Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NCC(N1CCC[C@H]1C(O)=O)=O)(OC(C)(C)C)=[O:17]>C1COCC1>[CH:10]1([NH:9][C:8](=[O:17])[NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.75 h

Procedure:
A portion (10.3g= 0.05 mole) of dicyclohexylcarbodiimide (DCC) was added dropwise under stirring at 0° C. to a solution of N-Boc-glycyl-L-proline prepared in accordance with the method described in J. Chem. Soc. (C), 954 (1969) (27.2g= 0.1 mole) in dried THF (100ml) and the reaction mixture was kept under continuous stirring for 45 minutes. To the filtrate obtained by filtering-off of dicyclohexyl urea precipitated in the mixture, was added at 0° C. a solution of 7-amino-4-methylcoumarin (8.75g= 0.05 mole) in dimethylformamide (DMF) (60ml). After standing overnight at room temperature, the reaction mixture was concentrated in vacuo to give a residue which was dissolved in ethyl acetate (300ml.). The solution was washed successively with 1 N hydrochloric acid, aqueous 5% sodium bicarbonate and water, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from a binary mixture of ethyl acetate (150ml) and n-hexance (70ml) to give 20.1g (yield, 93.4%) of crystalline 7-(n-BOC-glycyl-L-prolyl)-amino-4-methylcoumarin.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:28])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:26](=[O:27])[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1c2c(cc3c1c1c(C(N)=O)cccc1n3Cc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 31.2 %

Procedure:
40% Methanolic Triton B (0.148 mL, 0.325 mM) was added to a solution of 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid amide, (0.094 g, 0.25 mM) in 5 mL DMF at room temperature. After 2 minutes, methyl bromoacetate (0.049 mL, 0.076 g, 0.5 mM) was added and the resultant mixture stirred at room temperature for 2 h. Cesium carbonate (0.041 g, 0.125 mM) was then added as a solid, and the mixture allowed to stir at room temperature for an additional 2 h. The mixture was diluted with ethyl acetate, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting tan foam was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.035 g (31%) of the title compound (5-benzyl-1-carbamoyl-7,8,9,10-tetrahydro-5H-benzo[b]carbazol-11-yloxy)-acetic acid, methyl ester as a white solid (MP 174–177° C., MW 442.52).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:32][N:33]([CH:35]=[N:36][C:37]1[CH:38]=[C:39]([CH:46]=[CH:47][N:48]=1)[C:40](N(OC)C)=[O:41])[CH3:34]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:40]([C:39]3[CH:46]=[CH:47][N:48]=[C:37]([N:36]=[CH:35][N:33]([CH3:34])[CH3:32])[CH:38]=3)=[O:41])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccnc(N=CN(C)C)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(=O)c1ccnc(N=CN(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (367 mg, 0.775 mmol) in THF (2 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 0.94 mL, 1.866 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-(dimethylamino-methyleneamino)-N-methoxy-N-methyl-isonicotinamide (349 mg, 1.47 mmol) in THF (1 mL) at 0° C. The mixture was stirred at room temperature for 6 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (230 mg) in 52% yield. ESMS m/z (relative intensity): 570.1 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)[CH2:8]2)=[CH:4][CH:3]=1.O.NN.[OH-].[Na+]>C(O)C>[NH2:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=2)[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCC1CCCN(Cc2ccc(Cl)cc2)C1
Yield: 57.7 %

Procedure:
To a solution of 10.52 g of the crude 1-(p-chlorobenzyl)-3-phthalimidomethylpiperidine in ethanol (100 ml) was added hydrazine monohydrate (1.8 ml, 58 mmol) and the mixture was heated under reflux for 2 hours. After cooling, 10% aqueous sodium hydroxide (200 ml) was added to dissolve insolubles and the ethanol was distilled off under reduced pressure. The aqueous layer was extracted with chloroform (150 ml×3) and then the combined organic layer was then extracted with 10% aqueous hydrochloric acid (150 ml×3). The combined aqueous hydrochloric acid layer was washed with chloroform (100 ml), 10% aqueous sodium hydroxide was added until it became strongly basic and then extracted with chloroform (100 ml×3). The combined organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure to give crude 3-aminomethyl-1-(p-chlorobenzyl)piperidine (3.93 g). A total yield of two steps=92%. This compound was used for the subsequent reaction without purification.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19]S(OC)(=O)=O.O>CN(C)C=O>[CH3:19][N:12]([CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:13](=[O:18])[C:14]([F:16])([F:17])[F:15]
Reactant: O=C(NCCCc1ccccc1)C(F)(F)F
Reactant: COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCc1ccccc1)C(=O)C(F)(F)F
Reaction time: 0.67 h

