Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([S:14]N2C(=O)C=CC2=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:1]1([S:7][S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CC(=O)N1Sc1ccccc1
Reactant: Sc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(SSc2ccccc2)cc1
Yield: 84.3 %

Procedure:
5.5 Grams (0.05 mole) of thiophenol are stirred with 10.2 grams (0.05 mole) of N-(phenylthio)maleimide in 150 ml of benzene at room temperature for one hour. The benzene is removed from the reaction mixture by evaporation and the residue is added to 200 ml of methanol. A white solid forms upon contact with the methanol which is recovered by filtration. The solid recovered is 9.2 grams (84% yield) of phenyl disulfide. Recrystallized from methanol, the product melts sharply at 60° C.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-methoxyphenylboronic acid (152 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using methanol-chloroform to give the title compound (64 mg, yield 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:29][OH:30]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14]([NH:29][OH:30])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 76.8 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (1.00 g, 2.71 mmol), N,N′-carbonyldiimidazole (461 mg, 2.84 mmol) and hydroxylamine hydrochloride (208 mg, 2.99 mmol) in tetrahydrofuran (6 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (800 mg, 77% yield): mp, 163.0-165.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 3.11 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.67 (t, J=7.8 Hz, 1H, NCH), 6.90 (br s, 2H, Ar), 7.02 (br s, 1H, Ar), 7.86 (br s, 4H, Ar), 8.79 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.67, 34.22, 50.18, 55.44, 63.71, 111.73, 112.36, 119.65, 123.11, 131.18, 131.21, 134.56, 147.67, 148.53, 165.97, 167.61. Anal. Calcd for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.43; H, 5.04; N, 7.20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:21][O:20][N:19]([CH3:18])[C:12](=[O:14])[CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16][CH2:15]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 1-tert-butoxycarbonylisonipecotic acid (5 g, 21.8 mmol; Example 81, Step A), N,O-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide-hydrochloride (4.6 g, 24 mmol), 1-hydroxy-7-azabenzotriazole (0.3 g, 2.2 mmol), and anhydrous dimethylformamide (50 mL) was stirred at room temp. overnight. The resulting mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide N-Methoxy-N-methyl 1-tert-butoxycarbonylisonipecotamide.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
Triethylamine (0.115 g) and 0.200 g of benzoyl chloride were added to a solution of 0.500 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 5 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. A potassium hydrogencarbonate aqueous solution was added thereto to stop the reaction. The solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of water and methanol, and the solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were collected, and were dried to obtain 0.393 g of crude N-benzenesulfonyl-4-benzoylamino-3-(biphenyl-4-ylmethylamino)benzamide. This crude product was converted to 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole [(246), 0.270 g] in the same manner as in Example 183.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][NH:14][C:15](=O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=c1[nH]cnc2ccc(-c3ccc(F)cc3)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Yield: 96.3 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-pyrido[3,2-d]-pyrimidin-4(3H)one (482 mg, 2 mmol) in toluene (20 ml), was added diisopropylethylamine (1.0 ml, 6 mmol) and phosphorus oxychloride (0.56 ml, 6 mmol). The reaction mixture was refluxed for 1 hour. After concentration under reduced pressure, the residue was extracted with dichloromethane (100 ml), and washed with ice water till pH 6-7. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure yielding the title compound as a yellowish solid (0.50 g, yield 96%) which was characterised as follows: Rf=0.90 (MeOH/CH2Cl2=1/9).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18].C(O)(C)C>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCOC(COC1CCN(Cc2ccccc2)CC1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
1-Benzyl-4-hydroxy piperidine (11.5 g.) dissolved in dry dimethylformamide (DMF) (25 ml.) was added dropwise to a stirred suspension of sodium hydride (2.8 g. of 50% dispersion in oil in dry DMF [25 ml.]), under dry nitrogen, and then stirred at room temperature for 3 hours. The suspension was cooled in an ice/water bath while 2-bromoacetaldehyde diethylacetal (13.0 g.) in dry dimethylformamide (25 ml.) was added dropwise, followed by stirring at room temperature for 24 hours. The above process was repeated to add more sodium hydride (2.8 g.) and the acetal (13.0 g.). Iso-propyl alcohol (50 ml.) was added, and the mixture was stirred for 1/2 hour, followed by filtration through "Hyflo" (Trademark). The filtrate was concentrated in vacuo, suspended in water (100 ml.) and basified to pH 11 with 5 N sodium hydroxide. After extraction with chloroform (2×100 ml.) the combined extracts were taken to dryness in vacuo to give an orange oil which was distilled in vacuo to give 1-benzyl-4-(2,2-diethoxyethoxy)-piperidine (14.1 g.), b.p. 152° C.@0.1 mm.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].N#N.[CH2:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24]CC(=O)C[CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:1]=[C:2]1[CH2:4][CH2:20][CH:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:24][CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Agent: N#N
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC(CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a cooled (−78° C.) mixture of Ph3PCH2Br (5.42 g, 14.88 mmol) in THF (25 mL) was added KOtBu (1M in THF, 17.05 mL, 17.05 mmol) dropwise under N2. The resulting mixture was stirred at 0° C. for 1 h and warmed to rt for another 1.5 h. The reaction mixture was then cooled to −40° C., added a solution of 4-(2-(benzyloxy)ethyl)cyclohexanone (1.8 g, 7.75 mmol) in THF (15 mL) dropwise. The mixture was then stirred at rt overnight and quenched by brine, extracted with EtOAc, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the titled product (1.77 g, 99%). LC/MC: 231.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[N:10]=[C:9]([O:11][C:12]2[C:18]([CH3:19])=[CH:17][C:15]([NH2:16])=[C:14]([CH3:20])[CH:13]=2)[S:8][N:7]=1.CO[CH:26](OC)[N:27]([CH2:29][CH3:30])[CH3:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[N:10]=[C:9]([O:11][C:12]2[C:18]([CH3:19])=[CH:17][C:15]([N:16]=[CH:26][N:27]([CH2:29][CH3:30])[CH3:28])=[C:14]([CH3:20])[CH:13]=2)[S:8][N:7]=1
Reactant: Cc1cc(Oc2nc(Cc3cccc(Cl)c3)ns2)c(C)cc1N
Reactant: CCN(C)C(OC)OC
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(Cc3cccc(Cl)c3)ns2)cc1C
Yield: 27.6 %

