C)cc1C1CCC1
Reactant: NN
Solvent: CCO
Product: Cc1cc(C2CCC2)c(C(=O)NN)cc1C#N
Temperature: 90 °C
Yield: 95 %

Procedure:
To a solution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (compound 89.4, 2.0 g, 8.73 mmol) in EtOH (10 mL) was added anhydrous hydrazine (2 mL, excess) at room temperature. The mixture was heated at 90° C. overnight, then the mixture was cooled to room temperature and partitioned between water (60 mL) and EtOAc (200 mL). The organic layer was washed with water (×2), brine, dried (Na2SO4), filtered, and concentrated to yield 1.9 g (95%) of the title compound as a white solid. m/z (ES+) 230 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.32 (s, 1H), 6.91 (br, 1H), 4.08 (br, 2H), 3.89 (m, 1H), 2.61-2.52 (m, 3H), 2.42-2.28 (m, 2H), 2.18-1.98 (m, 3H), 1.91-1.78 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH2:56][C:57]([F:60])([F:59])[F:58])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCCC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCCC(F)(F)F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 82 mg (0.3 mmol) of (4-tert-butyl-benzyl)-(4,4,4-trifluoro-butyl)-amine in 1 ml DMF were added. After stirring for 19 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo to give 130 mg (99%) of an orange solid. MS (ISP) 416.2 (M+H)+.
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12].C>O1CCOCC1>[N-:9]=[C:4]=[O:3].[CH3:2][O:15][C:14](=[O:16])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH2:9]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)C(C)C
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of valine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give valine methyl ester isocyanate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[CH3:32]>>[CH2:31]([N:33]([CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: CCNCc1ccncc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCN(Cc1ccncc1)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-pyridin-4-ylmethyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 477.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]O.S(=O)(=O)(O)O>O>[CH3:14][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:8]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
Approximately 18.1 g of 4-methyl-3-nitrobenzoic acid was added to approximately 50 ml of methanol. Approximately 2 ml of concentrated sulfuric acid was added to this solution. The resulting solution was heated to reflux temperature and stirred at this temperature for 16 hours. The solution was cooled and approximately 300 ml of water was added. The resulting composition was extracted with 200 ml of ether. The ether phase was saved and the aqueous phase was discarded. The ether phase was then sequentially washed with 100 ml of water, followed by 100 ml of 10% aqueous sodium carbonate. The ether phase was dried over magnesium sulfate, filtered, and concentrated using a rotary evaporator and a water aspirator vacuum to yield 17.3 g of 4-methoxycarbonyl-2-nitrotoluene as a viscous oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[O:25]=[C:26]1[N:30]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[C:33]([F:43])[CH:32]=2)[CH2:29][C@H:28]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:27]1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:40]1[CH2:41][CH2:42][CH:37]([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[CH2:29][C@H:28]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:27][C:26]3=[O:25])=[CH:32][C:33]=2[F:43])[CH2:38][CH2:39]1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)c4cc5ccccc5[nH]4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of indole-2-carboxylic acid (79 mg) and 1,1'-carbonyldiimidazole (80 mg) in dry tetrahydrofuran (2.0 mL) is stirred at ambient temperature for one hour, and a solution of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) in dry tetrahydrofuran (6.0 mL) is added. The mixture is then stirred at ambient temperature for 19 hours, concentrated under reduced pressure, diluted with methylene chloride (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromagraphed on silica gel (70-230 mesh, 10 g), eluting with methanol/methylene chloride (7.5/92.5). Pooling and concentration of those fractions with an Rf =0.67 by TLC (methanol/chloroform, 10/90) and recrystallization from chloroform/diethyl ether gives the title compound, mp 223-225° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH2:11])=[CH:6][CH:5]=1)[CH3:3].[CH3:21][N:22]([CH3:40])[C:23]1[CH:39]=[CH:38][C:26]([CH:27](O)[C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O>CO>[CH3:20][N:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)=[CH:11][CH:27]([C:26]2[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:40])=[CH:39][CH:38]=2)[C:28]2[CH:29]=[CH:30][C:31]([N:34]([CH3:35])[CH3:36])=[CH:32][CH:33]=2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: C=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CN(C)c1ccc(C(=CC(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1

