Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:9][C:10]=1[CH2:11]Br)=[O:5])[CH3:2].[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:9][C:10]=1[CH2:11][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1sc(-c2ccccc2)nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
A mixture of 5-bromomethyl-2-phenyl-thiazole-4-carboxylic acid ethyl ester (596 mg, 1.83 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (511 mg, 2.02 mmol) and potassium carbonate (380 mg, 2.75 mmol) in anhydrous dimethylformamide (7 mL) was stirred at room temperature for 20 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (562 mg): MS: (+) m/z 521.1 (M+Na+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][NH2:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.OO.[O-]Cl.[Na+]>O.CO>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:9][N:10]=[N:1]1
Reactant: NCC1(CN)CCCCC1
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CO
Product: C1CCC2(CC1)CN=NC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
C-(1-Aminomethyl-cyclohexyl)-methylamine (10.0 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, H2O2 (44.3 mL of a 30% solution, 6 equiv.) and NaClO (125.5 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred for 45 min. at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure, yielded 8.7 g of a clear, light-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 1.24-1.53 (m, 10H), 4.17 (s, 4H).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[C].[Pd].[H][H]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(c1ccccc1)n1cc(-c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)N1CC(c2ccccc2)c2ccccc21
Yield: 97.3 %

Procedure:
A mixture of 3.0 g of 1-benzoyl-3-phenylindole, 0.33 g of 10% palladium-carbon catalyst, and 60 ml of acetic acid was stirred in hydrogen for six hours under the conditions of 60° C. and normal pressure, cooled, then filtered to remove the catalyst, and distilled to expel the acetic acid. The residue was alkalinized by addition of an aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then distilled to expel the ethyl acetate and obtain 2.94 g of 1-benzoyl-3-phenylindoline (97.4%) having a melting point of 127-129° C.
Reaction SMILES: B.[I:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl-].[NH4+]>C1COCC1>[I:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(I)c1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of borane (1M, THF, 2.5 eq., 38.2 mL) was added dropwise to a stirred solution of (3-iodophenyl)acetic acid (4.0 g) in THF (100 mL) cooled to 0□C. The resulting mixture was stirred at 0□C for 1 h then warmed to room temperature and stirred for a further 3 h. The mixture was poured into aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (sodium sulfate) and concentrated. The crude was purified by column chromatography (SPE cartridge, SiO2), using cyclohexane-ethyl acetate (70:30) as eluent to afford the title compound (3.5 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:11](=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.O.[OH-].[Na+].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1C(=O)ON=C1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(Cl)cc2)noc1Cl
Temperature: 2.5 °C
Yield: 57 %

Procedure:
A suspension of methyl 3-(4-chlorophenyl)-5-oxo-4,5-dihydroisoxazole-4-carboxylate (518 mg, 2.04 mmol; building block is commercially available) in POCl3 (3 mL) was cooled to 0-5° C., and upon stirring, Et3N (0.3 mL) was added dropwise. The resulting mixture was heated to 100-110° C. and stirred at this temperature for 2-2.5 h, cooled to room temperature, poured into iced water and neutralized with aqueous NaOH (10%). The product was extracted with ether and purified by column chromatography (hexane:EtOAc 25:2) to give 320 mg of a yellow solid. Yield 57%. 1H NMR (DMSO-D6, CCl4): 3.79 (3H, s, OCH3), 7.50 (2H, AB-syst., CH-arom.), 7.65 (2H, AB-syst., CH-arom.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)(=[O:8])=[O:7].[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O.C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[N:21][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])=[O:7]
Reactant: CCCCN
Reactant: O=Cc1ccccc1S(=O)(=O)CCCCCl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCN=Cc1ccccc1S(=O)(=O)CCCCCl

Procedure:
2.45 g of 2-[(4-chlorobutyl)sulfonyl]benzaldehyde was treated with 1.1 ml of n-butylamine, 3.4 g of magnesium sulfate, and 2 drops of concentrated sulfuric acid in 20 ml of diethyl ether in the same manner as described for Example 1, Part C to give 2.76 g of product. 1H-NMR (CDCl3) δ 0.96(t,3H,J=7 Hz); 1.32-1.50(m,2H); 1.65-1.79(m,2H); 1.84-1.93(m,4H); 3.11-3.20(m,2H); 3.46-3.53(m,2H); 3.67-3.74(m,2H); 7.55-7.73(m,2H); 8.00-8.13(m,2H); 9.12(s,1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[CH:14]=1)[C:6]([O:8]CC)=O)[CH3:2].CC1C(C2C=C([N+]([O-])=O)C=CC=2OC)=C(C)ON=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:27][C:22]1[C:21]([C:15]2[CH:14]=[C:13]3[C:18]([C:6]([OH:8])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(-c2c(C)noc2C)c1)C(=O)OCC
Agent: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(-c3c(C)noc3C)c(OC)cc2c1O
Reaction time: 8 h
Yield: 92 %