Procedure:
1.85 g (5.15 mmol) of 4-{[3-(3-chlorobenzyl)-1,2,4-thiadiazol-5-yl]oxy}-2,5-dimethylaniline are dissolved in 10 ml of toluene and treated with 1.37 g (10.31 mmol) of N-ethyl-N-methylformamide dimethylacetal. The reaction mixture is refluxed for 12 h, subsequently cooled, freed of solvent under vacuum and purified by column chromatography. 0.59 g of product is obtained (99.0% purity, 27.3% yield; log P (pH2.3)=2.31).
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([O:17][S:40]([CH3:39])(=[O:42])=[O:41])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Yield: 75.3 %

Procedure:
p-Nitrobenzyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e1) (147 mg) was suspended in dichloromethane (5 ml) containing triethylamine (100 mg), and the mixture was cooled to 0°. Whilst stirring the mixture at 0°, methanesulphonyl chloride (75 mg in 2.6 ml dichloromethane) was added dropwise over 5 minutes and the solution then stirred at a temperature of between 0° and -10° C. for a further 25 minutes. The solution was diluted with dichloromethane (10 ml) and washed with cold water (20 ml) phosphate buffer (pH 3.1) (20 ml) and 5% NaHCO3 solution (20 ml). The organic layer was dried (MgSO4) and evaporated down to afford a solid which was triturated with ether and collected by filtration to yield p-nitrobenzyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6 -[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e2) (130 mg); νmax (KBr) 1775, 1690, 1620, 1520, 1340, 1270 and 1175 cm-1.
Reaction SMILES: [O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=1)[C:2]#[N:3].[CH3:13][O:14][SiH:15]([O:18][CH3:19])[O:16][CH3:17]>C1(C)C(C)=CC=CC=1>[O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13])=[CH:6][CH:5]=1)[C:2]#[N:3]
Reactant: C=CCc1ccc(OC#N)cc1
Reactant: CO[SiH](OC)OC
Solvent: Cc1ccccc1C
Product: CO[Si](CCCc1ccc(OC#N)cc1)(OC)OC
Yield: 42 %

Procedure:
To 3.94 g (24.75 mmol) of purified 1-cyanato-4-(2-propenyl)benzene, prepared as described above, at 65° C. was added 10 μL of a 3% solution of Karstedt's™ catalyst (platinum-divinyltetramethyldisiloxane complex) in xylene (United Chemical Technologies, Bristol, Penn.). Trimethoxysilane (Aldrich) was added in 500 μL increments followed by 10 μL increments of the catalyst solution until NMR showed that the reaction was more than 80% complete. The product was distilled twice to yield 2.94 g (42%) of 3-(4-cyanatophenyl)propyltrimethoxysilane. The structure of the product was verified by IR and NMR.
Reaction SMILES: [Na].[CH3:2][OH:3].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1)([OH:6])=[O:5].Cl>O>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=[NH:14])[O:3][CH3:2])=[N:11][CH:12]=1)([OH:6])=[O:5]
Reactant: CO
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: Cl
Agent: [Na]
Solvent: O
Product: COC(=N)c1ccc(C(=O)O)cn1

Procedure:
Sodium (12 mmol) is added to a flask containing 20 ml of methanol. After the sodium has dissolved, 5 mmol of 5-carboxy-2-cyano-pyridine is added. The mixture is heated at 50° for 6 h. After cooling, the reaction mixture is diluted with water and acidified (pH=5)with 2N HCl. The solid is collected and dried, and corresponds to the title compound, m.p. 284°-286°.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][Mg]Br.Cl>C(OCC)C>[CH:1]1([CH2:6][CH2:7][C:8](=[O:10])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Mg]Br
Reactant: O=C(O)CCC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)CCC1CCCC1
Temperature: -20 °C

