Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=2[CH3:32])=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:35](Cl)(=[O:41])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39].Cl>O1CCCC1>[CH2:37]([O:36][C:35]([N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:14]([F:17])([F:15])[F:16])[C:18]([F:20])([F:21])[F:19])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=1[CH3:32])=[O:26])=[O:41])[CH:38]([CH3:40])[CH3:39]
Reactant: COC(c1ccc(NC(=O)c2c(C)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(N(C(=O)OCC(C)C)C(=O)c2c(C)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
Sodium hydride (29 mg, 60%, 0.73 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-1,3,5-trimethylpyrazole-4-carboxamide (260 mg, 0.48 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of isobutyl chlorocarbonate (100 mg, 0.73 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired compound (280 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2].[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:35]3[CH2:36][CH2:37][N:32]([CH:29]([CH3:31])[CH3:30])[CH2:33][CH2:34]3)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: CC(C)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(N3CCN(C(C)C)CC3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C

Procedure:
88.9 mg of (2S,4R)-1-acetyl-6-bromo-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline was dissolved in 4 mL of toluene, and 142.5 μL of 1-isopropylpiperazine, 9.2 mg of tris(dibenzylideneacetone)dipalladium(0), 6.0 mg of (2-biphenyl)-di-tert-butylphosphine, and 38.4 mg of tert-butoxysodium were sequentially added to the solution. The mixture was heated to reflux for 12 hours. The reaction liquid was cooled, and then was filtered through Celite. The filtrate was washed with chloroform, water was added to the filtrate, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform:methanol=10:1), and then was recrystallized from ethyl acetate-hexane. Thus, 22.0 mg (22.4%, cis:trans=9:1) of the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][CH2:22][NH2:23]>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:23][CH2:22][CH2:21][C:17]3[N:16]([CH3:15])[CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNCC(O)COc1cccc2[nH]ccc12
Yield: 60 %

Procedure:
The title compound was prepared in similar fashion from 4-(oxiranylmethoxy)-1H-indole and 2-(1-methyl-1H-pyrrol-2-yl)ethylamine in 60% yield. FDMS m/e=313. mp 105°-106°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:30]1([C:36]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:22][CH2:23][N:39]3[CH2:38][CH2:37][C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]3)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CC[C@@](CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Product: NC(=O)C1(c2ccccc2)CCN(CC[C@]2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccc3)C2)CC1

Procedure:
Prepare by the method of Example 1.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]=[C:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC=C2OC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCCC2OC(=O)NC2=O)cc1
Yield: 65.5 %

Procedure:
A mixture of 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione (0.38 g), palladium-carbon (10%, 0.2 g) and tetrahydrofuran (40 ml) was subjected to catalytic hydrogenation at room temperature and 3 atom. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:3) was obtained 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyl]-2,4-oxazolidinedione (0.25 g, 65%). This product was recrystallized from dichloromethane-methanol to give colorless prisms, m.p.136-137° C.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[C:1]([C:6]1[N:7]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Brc1cccnc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccccc2n1-c1cccnc1

Procedure:
A solution of 10.0 g of 2-carboethoxyindole and 5 ml of 3-bromopyridine in 50 ml of pyridine is refluxed with 5.0 g of copper oxide and 5.0 g of potassium carbonate for 72 hours. Filtration and evaporation yields an oil which is chromatographed on 110 g of silica with 15% ethyl acetate in toluene to yield 2-carboethoxy-N-(3-pyridyl)indole as an oil; IR (CH2Cl2) 1705 cm-1.
Reaction SMILES: [BrH:1].C([CH:6]1[CH:11]([OH:12])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:9]([CH2:20][OH:21])[CH2:8][N:7]1CC1C=CC=CC=1)(C)(C)C>[Pd].CO>[BrH:1].[OH:21][CH2:20][CH:9]1[CH2:8][NH:7][CH2:6][CH:11]([OH:12])[CH:10]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: CC(C)(C)C1C(O)C(c2ccc(O)cc2)C(CO)CN1Cc1ccccc1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: OCC1CNCC(O)C1c1ccc(O)cc1