Procedure:
Under nitrogen, 1.5 g (37.5 mM) of a 60% suspension of sodium hydride in liquid paraffin was added to a solution of 8.0 g (34.6 mM) of N-(3-phenylpropan-1-yl)trifluoroacetamide in N,N-dimethylformamide (70 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 40 minutes. To this reaction mixture was added 3.5 ml (41.3 mM) of methyl methanesulfonate and the mixture was stirred at room temperature for 1.5 hours. Then, water was added to the reaction system to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (ethyl acetate-hexane 15%) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([C:26]#[N:27])[CH:3]=1.C(C1C=C([N+]([O-])=O)C=CC=1N1CC[CH:42]([CH:45]([C:51]2C=CC=C[CH:52]=2)[C:46](NCC)=[O:47])[CH2:41]C1)#N>>[C:26]([C:4]1[CH:3]=[C:2]([NH:1][C:46](=[O:47])[CH:45]([CH2:51][CH3:52])[CH2:42][CH3:41])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:15](=[O:16])[NH:17][CH2:18][CH3:19])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:13]1)#[N:27]
Reactant: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Reactant: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2C#N)CC1
Product: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2C#N)CC1
Yield: 95 %

Procedure:
2-[1-(4-Amino-2-cyano-phenyl)-piperidin-4-yl]-N-ethyl-2-phenyl-acetamide. 2-[1-(2-Cyano-4-nitro-phenyl)-piperidin-4-yl]-N-ethyl-2-phenyl-acetamide was subjected to reaction conditions similar to those described in Step C to provide the title compound as a yellow powder (600 mg, 95%). MS (ESI): mass calcd. for C22H26N4O, 362.47. m/z found, 363.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1C=CC=CC=1.[CH:40](OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)(C)C.C(OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C=C.C(OC1C=C(CC(NC(C2C=C(OC)C=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:25]=[C:26]([CH3:40])[CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OC(C)C)c1)c1ccccc1N1CCCCC1
Agent: C=CCOc1cc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)ccc1C(=O)O
Agent: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1cc(OC)ccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(C=C(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
The mixing ratio of 75/25 is obtained from the corresponding ratio of intensities of the particularly characteristic signals in the 400 MHz-1H-NMR spectrum (CDCl3). The position of the signals is: 3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CH3 : 1.64 (s) and 1.77 (s). benzylic ##STR18## 6.00 (t), benzylic CH2 --; 3.52 ppm (s) 3-methyl-1-butyl compound: CH3 : 0.90 (d), benzylic ##STR19## 5.35 (m), benzylic --CH2 --: 3.54 ppm (s).
Reaction SMILES: [C@H:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18](Br)[CH:19]=[CH2:20]>C(Cl)Cl>[CH2:20]([NH:10][C@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH:19]=[CH2:18]
Reactant: N[C@@H]1CCc2ccccc21
Reactant: C=CCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN[C@@H]1CCc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1R)-indan-1-amine (1.00 g, 7.51 mmol) and triethylamine (1.52 g, 15.0 mmol) in DCM (75 mL) was added allyl bromide (1.36 g, 11.3 mmol) and the mixture was allowed to stir at ambient temperature for 3 days. An additional 1.5 equivalents of allyl bromide and 0.5 equivalents of triethylamine were then added, and the reaction mixture was stirred an additional 24 hours. LCMS analysis now indicates the reaction mixture is a 27:35:38 mixture of starting material:desired product:bis-allylation product. Use this solution as is.
Reaction SMILES: [C:1]([C:4]1[C:11]([OH:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2].[I:14]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([C:8]#[N:9])=[C:10]([I:14])[C:11]=1[OH:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C#N)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C#N)c(I)c1O
Temperature: 80 °C
Yield: 65.9 %