Procedure:
Diethyl({[3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amino}methylidene)propanedioate (for a preparation see Intermediate 3) (35 g, 90 mmol) was added in small portions over 10 min to boiling diphenyl ether (500 ml)—vigorous effervescence results. The mixture was heated at reflux for 20 min, the heater was switched off and removed from the vessel and the solution allowed to cool in air over 2 h to 40° C., giving some precipitation of a brown granular solid. The mixture was diluted with ether (300 ml) and allowed to stand overnight, then filtered and the solid washed with ether (2×200 ml) and dried to give ethyl 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylate (28.4 g, 83 mmol, 92% yield). LCMS (formate) Rt 0.73 min, MH+ 343
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]=1.CCN(CC)CC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: C1=CCCC1
Reactant: O=C(O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C2=CCCC2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
In a sealed tube is added 4-iodobenzoic acid (5.0 g, 20.16 mmol), cyclopentene (17.8 mL, 2101.6 mmol), Et3N (8.4 mL, 60.48 mmol) in toluene (100 mL). It is purged with N2 for 15 min. Pd(OAc)2 (0.23 g, 1.01 mmol) and P(o-Tol)3 (0.61 g, 2.01 mmol) are added. The reaction is stirred at 120° C. overnight. It is diluted with EtOAc, washed with 1M HCl, H2O, and brine. Purification of the crude material by chromatography gives the title compound (2.63 g, 69%).
Reaction SMILES: [CH3:1][S:2](=[N:10][C:11]([C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[S:25][C:24]([NH:26]C(=O)OC(C)(C)C)=[N:23][CH:22]=2)[CH:16]=[N:17][CH:18]=1)=[O:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:24]1[S:25][C:21]([C:20]#[C:19][C:15]2[CH:16]=[N:17][CH:18]=[C:13]([CH:14]=2)[C:11]([N:10]=[S@@:2]([CH3:1])(=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])=[CH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccccc3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cnc(N)s2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.5 %

Procedure:
To a solution containing tert-butyl (5-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}-1,3-thiazol-2-yl)carbamate (16 mg, 0.032 mmol) in 2.0 mL dichloromethane at room temperature was added trifluoroacetic acid (0.099 mL, 1.3 mmol). The reaction was stirred at room temperature for 17 hours, then partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc layer was washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid film was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a tan solid (9 mg, 74%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:27])=O>>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH:25]([CH3:27])[CH3:24])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Product: CC(C)N1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1

Procedure:
The title compound (0.1 g) was prepared from 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.10 g) and 32 μL of acetone as in Example 35. MS (ESI): exact mass calculated for C23H25ClN2, 364.17; found, m/z 365.2 [M+H]+, 367.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.21-7.17 (m, 3H), 5.15 (d, J=5.2 Hz, 2H), 4.58-4.54 (m, 1H), 4.28-4.25 (m, 1H), 3.78-3.65 (m, 2H), 3.45-3.35 (m, 1H), 3.03-2.85 (m, 2H), 1.42 (t, J=6.6 Hz, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:34])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one (4.15 g, 11.2 mmol) in chloroform (56 mL) was added 3-chloroperoxybenzoic acid (m-CPBA, approximately 77% purity, 2.75 g, 12.3 mmol) portionwise over a several minute period. After 1 hour, the reaction was not complete as judged by TLC, so an additional charge of m-CPBA (1.0 g) was added. After stirring for 30 minutes, the mixture was diluted with chloroform (200 mL), washed successively with a saturated aqueous sodium bicarbonate solution (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated to provide 4-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 156-158° C.; 1H NMR (300 MHz, CDCl3): δ 6.87 (s, 1 H), 6.65 (d, J=1.8 Hz, 1 H), 6.57 (d, J=2.2 Hz, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 4.10-4.02 (m, 1 H), 3.77 (s, 3 H), 3.02 (t, J=7.7 Hz, 2 H), 2.05 (s, 3 H), 1.93-1.73 (m, 2 H), 1.06-0.99 (m, 1 H), 0.95-0.87 (m, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.23 (m, 1 H); HRMS (ESI) calcd for C20H25N3O2Cl (M+H)+: 374.1635; found m/z 374.1634.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22].C(OCC)(=O)C>O>[OH:22][CH2:21][CH2:23][NH:24][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: NCCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(NCCO)c2)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.5 g, 0.0018 mol) and ethanolamine (15 mL) was heated at 100° C. for 18 hours. The reaction mixture was cooled and treated with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate) to give 0.44 g (80% yield) of product as a yellow oil: Anal. Calc'd. for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 69.89; H, 6.65; N, 18.35.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[S:46][C:47]3[CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][C:52]=3[N:53]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[S:46][C:47]3[CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][C:52]=3[N:53]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Product: CC(=O)OCc1c(-c2cc(Nc3nc4c(s3)CN(C)CC4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 78.4 %