Procedure:
In an analogous manner to that described in Example 2 (e), by catalytic hydrogenation at atmospheric pressure using a 10% palladium-charcoal catalyst in methanol from tert-butyl (3RS,4RS,5SR)-1-benzyl-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide there was obtained (3RS,4RS,5SR)-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide as a colourless foam; MS: 224 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:22][O:23][C:24]=3[CH3:25])=[O:19])[CH2:14][CH2:13]2)[C:9]([Cl:34])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:35][N:36]([CH3:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:34][C:9]1[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:22][O:23][C:24]=3[CH3:25])=[O:19])[CH2:16][CH2:17]2)=[CH:11][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([N:36]([CH3:35])[CH3:46])=[CH:45][CH:44]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1N
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1NC(=O)c1ccc(N(C)C)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69.4 %

Procedure:
The reaction mixture of methyl 2-amino-5-chloro-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate (27.5 mg, 0.057 mmol), 4-(dimethylamino)benzoyl chloride (52.1 mg, 0.284 mmol), N,N-dimethylpyridin-4-amine (0.693 mg, 5.67 μmol) and 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (78 mg, 0.284 mmol) in DCE (1.5 mL) was stirred at 80° C. for 6 hours. The product was purified by preparative HPLC (0.1% TFA MeOH/H2O) to give 25 mg (49% yield) of methyl 5-chloro-2-(4-(dimethylamino)benzamido)-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate. 1H-NMR (CDCl3, 400 MHz): δ 12.06 (1H, s), 8.53 (1H, s), 8.05-7.99 (3H, m), 7.59 (1H, dd, J1=7.5 Hz, J2=1.5 Hz), 7.53-7.46 (1H, m), 7.15-6.99 (4H, m), 3.95 (3H, s), 3.84 (2H, s), 3.82 (3H, s), 3.28 (2H, s), 3.15 (6H, s), 2.59 (3H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1([CH3:28])[S:21][CH:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]=[CH:18]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:16][C:17]1([CH3:28])[S:21][C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[C:3]4[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:24][CH2:23]2)=[N:19][CH2:18]1
Reactant: CC1(C)C=NC(N2CCNCC2)S1
Reactant: FC(F)(F)Cc1cc2c(Cl)ncnc2s1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN=C(N2CCN(c3ncnc4sc(CC(F)(F)F)cc34)CC2)S1
Yield: 82.2 %

