Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].N1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:39]([C:33]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=2[Cl:31])(=[O:41])=[O:40])[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCN(S(=O)(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)-phenyl]amide (AMR01038, 80 mg, 0.219 mmol) in dry DCM (6 mL) were added pyridine (0.035 mL, 0.438 mmol) and 2,5-dichlorobenzenesulphonyl chloride (59.2 mg, 0.241 mmol). The reaction mixture was stirred at room temperature for 24 h, and then at reflux for 3 h. After quenching with saturated NaHCO3, the resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash column chromatography on silica gel using hexane/EtOAc 8:2 as eluent gave 1-(2,5-dichlorobenzenesulfonyl)piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)-phenyl]amide (56 mg, 44%) as a white solid, mp 194-196° C. Rf: 0.81 (DCM/MeOH 9:1). 1H NMR (300 MHz, CDCl3) δ 1.74-1.96 (4H, m, 2CH2), 2.34 (1H, m, CH), 3.80 (2H, td, J=13.1, 3.4 Hz, CH2), 6.65 (1H, dd, J=8.1, 1.4 Hz, ArH), 6.87 (1H, d, J=8.8 Hz, ArH), 6.94 (1H, td, J=7.7, 1.7 Hz, ArH), 7.05 (1H, td, J=8.0, 1.4 Hz, ArH), 7.15 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.37 (2H, d, J=1.4 Hz, ArH), 7.41 (1H, d, J=2.5 Hz, ArH), 7.68 (1H, br s, NH), 7.97 (1H, t, J=1.4 Hz, ArH) and 8.29 (1H, dd, J=8.0, 1.0 Hz, ArH). LC/MS (APCI) tr=5.62 min, m/z 577.21 (59), 575.26 (100), 573.24 (M++H, 90) HPLC tr=3.363 min (97.70%)
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N:20]1([CH2:2][C:3]2[S:7][C:6]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=4[N:12]=3)=[CH:5][CH:4]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(CBr)s3)nc2c1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3ccc(CN4CCOCC4)s3)nc2c1
Yield: 91.7 %

Procedure:
2-(5-Bromomethyl-2-thienyl)-5-nitrobenzoxazole (2.0 g, 0.006 mole) and morpholine (2.6 g, 0.03 mole) are dissolved in 100 ml of benzene and heated at reflux for 36 hours. The precipitated morpholine hydrobromide is removed by filtration and the benzene is evaporated yielding an oil. Crystallization from ethanol yields 1.9 g of product, melting point 149°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19]3[C:18]([O:20][CH3:21])=[CH:17][CH:16]=[C:15]([C:22](OC4C=CC([N+]([O-])=O)=CC=4)=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([Cl:34])[CH:12]=3)=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH2:44].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH:44][C:22]([C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:34])[CH:12]=3)[N:7]([CH2:6][C:5]3[CH:35]=[CH:36][C:2]([F:1])=[CH:3][CH:4]=3)[C:19]=2[C:18]([O:20][CH3:21])=[CH:17][CH:16]=1)=[O:23]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3cc(Cl)ccc3n(Cc3ccc(F)cc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(Cc3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 169.5 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-fluoro benzyl)-6-chloro-1-methoxy-4-carbazole carboxylate (170 mg, 0.4276 mmoles) in dry DMF (6 ml) under nitrogen atmosphere, 3,5-dichloro-4-amino pyridine (69.7 mg, 0.1116 mmoles) was added followed by sodium hydride (60% suspension, 37.0 mg, 0.8553 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 100 mg of the title compound as an off white solid, m. p: 249-250° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[CH:21]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCCCC1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)C1CCCCC1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and cyclohexane-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[C:8]1(=[O:12])[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)CBr
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)CCCC2=O
Reaction time: 18 h

Procedure:
To a solution of 6-hydroxy-1-tetralone (2.62 g) in acetone (50 ml) was added anhydrous potassium carbonate (2.23 g) followed by methyl bromoacetate (1.52 ml) and the resulting mixture was stirred for 18 hours. The mixture was filtered and the solvent was evaporated to give a yellow solid. Recrystallisation from ethyl acetate gave methyl tetralone-6-oxyacetate (2.28 g): NMR (d6DMSO) δ 1.95-2.05(m,2H), 2.45-2.55(m,2H), 2.9(t,2H), 3.7(s,3H), 4.9(s,2H), 6.85-6.9(m,2H), 7.8(d,1H); m/e 235(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH:22]3[CH2:24][CH2:23]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH2:32]([OH:35])[C:33]#[CH:34]>CN(C=O)C.[Cu]I.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>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:34]#[C:33][CH2:32][OH:35])[CH:17]=3)[N:12]([CH:22]3[CH2:24][CH2:23]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(I)cc2c1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(C#CCO)cc2c1=O
Reaction time: 8 h