Procedure:
Michler's Ethylene (5g) and of 4,4'-bis-(dimethylamino)-benzhydrol (5g, Michler's Hydrol) were dissolved in methanol (50g) and 4-sulphotoluene (0.1g) was added. After stirring and heating under reflux for 2 hours, the insoluble crude product was isolated by filtration, washed with methanol and crystallised from toluene as a white solid (7g), MP 189°-190° C. It has the structure: ##STR12## Use of TDPP as a colour former in a pressure-sensitive copying paper
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1OC
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added to a solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and the mixture was stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (410 mg, 41.2%) as a colourless oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>>[CH:8]1([N:11]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: C=CC(=O)OCC
Reactant: NC1CC1
Product: CCOC(=O)CCN(CCC(=O)OCC)C1CC1

Procedure:
A mixture of 400 g. of ethyl acrylate (containing 0.75% hydroquinone inhibitor) and 114 g. of cyclopropylamine is heated in a bomb in an oil bath at 175° C. for 10 hours. The reaction mixture is then removed and distilled in vacuo to give N-cyclopropyl-N,N-di(β-carbethoxyethyl)amine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:41])[C:27]([O:29][CH2:30][CH2:31][S:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:28]>C(#N)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:26]([CH3:41])[C:27]([O:29][CH2:30][CH2:31][S:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:28])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(Br)C(=O)OCCSCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCSCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture consisting of 25.4 g of 4-(4-trifluoromethylphenoxy)phenol, 14.5 g of anhydrous potassium carbonate, 33.8 g of 2-(4-chlorobenzylthio)ethyl 2-bromopropionate and 150 ml of dry acetonitrile was refluxed for 3 hours with vigorous stirring. After cooling the reaction mixture to room temperature, the acetonitrile was removed under reduced pressure. Then, 150 ml of toluene were added to the residue and the resulting mixture was washed successively with 1% strength by weight aqueous sodium hydroxide solution and water, followed by dehydration. Upon distilling off the toluene under reduced pressure, there were obtained 46.4 g of 2-(4-chlorobenzylthio)-ethyl 2-[4-(4-trifluoromethylphenoxy)-phenoxy]-propionate in the form of a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:4].[Na].[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1>>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[N:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3](=[O:4])[CH2:2][N:26]1[CH:27]=[CH:28][N:29]=[C:25]1[CH3:24]
Reactant: Cc1ncc[nH]1
Reactant: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)CCl
Agent: [Na]
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)Cn1ccnc1C

Procedure:
This material was prepared in an analogous manner as the previous example from 2.9 g of 2-chloro-N-(2,6-dimethylphenyl)-N-[3-(3-pyridinyl)propyl]acetamide and the sodium salt of 2-methyl imidazole. After filtration through silica gel, the residue (3 g) was crystallized from ethyl acetate-hexane to give 2.1 g of analytically pure free base, mp 89°-90° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:55]([CH2:57][NH2:58])[OH:56]>C(OCC)(=O)C.CN(C=O)C>[OH:56][CH2:55][CH2:57][NH:58][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NCCO)cn1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a mixture of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol) was added DMF (2 mL). After stirring for 2 min at ambient temperature N,N-diisopropyl ethyl amine (553 μL, 3.23 mmol) and ethanolamine (47 μl, 0.78 mmol) were added and the resulting solution was stirred for 2 h at this temperature. It was diluted with ethyl acetate (15 mL) and washed with water (20 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate: methanol=30:70:0 to 0:95:5) afforded the title compound (200 mg, 88%) as a white solid. MS: m/e=353.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[N+:18]([O-])=O.C(O)(=O)C>C(Cl)Cl.CO.[Fe]>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH2:18]
Reactant: Cc1ccc2c(ncn2Cc2ccncc2)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc2c(ncn2Cc2ccncc2)c1N
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A 200-mL round-bottomed flask equipped with mechanical stirrer was charged with 5-Methyl-4-nitro-1-(pyridin-4-yl)methyl-1H-benzimidazole (881 mg, 3.46 mmol), iron powder (˜325 mesh, 3.87 g, 6.92 mmol) and acetic acid (50 mL), and the resulting mixture stirred at 50° C. for 15 min. After this time the reaction was cooled to room temperature, diluted with 1:1 methylene chloride/methanol (1 L) and filtered through a pad of Celite 521. After washing the filter cake with 1:1 methylene chloride/methanol (2×50 mL), the filtrate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride (50 mL) and vigorously stirred with 1M aqueous sodium hydroxide (50 mL). The resulting emulsion was filtered through a pad of Celite 521, the pad washed with methylene chloride (2×25 mL) and the organic layer of the filtrate separated and dried over sodium sulfate. Removal of the drying agent by filtration, followed by evaporation of the filtrate in vacuo gave a residue which was purified by flash chromatography. This purified material was dissolved in warm methylene chloride (15 mL) and the solution diluted with hexanes (35 mL). The resulting precipitate was filtered, washed with hexanes (3×100 mL) and dried under reduced pressure for 1.5 h to afford compound 2d as an off-white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:12])=[N:7][N:8]([CH3:11])[C:9]=1[Cl:10])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.[NH4+].[OH-]>C1COCC1>[ClH:10].[Cl:10][C:9]1[N:8]([CH3:11])[N:7]=[C:6]([CH3:12])[C:5]=1[CH2:4][NH2:1]
Reactant: Cc1nn(C)c(Cl)c1CN=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(C)c(Cl)c1CN
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of compound 3 (175 mg, 0.95 mmol) in THF (5 mL) was added PPh3 (248 mg, 0.95 mmol) at 0° C. After stirring for 1 hr, water (0.03 mL) and NH4OH (0.07 mL) were added sequentially and the resulting mixture was stirred at room temperature for overnight. After the solvent was evaporated, the residue was purified with reversed flash to give a white solid. LCMS (ESI) m/z=160 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH3:12][C:13]1[CH:21]=[CH:20]C(C(Cl)=O)=[CH:15][CH:14]=1>O.C1(C)C=CC=CC=1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[C:7]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1)[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Yield: 34.9 %