Procedure:
A solution of 0.5 g of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (2.4 mmol), 0.56 g of 5,5-dimethyl-2-(piperazin-1-yl)-2,5-dihydrothiazole (2.8 mmol), and 0.91 g of N,N-diisopropylethylamine (7.1 mmol) in 20 mL of THF was refluxed for 6 h. After cooling, the mixture was partitioned between ethyl acetate and H2O. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated to a pale yellow solid. Purification by silica gel column chromatography using dichloromethane/methanol (97:3) as eluent gave 0.82 g of 4-(4-(5,5-dimethyl-4,5-dihydrothiazol-2-yl)piperazin-1-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (compound 1) as a pale yellow solid. Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. 1H NMR (400 MHz DMSO-d6): δ 8.46 (s, 1H), 7.70 (s, 1H), 4.37 (s, 1H), 4.09 (m, 4H), 3.81, (m, 4H), 3.45 (q, 2H, J=10.1 Hz), 1.61 (s, 6H). ESI MS [MH+]: 416.1.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([C:29]1([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]1=[O:42])[C:22]([O:24]C(C)(C)C)=[O:23]>C(Cl)Cl>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([C:29]1([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]1=[O:42])[C:22]([OH:24])=[O:23]
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)O)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Trifluoroacetic acid (2.0 mL) is added to a solution of tert-butyl α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (282 mg, 0.507 mmol) in CH2Cl2 (4.0 mL) at 0° C. The solution is stirred for 1 hour at 0° C. A second portion of trifluoroacetic acid (2.0 mL) is added, and the solution is stirred for 30 minutes at 0° C. and for 30 minutes at room temperature. Concentration and aqueous workup (CH2Cl2, MgSO4) to give 217 mg (90%) of the title compound as a colorless oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([F:10])[CH:4]=1.Cl[CH2:12][C:13]([CH3:15])=[CH2:14].[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.[Cu](I)I.II>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:14][C:13]([CH3:15])=[CH2:12])=[CH:4][C:5]=1[F:10]
Reactant: C=C(C)CCl
Reactant: Fc1cc(Br)ccc1Cl
Agent: I[Cu]I
Agent: II
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: C=C(C)Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium (2.43 g) and iodine (10 mg) were added to tetrahydrofuran (40 ml) and a solution of 4-bromo-1-chloro-2-fluorobenzene (21.0 g) in tetrahydrofuran (40 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr to give a Grignard's reagent. The reaction mixture was ice-cooled and copper iodide (1.90 g) was added. 3-Chloro-2-methyl-1-propene (14.8 ml) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled and saturated aqueous ammonium chloride solution (10 ml) was added. The mixture was stirred at room temperature for 20 min and magnesium sulfate (40 g) was added. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Hexane (100 ml) was added to the obtained residue and insoluble materials were filtered off. The resulting solution was concentrated under reduced pressure to give the title compound (16.9 g).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][Mg]Br.Cl[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.CN1CCCC1=O.O>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)CC[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
(3,3,3-trifluoropropyl)magnesium bromide (8.16 mL, 8.16 mmol, Step-1) is added to a solution of methyl 6-chloronicotinate (0.70 g, 4.08 mmol), iron(III) acetylacetonate (0.14 g, 0.41 mmol) and 1-methyl-2-pyrrolidinone (0.23 mL, 2.39 mmol) in tetrahydrofuran (23 mL) and stirred at room temperature for 30 minutes. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (3:1) to give 0.95 g (99% yield) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH2:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[Cl:10][C:6]1[N:5]=[C:4]([S:11][CH2:12][CH3:13])[N:3]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:7]=1[O:8][CH3:9]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCSc1nc(Cl)c(OC)c(Cl)n1
Solvent: CCO
Product: CCSc1nc(Cl)c(OC)c(Nc2ccc(Cl)cc2)n1

Procedure:
A solution of the product from step (iii) (4 g) and 4-chloroaniline (5.3 g) in ethanol (40 ml) was heated under reflux for 16 h then the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and 2M hydrochloric acid, the organics washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10–15% ethyl acetate in isohexane. Yield 4.99 g
Reaction SMILES: [C:1](=[O:11])(SCC)[O:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].S(Cl)([Cl:15])(=O)=O>>[C:1]([Cl:15])(=[O:11])[O:2][CH2:3][O:4][C:5](=[O:7])[CH3:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OCOC(C)=O
Product: CC(=O)OCOC(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.4 %

Procedure:
To the thioester from Step 3 (2.50 g, 14.0 mmol) cooled to 0° C. is added sulfuryl chloride (1.5 mL, 18.25 mmol) over 2 min. The reaction mixture is stirred at 0° C. for 30 min then at RT for 2.5 h. The reaction mixture is concentrated and then dried on house vacuum overnight to afford 2.4 g of the desired crude product, which is used without further purification. 1H NMR (CDCl3) δ 5.83 (s, 2H), 2.19 (s, 3H);
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:23])[CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH3:24][NH:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2)(=[O:28])=[O:27]>>[CH3:24][NH:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])/[C:32]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][C:9]([N:4]1[CH2:3][CH:2]([CH3:1])[NH:7][CH:6]([CH3:8])[CH2:5]1)=[O:23])(=[O:28])=[O:27]
Reactant: CC1CN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 61.5 %

