Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][C:7]=1[Br:17]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)OC(C)(C)C)c1ccc(N)c(Br)c1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 2-(4-aminophenyl)propanoate (5.00 g, 22.6 mmol) in DMF (15 mL) was added a solution of N-bromosuccinimide (4.22 g, 23.7 mmol) in DMF (15 ML) at room temperature which was maintained by water bath. The mixture was stirred overnight, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, then brine, dried over sodium sulfate, and filtered. After concentration, the residue was purified by flash chromatography (9:1 hexanes/ethyl acetate) to give tert-butyl 2-(4-amino-3-bromophenyl)propanoate (6.00 g, 85%) as a brown oil: 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J=1.6 Hz, 1H), 7.04 (dd, J=8.1, 1.7 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 4.01 (br s, 2H), 3.46 (q, J=7.1 Hz, 1H), 1.39 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>O1CCCC1.CCCCCC>[Br:8][C:4]1[CH:3]=[C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(Br)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a solution of 1,3-dibromo-benzene (2.36 grams, 10 mmol) in tetrahydrofuran at −78° C. was added a 1.6M solution of n-butyllithium (6.3 ml, 10 mmol) in hexane and stirred for 4 hours. Cyclobutanone (700 mg, 10 mmol) was then added in one portion. After stirring for 2 hours at −78° C., the reaction was quenched with 2N hydrochloric acid. The reaction was warmed to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give 2.5 grams of crude product which was purified on silica gel eluting with 50% methylene chloride in hexane to give 1.5 grams of the titled compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][NH:17][C:18]2[N:23]=[C:22]3[NH:24][CH:25]=[C:26]([C:27](=[O:29])[CH3:28])[C:21]3=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C1COCC1>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:24]1[C:22]2=[N:23][C:18]([NH:17][CH2:16][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:31][CH:30]=3)=[CH:19][CH:20]=[C:21]2[C:26]([C:27](=[O:29])[CH3:28])=[CH:25]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1ccc(CNc2ccc3c(C(C)=O)c[nH]c3n2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc3c(C(C)=O)cn(CC(=O)OC(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Tert-butyl bromoacetate (27 μL, 0.18 mmol) was added to a suspension of 1-[6-(4-methoxy-benzylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-ethanone (0.17 mmol) and potassium carbonate (27.5 mg, 0.20 mmol) in CH3CN (0.33 mL) and THF (0.33 mL). The reaction mixture was stirred at RT for 7 h. Potassium carbonate (27.5 mg, 0.20 mmol) and tert-butyl bromoacetate (27 μL, 0.18 mmol) were added again and stirring was continued overnight, this operation was repeated the next day. The suspension was filtered, the filtrate concentrated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 98:2). TLC, Rf (CH2Cl2/MeOH 9:1)=0.9; MS (UPLC/MS): 410.2 [M+H]+, 819.4 [2M+H]+, 841.3 [2M+Na]+, 454.1 [M+HCOO]−; tR (HPLC conditions f): 2.30 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[C:13]([CH3:20])=[C:14]([N:19]3[CH2:30][C:25]4[C:24](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1
Reactant: BrCc1ccccc1CBr
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.55 mmol), 1,2-bis(bromomethyl)benzene (1.03 g, 3.91 mmol), potassium carbonate (540 mg, 3.91 mmol), and N, N-dimethylformamide (20 ml) was stirred at room temperature for 1 hour. Water was added into the reaction mixture and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain 208 mg (15% yield) of the title compound. Melting point: 164-166° C. (Ethyl acetate-hexane).