Procedure:
Sodium hydroxide solution (33%, 32.5 ml) was added to ethyl acetoacetate (97.5 g, 750 mmol) in a mixture of water (250 ml) and toluene (12 ml) at 0–5° C. under stirring (pH 11). After 30 minutes 4-methylbenzoylchloride (127.46 g, 825 mmol) and sodium hydroxide solution (33%, 135 ml) was added simultaneously over a period two hours. The reaction mixture was stirred for 15 minutes at 0° C. and for 1 hour at 35° C. Aqueous layer was separated, ammonium chloride (40 g) was added and stirred slowly over night. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulphate and concentrated to dryness in vacuum. The crude product thus obtained was purified by column chromatography to yield the title compound as viscous oil (54 g, 35%). MS m/z: 207.1 (M+). Preparation 2 Synthesis of ethyl(4-chloro)benzoylacetate
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][NH2:13])=O)=[CH:4][CH:3]=1.[NH3:14].[CH2:15](O)[CH3:16].[CH2:18](O)C>>[CH3:18][C:15]1[N:14]=[C:10]([CH2:9][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:12]=[N:13][CH:16]=1
Reactant: N
Reactant: NNC(=O)CSc1ccc(N)cc1
Reactant: CCO
Product: Cc1cnnc(CSc2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(4-aminophenylthio)acetohydrazide (5 g) was suspended in ethanol (50 ml) and to the suspension was added 40% piruvaldehyde solution (6.8 ml), at room temperature, and the mixture was stirred for 20 minutes. 13% ammonia-ethanol solution (60 ml) was added to the mixture, and the mixture was heated for 4.5 hours at 150° C. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to give 4-[(5-methyl-1,2,4-triazin-3-yl)methylthio]aniline (1.2 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=O)[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[C:6]=2[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([Cl:22])[N:10]([CH2:11][CH2:12][CH2:13][Cl:14])[C:6]=2[C:5]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)c2[nH]c(=O)n(CCCCl)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)c2nc(Cl)n(CCCCl)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of methyl 7-bromo-3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (490 mg, 1.41 mmol) and phosphoryl chloride (14 mL) was stirred at 100° C. for 2 h. Phosphoryl chloride (9 mL) was added to the reaction mixture and the resultant mixture was stirred at 100° C. for 3 h. Phosphoryl chloride (15 mL) was added to the reaction mixture, and the resultant mixture was stirred at 100° C. for 3 h, concentrated in vacuo, and diluted with ethyl acetate and aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (429 mg, 1.17 mmol, 83%).