Procedure:
To a dry flask under an atmosphere of argon gas containing 0.24 g of N-(4-chlorobenzyl)-1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 20, 0.01 g of copper (I) iodide and 0.04 g of dichlorobis(triphenylphosphine)palladium (II) is added diethylamine (1.5 mL) and propargyl alcohol (0.04 mL). After 3 hours reaction is diluted with DMF (0.5 mL) and left to stir overnight. The reaction is concentrated under reduced pressure, diluted with dichloromethane containing a small amount of methanol, and partioned against water. The organic layer is washed with brine, dried and concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane . The product-containing fractions are combined and concentrated under reduced pressure to afford 0.17 g of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])[CH2:10]1)=[O:7])#[N:2].C([Sn]([N:46]=[N+:47]=[N-:48])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[NH:46]1[C:1]([C:3]2[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=2)[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[O:20][C:21]=3[CH3:22])[CH2:10]2)=[O:7])=[N:2][N:48]=[N:47]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OC(=O)c2cccc(C#N)c2)C1
Solvent: Cc1ccccc1C
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OC(=O)c2cccc(-c3nnn[nH]3)c2)C1
Temperature: 160 °C

Procedure:
0.06 g of cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-cyanobenzoate is dissolved in 5 ml of xylene, 150 μm of tributyltin azide are added and the mixture is heated under reflux at 160° C. for 24 hours. The reaction is terminated by addition of 1 ml of trifluoroacetic acid (in 1 ml of methanol), 3 ml of water are added and the mixture is extracted with ethyl acetate (2×10 ml). The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. Purification by preparative HPLC gives 0.04 g of the desired cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-(1H-tetrazol-5-yl)benzoate as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=3)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:41])[C:13]=2[CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:45](O)C>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:45])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:14]([CH3:41])[C:13]=2[CH:42]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C2CCCCC2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Ethyl 3-({[4-({[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}amino)propanoate (0.78 g) synthesized in the above-mentioned (1) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (3.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (3.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.70 g, 94%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22]Br)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:21][O:20][C:19]3[CH:24]=[CH:25][C:16]([CH3:15])=[CH:17][CH:18]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(OCCBr)cc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2CCN(CCOc3ccc(C)cc3)CC2)cc1
Yield: 82.2 %

Procedure:
From a mixture of 4-(4-methylbenzyl)piperidine (1.14 g, 6.02 mmol), 2-(4-methylphenoxy)ethyl bromide (630 mg, 3.01 mmol) and KI (90 mg) in toluene (20 mL) was obtained 800 mg (85%) of the title compound as a yellow oil, 1H NMR (CDCl3): 1.26-1.38 (m, 2H), 1.45-1.53 (m, 1H), 1.61-1.66 (m, 2H), 1.99-2.07 (m, 2H), 2.277 (s, 3H), 2.317 (s, 3H), 2.494 (d, 2H, J=7), 2.761 (t, 2H, J=6), 2.95-2.99 (m, 2H), 4.067 (t, 2H, J=6), 6.792 (d, 2H, J=78), (d, 2H, J=8), 7.01-7.10 (m, 6H). The hydrocloride, mp 170-1° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.CO.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([C:15](=[O:17])[CH3:16])=[CH:4][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)c1cc(C(=O)N2CCCC2)ccc1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)c1cc(C(=O)N2CCCC2)ccc1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
A mixture of Compound 419c (0.29 g, 0.845 mmol), 4-chlorobenzeneboronic acid (0.159 g, 1.02 mmol)) and Pd(PPh3)4 (97 mg) in toluene (25 mL), MeOH (6 mL) and saturated NaHCO3 (2.5 mL) was stirred under Ar at 70° C. for 16 h. After evaporation of solvent, the residue was dissolved in CHCl3 (30 mL) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography using CHCl3-MeOH (80:1 to 30:1) as the eluent to give an oil (0.266 g, 96%). MS: 328.08 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][CH:33]=[O:34])[CH:31]=1)[NH:28][C:27](=[O:35])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][CH:33]=[O:34])[CH:31]=1)[NH:28][C:27](=[O:35])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=CNc1cc(F)cc2c1NC(=O)C2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3c(NC=O)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 95 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide 20c obtained from step 3 of Example 20 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide 29 (59 mg, yield 95%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[C:8](Cl)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCN
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.0 g. (0.0196 moles) of 3-dimethylaminopropylamine in 40 ml chloroform was added dropwise to an ice cold chloroform solution (50 ml) of myristoyl chloride (4.17 g., 0.0169 moles). After addition, the ice bath was removed and the solution was stirred for 2 hours. A 25 ml aqueous sodium bicarbonate solution was added and stirred for 30 minutes. The organic layer was then washed with 30 ml aqueous sodium bicarbonate/sodium chloride solution and dried with magnesium sulfate. The solution was concentrated in vacuo and the amide was recrystallized in ethyl acetate to yield 3.29 g. (0.0105 moles, 62.3%) of the subject compound.
Reaction SMILES: [C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)P(Cc1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
Di-t-butylchlorophosphine (75.0 g (0.415 mole)) and 0.5 mole of 12M solution of benzylmagnesium chloride in THF (200 ml) were refluxed under argon for 2 days. The reaction mixture was allowed to cool off to RT and an aqueous solution of ammonium chloride was added slowly. The organic phase was separated, and dried with magnesium sulfate. After removal of the solvent, the product was purified by distillation in vacuum. The yield of benzyldi-t-butylphosphine was 94.3 g (96%) with b.p. 56-59° C./0.1 mm. 31-P-NMR (CDCl3)+36.63 ppm. 1H NMR (CDCl3) 1.18 (s, 9H, Me3C), 1.20 (s, 9H, Me3C), 2.90 (d, 2JPH=2.92 Hz, P—CH2-Ph), 7.1-7.6 (m, 5H, aromatic protons).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([O:8][C:9](=[O:20])[CH:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[C:13]1=[O:19])[CH3:11])[CH3:7].CN1CCOCC1>ClCCl>[CH2:6]([O:8][C:9](=[O:20])[CH:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:2]([O:4][CH3:5])=[O:3])[C:13]1=[O:19])[CH3:11])[CH3:7]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C(C)N1CCCC(N)C1=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)N1CCCC(NC(=O)OC)C1=O
Yield: 75 %