Procedure:
3-[3-(3,5-Dimethylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (136 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyloxindole (68 mg, 0.3 mmol) following the same procedure used in Example 1 above to give 3-[1-{3-[3-(3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl}-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (97 mg, 62% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[CH3:7][C:8]1[N:9]=[C:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[S:11][CH:12]=1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:13]([C:10]2[S:11][CH:12]=[C:8]([CH3:7])[N:9]=2)([OH:18])[C:14]([F:17])([F:16])[F:15])[S:5][CH:6]=1
Reactant: Cc1csc(C(=O)C(F)(F)F)n1
Reactant: Cc1cscn1
Solvent: C1CCOC1
Product: Cc1csc(C(O)(c2nc(C)cs2)C(F)(F)F)n1

Procedure:
From 4-methylthiazole and 4-methyl-2-trifluoroacetylthiazole and using anhydrous tetrahydrofuran as solvent. M.p. 140°-142.5° C. 13C Nmr (CDCl3) 17.0, 77.5 (q, J 31 Hz), 117.1, 122.6 (q, J 284 Hz), 152.5 and 163.9 ppm.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:11][C:12]#[N:13].C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:11][C:12]1[NH:13][C:17](=[O:26])[C:18]2[C:19]([CH:25]=1)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2
Reactant: C[C@H]1CCCN(CCC#N)[C@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@H](C)[C@@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using cis-2-hydroxymethyl-3-methylpiperidine described in J. Heterocycl. Chem., vol. 9, pp. 875-878 (1972), 3-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-[2-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]([F:23])([F:22])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.C1(P(=CC(OCC2C=CC=CC=2)=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:22][C:7]([F:23])([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)C=CC(F)(F)c1ccc(-c2ccc(OC)cc2)cc1
Agent: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(F)(F)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4,4-Difluoro-4-(4′-methoxy-biphenyl-4-yl)-but-2-enoic acid ethyl ester. A solution of benzyl (triphenylphosphoranylidene)acetate (320 mg, 0.779 mmol) and 2,2-difluoro-2-(4′-methoxy-4-biphenyl)acetaldehyde (198 mg, 0.755 mmol) in toluene (4 mL) is heated to 90° C. with stirring for 2 hours. The reaction is cooled to room temperature and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 20% EtOAc/hexanes) to give the desired product as a pale yellow oil.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:46][CH3:47])=[C:21]([NH:24][C:25](=[O:45])[CH:26]=[CH:27][CH2:28][N:29]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:30][CH2:31]OS(C)(=O)=O)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.O>CN(C)C=O>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:46][CH3:47])=[C:21]([NH:24][C:25](=[O:45])[CH:26]=[CH:27][CH2:28][N:29]([CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:30][CH2:31][S:3][C:1](=[O:4])[CH3:2])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCOS(C)(=O)=O)CC(=O)OC(C)(C)C
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCSC(C)=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 mg of potassium thioacetate are added to 150 mg of 4-[(3-bromophenyl)amino]-6-[(4-(N-[(tert-butyloxycarbonyl)methyl]-N-[2-(methylsulphonyloxy)ethyl]amino}-1-oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline in 1 ml of dimethylformamide at ambient temperature. The reaction mixture is stirred overnight at ambient temperature and then combined with water for working up. The aqueous phase is separated off and extracted with ethyl acetate, the combined organic phases are dried over magnesium sulphate and freed from solvent in the rotary evaporator. Yield: 20 mg (14% of theory), Rf value: 0.62 (silica gel, ethyl acetate/methanol=15:1) Mass spectrum (EI): m/z=643, 645 [M]+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:17]1[CH:18]=[CH:19][C:20]([OH:25])=[C:21]([CH:23]=O)[CH:22]=1>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:23][C:21]3[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=3[OH:25])[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccccc1O
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccccc1O
Temperature: 25 °C

Procedure:
218 g (1 mole) of 1-p-carboxyphenyl-3-methyl-2-pyrazolin-5-one were suspended in 1000 ml of acetic acid. The suspension was heated to boiling temperature and 112 g (1 mole) of salicyladehyde were added. In the resulting solution the dye started crystallizing very quickly. After 2 h of refluxing the reaction mixture was cooled to room temperature. The dye was filtered with suction and rinsed with acetone.