Procedure:
The 4-acetyl-2-chloro-5-hydroxybenzonitrile (4.9 g, 25 mmol) was dissolved in acetic acid (61.2 mL), and the N-iodosuccinimide (6.8 g, 30 mmol) was added. The reaction was heated to 80° C. and, after heating for 18 hrs, the reaction was concentrated in vacuo to remove the acetic acid. The residue was taken up in ethyl acetate, washed with sodium bicarbonate water, brine, dried over magnesium sulfate and concentrated to give a dark oil. The crude product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile as a yellow solid (5.3 g, 66%).
Reaction SMILES: Cl[CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[C:18](=[O:19])[N:17]([CH:20]([F:22])[F:21])[C:16]([CH3:23])=[N:15]2)[C:11]([Cl:24])=[CH:10][C:9]=1[Cl:25])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+]>CN(C)C=O>[Cl:25][C:9]1[CH:10]=[C:11]([Cl:24])[C:12]([N:14]2[C:18](=[O:19])[N:17]([CH:20]([F:21])[F:22])[C:16]([CH3:23])=[N:15]2)=[CH:13][C:8]=1[CH:7]=[CH:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a stirred, cold (0° C.) solution of 4.16 g (0.0100 mole) of methyl 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionate in 15 mL of N,N-dimethylformamide was added portionwise 0.29 g (0.012 mole) of sodium hydride. After complete addition the reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The reaction mixture was heated at 60° C. for six hours, then was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into ice water, and the resultant aqueous mixture was extracted with four portions of diethyl ether. The extracts were combined and washed successively with water and an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to give a white foam. The foam was purified by column chromatography on silica gel, eluting with n-heptane:ethyl acetate (4:1), to give 1.63 g of methyl 3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-2-propenoate as a solid, m.p. 148°-151° C., Compound 39 of Table 1.
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[C:8]([C:24]([F:27])([F:26])[F:25])[CH:7]=1)([O-])=O.O.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([NH2:3])=[CH:7][C:8]=2[C:24]([F:25])([F:26])[F:27])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2)c(C(F)(F)F)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
Iron powder (72.7 g), 251 mL of ethanol, 103 mL of distilled water, and 0.55 mL of 35% hydrochloric acid were mixed together, and the mixture was heated to reflux. Subsequently, a solution of 66.9 g of 4-nitro-1-(4-trifluoromethoxyphenoxy)-2-trifluoromethylbenzene dissolved in 77 mL of ethanol was added dropwise to the mixed solution, and the mixture was heated under reflux for 2.5 hr. The reaction solution was cooled to room temperature, sodium bicarbonate water was added thereto, and the mixture was filtered. The filtrate was concentrated under the reduced pressure, and ethyl acetate and brine were added to the residue, followed by separation. The ethyl acetate layer was washed with brine and was then concentrated under the reduced pressure to give 61.0 g of 4-(4-trifluoromethoxyphenoxy)-3-trifluoromethylaniline (yield 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1I>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: Clc1ccc(Cl)c(I)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(Cl)ccc3Cl)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,4-dichloro-2-iodobenzene according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 7.85 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.7, 2.4 Hz, 1H), 7.09 (m, 2H), 6.89 (d, J=2.4 Hz, 1H), 6.83 (dd, J=8.5, 2.4 Hz, 1H), 3.29 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z [M+H]+(379/381/383); Anal. calcd for C19H20C12N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.11; H, 5.36; N, 6.84.
Reaction SMILES: C(S[C:9]([CH2:11][C:12]1[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=1)=[NH:10])C1C=CC=CC=1.[NH2:22][CH:23]([C:27]#[N:28])[C:24]([NH2:26])=[O:25].C(=O)([O-])O.[Na+]>CO>[NH2:28][C:27]1[NH:10][C:9]([CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=2)=[N:22][C:23]=1[C:24](=[O:25])[NH2:26]
Reactant: N#CC(N)C(N)=O
Reactant: CCOC(=O)c1ccc(CC(=N)SCc2ccccc2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(Cc2nc(C(N)=O)c(N)[nH]2)o1
Reaction time: 5 h
Yield: 68 %