Reaction SMILES: C([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5]1)(=O)N.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C(#[N:44])C>O>[NH2:44][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5]1
Reactant: NC(=O)[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: CC#N
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Benzyl N-[(1S,3R)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 32.9 mmol) was suspended in a mixture of acetonitrile (100 mL) and water (100 mL) and treated with bis(trifluoroacetoxy)iodobenzene (15.5 g, 36.1 mmol). The suspension was allowed to stir at room temperature overnight and was then quenched with 1N HCl (100 mL). After evaporation of the acetonitrile, the acidic aqueous solution was washed with EtOAc (2×150 mL). The pH was adjusted to basic by addition of solid KOH and the resulting emulsion was extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide product 18e (6.2 g, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH2:63])[CH2:60][O:61][CH3:62])=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27]([NH:63][C@H:59]([C:56]3[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=3)[CH2:60][O:61][CH3:62])=[O:28])[CH2:25][CH2:26]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1
Reactant: COC[C@H](N)c1ccc(F)cc1
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)cc3F)ccn2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)C1(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(F)c2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of Example B3 (65 mg, 0.164 mmol), TBTU (79 mg, 0.246 mmol) and (R)-1-(4-fluorophenyl)-2-methoxyethanamine (40.5 mg, 0.197 mmol; prepared according to the published method: J. Med. Chem. (1999), 42(24), 4981) in DMF (2 ml) was added DIEA (0.171 ml, 0.984 mmol). The resulting clear solution was stirred at RT overnight. After stirring overnight, the reaction was diluted with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with satd. NaHCO3 (1×), satd. LiCl (2×), and brine (1×), dried (MgSO4), evaporated in vacuo and purified by reverse phase chromatography. Pure fractions were pooled, treated with satd. NaHCO3 (pH 8) and extracted with EtOAc (3×). The combined organics were washed with satd. NaHCO3 (1×), brine (1×), dried (MgSO4), and evaporated to afford N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamide as an oil. This was dissolved in 4:1 MeCN/H2O, treated with certified 0.1N HCl (1.37 ml, 1.0 eq), frozen and lyophilized to afford 63 mg (66% yield) of the HCl salt as a solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.49-8.48 (m, 2H), 8.44-8.42 (m, 1H), 8.18 (brs, 1H), 7.89-7.85 (m, 1H), 7.54 (brs, 1H), 7.48-7.35 (m, 4H), 7.16-7.11 (m, 2H), 6.92 (brs, 1H), 5.13-5.06 (m, 1H), 3.89 (s, 3H), 3.61-3.56 (m, 1H), 3.49-3.46 (m, 1H), 3.25 (s, 3H), 1.45-1.33 (m, 4H); MS (ESI) m/z: 516.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C:13]([O:15]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:17].[OH-]>CO.C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C:13]([NH2:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 50 mg of methyl (2R-cis)-3-(benzyloxymethyl)oxirane carboxylate in 3 ml of MeOH was added 1 ml of concentrated NH4OH with rapid stirring. The mixture was allowed to stir for two days. The reaction was then diluted with 20 ml of CHCl3 and the organic layer separated and washed three times with 10 ml of 0.1N HCl. The combined organic layers were dried over MgSO4, filtered and evaporated to yield a pale yellow residue. Flash chromatography (7 mm column, 5% MeOH: CHCl3) afforded 24.2 mg of a clear oil which solidified upon standing. 1H NMR (CDCl3) 7.4-7.2 (m, 5), 6.08 (br, 1), 5.64 (br, 1), 4.58 (dd, 2, J=12, 15 Hz), 3.8 (m, 1), 3.5-3.4 (m, 3). Mass Spectra: EI: M-41 (--CONH2) Calc. 163.0758, Found 163.0745.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:19])[C:13]([CH2:17]Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:19])[C:13]([CH2:17][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CBr)ccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 316 (16.1 g, 0.0467 mol) and potassium phthalimide (26.1 g, 0.141 mol) in anhydrous DMF (150 mL) was stirred at 80° C. overnight. The cooled reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 20% EtOAc) to afford 10.8 g (56%) of tert-butyl-4-chloro-5-((1,3-dioxoisoindolin-2-yl)methyl)-1H-indole-1-carboxylate (318) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.2 Hz, 1H), 7.88-7.86 (m, 2H), 7.74-7.72 (m, 2H), 7.62 (d, J=3.7 Hz, 1H), 7.27-7.25 (m, 2H), 5.12 (s, 2H), 1.65 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6][C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:24][N:2]([CH3:1])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6]([C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1)=[O:33]