Procedure:
Following Example 147b, 232 mg of 114a and 178 mg of 141b were reacted to give 141c as a yellow solid (240 mg, 80%). LCMS: [M+H]+ 613
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.CN(C)C=O>CCOCC>[C:10]([Si:14]([O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1])([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCC(O)CCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCC(CCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture consisting of 5 parts of 1-octyn-4(RS)-ol, 6.6 parts of tertiary-butyldimethylsilyl chloride, 6.8 parts of imidazole and 10 parts by volume of dimethylformamide is stirred at room temperature for about 16 hours, then is poured into ether. The resulting organic solution is washed several times with water, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford 1-octyn-4(RS)-ol tertiary-butyldimethylsilyl ether, which exhibits a nuclear magnetic resonance maximum at δ0.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of pyridine for 10 hours gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 133° C (from ethanol).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1.CC1C=CC(S(N)(=O)=O)=CC=1>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: NC1CCCCC1
Agent: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Yield: 249.7 %

Procedure:
500 g of chlorobenzene and 4.3 g of p-toluenesulfonamide (0.025 mol) were placed in the glass vessel and 33 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 79° C., with vigorous phosgene reflux being established. While stirring vigorously at 78–81° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 122 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 78–81° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 50° C. by means of nitrogen. The reaction mixture obtained was a fluid suspension from which the solid obtained was separated by filtration. <0.5 g of solid was able to be isolated in this way. Cyclohexyl isocyanate was worked up by distillation. Removal of the solvent and fractional distillation gave 105.1 g of cyclohexyl isocyanate (0.833 mol). This corresponds to 83.3% of the theoretical yield.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C(NC(C)C)(C)C.[Li].[C:14]1([Bi:20](Br)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:3][C:2]([Bi:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: Br[Bi](c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C#N)[Bi](c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 0.45 ml (5 mmole) of isobutyronitrile (Tokyo Kasei Co., Ltd.) was dissolved in 5 ml of THF, and the mixture was chilled to −78° C. under nitrogen atmosphere. Thereto was slowly added dropwise lithium diisopropylamine obtained above. The reaction mixture was stirred at −78° C. for 10 minutes and then heated to 0° C. Thereto was added dropwise a solution of 2.223 g (5 mmole) of diphenylbismuthanyl bromide prepared in Preparation Example 3 in 5 ml of THF.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(#N)C>[CH2:18]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:3][CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1Cc2cc(N3CCNCC3)ccc2N1
Reactant: ClCc1ccccc1
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
A mixture of 5-(1-piperazinyl)oxindol.hydrobromide (1.0 g), 1.2 g of benzyl chloride and 1.1 g of triethylamine in 20 ml of acetonitrile was stirred at room temperature for 6 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate and chloroform was removed. The residue was recrystallized from isopropyl alcohol to give 0.7 g of 5-(4-benzyl-1-piperazinyl)oxindol.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:22])[C@H:6]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](F)[N:9]=1)#[N:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:10]3[N:9]=[C:8]([NH:7][C@H:6]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:22])[CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:13]=[CH:12][N:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: N#CCNC(=O)[C@H](CC1CCCCC1)Nc1ccnc(F)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: N#CCNC(=O)[C@H](CC1CCCCC1)Nc1ccnc(N2CCN(c3ccc(Cl)cc3)CC2)n1

Procedure:
The title compound was prepared from the product of example 8 step (ii) (0.2 g) and 4(4-chlorophenyl)piperazine (0.66 g) by the method of example 1 step (iv). Yield 0.2 g.