Procedure:
30.5 g (0.09 M) of ethyl 5-benzylsulfanylcarbonimidoylmethylfuran-2-carboxylate, 8.9 g (0.09 M) of aminocyanoacetamide and 7.5 g (0.09 M) of sodium hydrogen carbonate in 180 ml of methanol are refluxed with stirring for 5 hours. The crude product obtained is purified by chromatography on silica using a dichloromethane/methanol mixture (90/10) as eluent, to give 17 g of ethyl 5-(5-amino-4-carbamoyl-1H-imidazol-2-ylmethyl)furan-2-carboxylate in the form of a vitreous brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.Cl>C(O)C.[H][H].[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCNCC1
Reaction time: 1 h
Yield: 162.3 %

Procedure:
16.5 g (0.1 mol) Ethyl 4-pyridylacetate, 8.4 mL (0.1 mol) 12N hydrochloric acid and 2.5 g platinum oxide were dissolved in absolute ethanol and hydrogenated at 40 psi hydrogen on a Parr shaker. After 1 hour, the contents of the vessel were filtered and concentrated in vacuo yielding 27.79 g of ethyl 4-piperidinylacetate.
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)/[C:10](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)/[C:9]([CH3:23])=[C:8]2[CH2:24][C:25](Cl)=[O:26]>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)/[C:10](=[CH:14]\[C:15]1[CH:16]=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=1)/[C:9]([CH3:23])=[C:8]2[CH2:24][CH2:25][OH:26]
Reactant: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccc(SC)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCO)=C(C)/C2=C/c1ccc(SC)cc1

Procedure:
Lithium borohydride (1.38 mmol) in THF (2 ml) is added slowly to a solution of (Z)-5-methoxy-2-methyl-1-(4-methylthiobenzylidene)-3-indenylacetyl chloride (2.78 mmol) in THF (20 ml) at 0° C. The reaction is quenched after 5 minutes with HCl (10%, aqueous, 30 ml). Ethyl acetate (50 ml) is added to extract the product.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([I:21])[C:18]([OH:22])=[C:17]([I:23])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>C(O)=O>[CH2:1]([C:8]1[O:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([I:21])[C:18]([O:22][CH2:29][C:30]([OH:32])=[O:31])=[C:17]([I:23])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(I)c(O)c(I)c1)c1c(Cc2ccccc2)oc2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=CO
Product: O=C(O)COc1c(I)cc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)cc1I

Procedure:
This compound was prepared from (2-benzyl-benzofuran-3-yl)-(3,5-diiodo-4-hydroxy-phenyl)-methanone and tert-butyl bromoacetate in substantially the same manner, as described in Example 2. Formic acid was used in the place of trifluoroacetic acid. The product was obtained as an off-white solid, mp 144-146° C.; MS m/e 638 (M+);
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][Si:13]([CH3:27])([CH3:26])[C:14]#[C:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])(=O)C.[K+].[Cl-].[Li+]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:9]([C:7]1[CH:8]=[C:2]2[C:3](=[CH:5][CH:6]=1)[NH:4][C:14]([Si:13]([CH3:12])([CH3:27])[CH3:26])=[C:15]2[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: CC(C)(C)[Si](C)(C)OCCC#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCc1c([Si](C)(C)C)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 70 °C
Yield: 42.4 %

Procedure:
A mixture of 2-iodo-4-nitroaniline (7.92 g, 0.030 mol), 1-(trimethylsilyl)-4-(t-butyldimethylsiloxy)-1-butyne (15.36 g, 0.060 mol), potassium acetate (14.70 g, 0.15 mol), lithium chloride (1.27 g, 0.030 mol) and palladium (II) acetate (0.675 g, 0.003 mol) in 100 mL of dry DMF was heated at 70° C. (oil-bath temperature) under Ar for 2.5 h. The cooled reaction mixture was diluted with ether and the aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed (H2O, brine), dried (Na2SO4) and evaporated. The resulting residue was chromatographed (SiO2 /hexane-ethyl acetate, 4:1) to give a dark orange solid which was rechromatographed (SiO2 /hexane-CH2Cl2, 4:1 to 6:4) to give the title compound (5.00 g, 42%) as a yellow solid: IR (neat) 3414, 1328, 1253, 845 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ 8.63 (d, J=2.2 Hz, 1H), 8.21 (br s, 1H), 8.09 (dd, J=9.0, 2.2 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 3.84 (t, J=7.2 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H), 0.85 (s, 9H), 0.42 (s, 9H), -0.01 (s, 6H).