Procedure:
10 Parts of 3-cyclopentyl propionic acid are dissolved in 150 parts by volume of ethyl ether and chilled to -20° C. under argon. 50 Parts by volume of 2.8 molar methyl magnesium bromide are added dropwise. After the addition of the methyl magnesium bromide is completed, the mixture is allowed to warm to room temperature. The cloudy reaction mixture is treated with 1N hydrochloric acid and the clearified reaction mixture is extracted with ether followed by ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residual oil is chromatographed on silica gel using 10% ethyl acetate/hexane as the eluent, to provide 4-cyclopentyl-2-butanone.
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.O>CN(C=O)C>[SH:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: S
Reactant: O=C(c1ccncc1)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccncc1)c1ccc(S)cc1
Yield: 48.5 %

Procedure:
A suspension of sodium hydrogen sulfide (6 g) in DMF (100 ml) was heated to reflux for 1 h, then cooled and 4-(4-chlorobenzoyl)pyridine (5 g) was added. The mixture was heated at reflux for 2 h, then cooled and added to water. The brown solution was washed with ether, then acidified with citric acid and extracted with dichloromethane (2×100 ml). The solvent was dried and evaporated to give the title compound as beige powder (2.4 g, 50%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:7]1[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[S:12][CH:11]=[CH:10][C:6]1=2
Reactant: Fc1ccccc1Br
Reactant: CN1CCc2sccc2C(O)C1
Product: CN1CCc2sccc2C(Oc2ccccc2Br)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:41]([C:35]3[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=3[F:33])(=[O:43])=[O:42])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline (1.24 g, 3.17 mmol) in DCM (31.7 mL) was added pyridine (0.269 mL, 3.33 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.448 mL, 3.33 mmol). The reaction was stirred 18 h at rt. The reaction mixture was concentrated onto silica gel. Purification by chromatography (5 to 100% EtOAc:DCM) afforded the title compound (1.21 g, 2.13 mmol, 67.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 7.37-7.67 (m, 5H), 7.32 (t, J=7.9 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 3.93 (dd, J=11.4, 2.0 Hz, 2H), 3.39-3.58 (m, 2H), 3.26-3.40 (m, 1H), 1.98-2.09 (m, 2H), 1.63-1.86 (m, 2H). MS (ESI): 567.06 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 56 %

Procedure:
Upon boiling a solution of 7.6 g 2-nitrobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 142°C (ethanol) is obtained. Yield: 56% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:12]=O.[C:14]1([CH2:20][C:21](OC)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>CN(C=O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[CH:4][C:3]3[CH:12]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:21](=[O:22])[NH:1][C:2]=3[N:7]2[N:8]=1
Reactant: Cc1cc2ncc(C=O)c(N)n2n1
Reactant: COC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
Into a round bottom flask was added 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (1-2) (5.30 g, 30 mmol), methy phenylacetate (18.0 g, 120 mmol), potassium tert-butoxide (5.80 g, 60 mmol), and toluene (100 mL). The reaction mixture was heated to 105° C. while stirring under an atmosphere of nitrogen for 30 min. Then DMF (100 mL) was added and the mixture was stirred at 100° C. for 3 days. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in DCM (600 mL) and then water (400 mL) was added to the solution. The precipitated solid was collected by filtration and the solid was washed with water (50 mL) and DCM (100 mL). The solid was dried over an oil pump for 2 days to give 2-methyl-7-phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-8(9H)-one (1-3) as a yellow solid.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[CH2:8]([O:10][CH:11](OCC)OCC)[CH3:9]>>[CH2:8]([O:10][CH:11]=[N:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: Nc1nnn[nH]1
Solvent: O
Product: CCOC=Nc1nnn[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 25 g of 5-aminotetrazole monohydrate and 356 g of triethoxymethane was heated under nitrogen with stirring at 100° C. for 4 hours during which time a distillate was collected. Then, 30 ml of cyclohexane was added and the mixture was cooled first to room temperature and then briefly with an ice-water bath. The white crystals which formed were separated by filtration and vacuum oven dried to give 5-(ethoxymethyleneamino)tetrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5].[BH4-].[Na+].[CH:33](OCC)(OCC)OCC>C(O)C.ClCCl>[Br:30][C:27]1[CH:28]=[CH:29][C:2]([NH:1][CH3:33])=[C:3]([CH:26]=1)[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CNc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1042) (50 mg, 0.10 mmol) in triethyl orthoformate (6.5 mL) was stirred at 150° C. for 17 h. Concentration afforded a yellow solid. To a solution of the yellow solid in ethanol (3 mL) was added sodium borohydride (7.6 mg, 0.2 mmol) and the mixture was stirred at room temperature for 14 h. A resulting white precipitate was resolved in dichloromethane and the solution was washed with 1 N aqueous NaOH (2 mL). The organic layer was separated, dried over K2CO3, filtered and evaporated. Column chromatography (SiO2, 20% MeOH/CHCl3) gave 4-[N-{5-bromo-2-(methylamino)benzoyl)glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1427) (40 mg, 80%) The purity was determined by RPLC/MS (100%); ESI/MS m/e 505 (C23H28BrClF6N4O2).