Procedure:
Methyl chloroformate (192 μL, 2.5 mmol) was added to a solution of 2-(3-amino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester (353 mg, 1.6 mmol) and 4-methylmorpholine (907 μL, 8.24 mmol) in dichloromethane (10 mL). After 15 minutes the mixture was diluted with dichloromethane (20 mL) and washed with water (10 mL), and aqueous hydrogen chloride (0.5 N, 10 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to provide 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester (332 mg, 1.2 mmol, 75%). C12H20N2O5 calculated 272.1 observed [M+1]+ 273.0; rt=1.82 min.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[CH:2].[CH2:8]([O:10][C:11](=[O:15])/[CH:12]=[CH:13]\I)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:15])[CH:12]=[CH:13][C:2]#[C:1][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:9]
Reactant: C#Cc1cccs1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1cccs1

Procedure:
The general procedure was used to convert 2-Ethynyl-thiophene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (230 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.36-7.35 (dd, J=5.1, 1.0, 1H), 7.33-7.32 (dd, J=3.6, 1.0, 1H), 7.02-7.00 (m, 1H), 6.36-6.33 (d, J=11.4, 1H), 6.10-6.08 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 1.36-1.32 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.79, 133.49, 129.19, 127.62, 127.36, 122.57, 122.29, 94.50, 90.82, 60.51, 14.31. Anal. Calcd. for C11H10O2S: C, 64.05; H, 4.89; S, 15.55; Found C, 64.01; H, 4.95; S, 15.27.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[K+].O>CO>[CH3:1][C:2]([CH3:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Cc1ccccc1)C(=O)O

Procedure:
A solution of 1 g (20 mmol) of ethyl 2,2-dimethyl-3-phenylpropionate (stage 1) and 3.5 g (61 mmol) of potassium hydroxide in 15 ml of methanol was heated under reflux for 2 hours. Thereafter, 50 ml of water were added and the mixture was extracted twice with ether. The aqueous phase was acidified with concentrated hydrochloric acid and extracted again with ether, the organic phase was dried over magnesium sulfate and the solvent was stripped off in vacuo.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]([N:19]=[C:20]=[S:21])[CH3:18]>CCOCC>[CH2:17]([NH:19][C:20]([N:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:12][CH2:13]1)=[S:21])[CH3:18]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CCN=C=S
Solvent: CCOCC
Product: CCNC(=S)N1CCN(c2ccc3ccccc3n2)CC1
Reaction time: 1 h

Procedure:
To a slurry of 4.26 g. of 1-(2-quinolinyl)piperazine in 30 ml. of anhydrousether is added dropwise a solution of 1.74 g. of ethyl isothiocyanate in 30ml. of anhydrous ether. The mixture is stirred for one hour and the resulting solid is collected and recrystallized from 150 ml. of ethanol, giving 4.43 g. of the desired product as a white crystalline solid, m.p. 193°-195° C.
Reaction SMILES: [C:1]([NH:9][C:10](=[S:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[C:1]([NH:9][C:10](=[S:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[C:31]2[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]2=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=S)NC(=O)c2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)NC(=O)c2ccccc2)n1

Procedure:
The reaction described in Example 1 was repeated, but using 1.5 g of ethyl 2-(3-benzoylthioureido)thiazol-4-ylglyoxylate, 0.79 g of rhodanine-3-acetic acid, 0.1 g of ammonium chloride, 0.4 ml of 28% v/v aqueous ammonia, and 20 ml of ethanol, giving the title compound as a yellow powder.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H][H]>C1(C)C=CC=CC=1>[CH3:12][C:7]1[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: Cc1cccc2c1CCCC2C
Solvent: Cc1ccccc1
Product: Cc1cccc2c(C)cccc12

Procedure:
Using a 10% toluene solution of 1,5-dimethyltetralin obtained by the above method (A), dehydrogenation was conducted at 400° C. in a hydrogen atmosphere in the presence of a 0.3% Pt/Al2O3 catalyst for dehydrogenation to obtain 1,5-dimethylnaphthalene. Conversion of 1,5-dimethyltetralin was 100%, and selectivity to 1,5-dimethylnaphthalene was 97%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}phenyl)carbonyl]amino}propanoate (253 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (133 mg, 56%) as a pale-brown solid.