Reactant: Cc1cc2nc(C)c(SCc3ccccc3N(C)C)nc2cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc(C)c(S(=O)Cc3ccccc3N(C)C)nc2cc1C
Yield: 28.8 %

Procedure:
In a mixture of 35 ml of chloroform and 3 ml of methanol was dissolved 3.71 g of 2-(2-dimethylaminobenzylthio)-3,6,7-trimethylquinoxaline. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was slowly added 2.45 g of m-chloroperbenzoic acid (purity: 80%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (acetone/hexane). The eluate was concentrated and the resulting residue was crystallized from ether/hexane to give 1.12 g of 2-(2-dimethylaminobenzylsulfinyl)-3,6,7-trimethylquinoxaline as a yellow crystalline powder, m.p. 83°-88° C. (decompn.).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Br)cnc1Br
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc.) (12.6 g, 50.3 mmol), piperazine-1-carboxylic acid tert-butyl ester (11.7 g, 62.9 mmol) and DIEA (13.3 g, 102.0 mmol) in DMA at 130° C. for 36 h. Partition the dark brown reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the crude product. Purify by flash chromatography, eluting with 9:1 hexanes:EtOAc, increasing to 3:1 hexanes:EtOAc to provide the title compound as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH3:11])[CH:6]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Cc1cc(O)ccc1C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
4-Isopropyl-3-methylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was dried under the reduced pressure to give 4-isopropyl-3-methylphenyl acetate (1.41 g, yield 100%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[CH:10]1([NH2:13])[CH2:12][CH2:11]1>CCOCC>[CH:10]1([NH:13][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: CCOC(CBr)OCC
Solvent: CCOCC
Product: CCOC(CNC1CC1)OCC
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of 2.36 g (12 mmol) of 2-bromoacetaldehyde diethyl acetal and 4.94 g (86.6 mmol) of cyclopropylamine was heated in a closed vessel at 120° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with 75 ml of ether and washed with 5% aq NaOH, followed by water and saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was distilled in vacuo (130° C.-140° C.). 2.01 g of the desired compound were obtained. LC/MS M+H=173
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4C(=O)C5=CC=CC=C5C4=O)[N:18]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.C(N)CN>CCO>[NH2:24][CH2:23][C:19]1[N:18]=[C:17]([CH2:16][N:13]2[C:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[C:7]=3[N:15]=[N:14]2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CN4C(=O)c5ccccc5C4=O)n3)c2n1
Solvent: NCCN
Solvent: CCO
Product: NCc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of 7-(2-furyl)-3-(6-phthalimidomethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (210 mg, 0.465 mmol) in EtOH (50 mL) was treated with ethylenediamine (62 μl, 0.929 mmol), stirred for 3 h at 90° C. and the resulting clear solution, cooled to room temperature and concentrated in vacuo to give 3-(6-aminomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine. A solution of this material in pyridine (10 mL) at 0° C. was treated with acetyl chloride (109 ml, 1.53 mmol), stirred for 10 min, poured into water (70 mL), extracted with EtOAc (3×20 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (110 mg, 65%) as a beige solid.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.[OH-].[Na+]>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:35]2)=[CH:30][CH:29]=1
Reactant: N#CC(C#N)=NNc1ccccc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: N#CCC#N
Solvent: Nc1ccccc1
Product: Nc1nn(-c2ccc(F)cc2)c(N)c1N=Nc1ccccc1
Reaction time: 4 h

Procedure:
1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-fluorophenylhydrazine hydrochloride (81 mg, 0.5 mmol) with the addition of 0.5 mL of 5% sodium hydroxide solution. After reacting for 4 hrs, very little solid had formed; however, analysis of the reaction solution by TLC indicated that no starting material remained. The resulting solid was removed by filtration and the solvent was evaporated from the filtrate to yield 29 mg (20%) of the compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:41].[N:42]1([CH2:48][CH2:49][C:50](O)=[O:51])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.Cl>CCOCC.C(Cl)Cl>[ClH:41].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:50](=[O:51])[CH2:49][CH2:48][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
2.8 g. (8.2 mmoles) of 4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [l] benzopyran, 1.77 g. (8.6 mmoles) of dicyclohexylcarbodiimide and 1.65 g. (8.5 mmoles) of β-piperidinopropionic acid hydrochloride (m.p. 216°-220°, J. Am. Chem. Soc. 73, 3168 (1951)) were combined with 125 ml. of methylene chloride and stirred at room temperature for about 20 hours. The reaction mixture was filtered and the methylene chloride removed using a rotary evaporator. The residue was treated with benzene and filtered to remove a small quantity of insoluble material. The benzene was evaporated and the dark viscous residue was chromatographed using 100 g. of 60-100 mesh Florisil activated magnesium silicate and methanol/chloroform graded solvent mixtures. Chromatography gave a small quantity of orange oil which was dissolved in ether and treated with a solution of ethereal HCl. The desired compound appeared as white crystals which were filtered and washed with additional ether. The colorless crystals (86 mg., m.p. 106°-107°) were pure by thin layer chromatography (10% MeOH/CHCl3) and the nmr and infrared spectra are in agreement with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:18][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=2)[C:5]([C:16]#[N:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CCl)ccn1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g (3.96 mmol) of 2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile, 0.96 g (4.36 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride and 1.33 g (15.84 mmol) of sodium bicarbonate are dissolved in 20 ml of DMF and stirred at RT for 2 h. 500 ml of water are added to the reaction mixture. The precipitate is filtered off and washed with water.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:11]1([C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCCCC2)CC1
Temperature: 25 °C

Procedure:
A flask equipped with a Dean-Stark trap and a reflux condenser was charged with 1-acetyl-piperdin-4-one (100 g, 0.71 mol) and toluene (1 L). Piperidine (63.4 g, 0.75 mol) and p-toluenesulfonic acid monohydrate (0.27 g, 1.4 mmol, 0.2 mol %) were added, and the resulting solution was heated at reflux for 8 h. The mixture was cooled to rt and concentrated to give a crude product which was used directly in the next reaction.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CCC([O-])(C)C.[K+].C1(C)C=CC=CC=1.[NH:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.Cl[CH2:39][N:40]1[CH2:44][CH:43]([CH2:45][CH2:46][CH3:47])[CH2:42][C:41]1=[O:48]>CCOCC>[CH2:45]([CH:43]1[CH2:44][N:40]([CH2:39][N:33]2[CH:37]=[CH:36][CH:35]=[CH:34]2)[C:41](=[O:48])[CH2:42]1)[CH2:46][CH3:47]
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: c1cc[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC1CC(=O)N(Cn2cccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.8 %

Procedure:
18-Crown-6 (0.158 g, 0.2 eq, 0.6 mmol) is dissolved in absolute ether (20 ml). A 1.7 M solution of potassium tert-amylate in toluene (1.93 ml, 1.1 eq, 3.28 mmol) is added dropwise in a flow of argon. The reaction mixture is stirred for 15 min at room temperature. Pyrrole (0.2 g, 1 eq, 2.98 mmol) is added. The reaction mixture is cooled to −15° C., and a solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.603 g, 1.15 eq, 3.43 mmol) in absolute ether (5 ml) is added dropwise. The resulting solution is stirred for 16 h at 20° C. The contents of the flask are partitioned between 10 ml of water and 30 ml of ethyl acetate. The organic layer is separated. The aqueous one is subjected to additional extraction with ethyl acetate (2×20 ml). The combined extracts are dried with anhydrous Na2SO4 and evaporated. Purification by chromatography on silicagel (dichloromethane/acetone) afford 0.091 g of 4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264.