Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]([O:20]CC)=[O:19])([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([CH2:17][C:18]([OH:20])=[O:19])([OH:16])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(O)(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2M aq solution of NaOH (13.5 ml, 27 mmol) was added to a solution of 4-ethoxycarbonylmethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (39) (5.17 g, 18 mmol) at rt. After stirring at rt for 1 h, methanol was evaporated and the residue was treated with water and extracted twice with Et2O, the water layer was then acidified with 2M aq solution of HCl (15 ml), extracted twice with EtOAc and the combined organic layers were dried over Na2 SO4 and concentrated to provide the product as white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]C(O)=O)=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7].C([N:21](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:21])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1ccc(N(CCCl)CCCl)cc1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
3-[4-[N,N-Bis(2-chloroethyl)amino]phenyl]propionic acid (0.20 g; 0.69 mmol) was suspended in 1 ml of acetone and the resulting mixture was stirred under a nitrogen gas atmosphere and ice-cooling. Triethylamine (115 μl; 0.82 mmol; 1.2 equivalents) and ethyl chloroformate (79 μl; 0.82 mmol; 1.2 equivalents) were added successively. Fifteen minutes later, a solution of 90 mg (1.38 mmol; 2.0 equivalents) of sodium azide in 1 ml of water was added dropwise. The resulting mixture was stirred, as was, for 30 minutes, to which ice was added to terminate the reaction. The thus-obtained mixture was extracted three times with 15 ml portions of benzene. The benzene layers were combined, dried over sodium sulfate and then heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was added with 7.5 ml of 8N hydrochloric acid, followed by heating for 15 minutes at 100° C. The resulting mixture was concentrated under reduced pressure and the residue was diluted with water. The thus-obtained mixture was adjusted to pH 12 with concentrated aqueous ammonia, followed by extraction with ethyl acetate. The extract was dried and concentrated, whereby 0.15 g of the title compound was obtained as a brown oil. This reaction product was provided for use in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(Br)c1
Temperature: 60 °C
Yield: 81 %

Procedure:
To a solution of 7.0 g of 3-bromophenol and 7.8 g of ethyl 4-bromobutyrate in 50 ml of DMF is added 11.2 g of K2CO3. The mixture is heated at 60° C. for 1 day and then poured into an ice-water mixture. This mixture is extracted with ether, and the ether extract is washed with water and dried over MgSO4. After filtration and concentration, a solution of 9.3 g of the ethyl 4-(3-bromophenoxy)butyrate obtained in 100 ml of THF is cooled to 0° C.; and 130 ml of a 1.5M solution of DIBAL-H in toluene is added dropwise. The reaction is stirred for 1 hour at 0° C. and 2 hours at room temperature, following which the reaction mixture is poured into a mixture of ice/3N HCl and extracted with ether. The ether extract is washed with water and dried over MgSO4. Filtration and concentration yields 4-(3 -Bromophenoxy) butan-1-ol.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@:5]([C:12]([O:14]C)=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18](=[O:60])[CH2:19][NH:20][C:21](=[O:59])[CH2:22][N:23]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30][N:29]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:28][CH2:27][N:26]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:25][CH2:24]1>CO>[OH:1][C@H:2]1[C@H:9]2[C@:5]([C:12]([OH:14])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18](=[O:60])[CH2:19][NH:20][C:21](=[O:59])[CH2:22][N:23]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH2:31][CH2:30][N:29]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[CH2:28][CH2:27][N:26]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:25][CH2:24]1
Reactant: COC(=O)[C@@]12O[C@@H](CNC(=O)CNC(=O)CN3CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC3)[C@@H](O)[C@@H]1OC(C)(C)O2
Solvent: CO
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCC(=O)NC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 19a (1.0 g, 1.17 mmol) in MeOH (2 mL) was added a solution of LiOHH2O (48.5 mg, 1.17 mmol, Aldrich). The resulting solution was stirred at room temperature for 4 h. Solvents were evaporated and the residue was purified by silica column chromatography. Product 20a was obtained as a white solid (0.8 g; yield 81%).
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@@H]3[C@@H]1CCC2=C(F)F
Yield: 95.7 %

Procedure:
A suspension of 1.2 g of 17-difluoromethylene-3-tetrahydropyranyloxy-8α-estra-1,3,5(10)-triene in 25 ml of methanol and 2.5 ml of water is refluxed with 1.2 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.9 g of 17-difluoromethylene-8α-estra-1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 119-120° C., [α]D22 =-10.6° (c=0.5% in pyridine).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:12]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)cc1C
Yield: 98 %

Procedure:
According to J. Org. Chem. 33:494 (1968), a mixture of 4-methoxy-2-methylbenzoic acid (20 g, 120 mmol) and MeOH (97 mL) containing sulfuric acid (conc., 0.6 mL) was heated under reflux 48 h. After cooling the mixture was evaporated and the residue diluted with diethyl ether and washed with a saturated sodium hydrogen carbonate solution and brine. The organic phase was then separated and dried over sodium sulphate. After evaporation the residue was distilled through a 8 cm Vigreux column to afford the title compound (21.2 g, 98%) as a colourless liquid. Bp 60° C./1 mbar. MS: m/e=180.3 (M+).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][OH:5])#[N:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][S:23]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(2,4-dichlorophenyl)decan-1-ol (40g., 0.12 mole) and methane sulfonyl chloride (15.3g., 0.13 mole) in 2 liters of benzene is added dropwise at 10° C., 14.8g., (0.14 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 41.3g. of product, which is identified by nmr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[C:5]([C:7]1[CH:35]=[CH:34][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=O.[CH3:39][O:40][NH2:41].N1C=CC=CC=1>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:41][O:40][CH3:39])[C:7]2[CH:35]=[CH:34][C:10]3[N:11]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[CH:20][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:32][CH:33]=4)[C:12](=[O:14])[S:13][C:9]=3[CH:8]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC
Reactant: CON
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CON=C(c1cccc(Cl)c1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(C=C(C(=O)OC)C(=O)OC)cc1

Procedure:
The compound obtained in Example 41 is dissolved in a minimum of methanol, and then 4 equivalents of O-methylhydroxylamine, previously dissolved in a few milliliters of water, and 4.5 equivalents of pyridine are added in succession. The reaction mixture is heated at reflux for 24 hours and then hydrolysed in water and filtered; the resulting precipitate is recrystallised from acetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].[OH-].[Na+]>COCCOCCOC>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: COc1cc2nccc(Oc3ccc(C)cc3C)c2cc1OC
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 2,4-dimethylphenol (0.267 ml) were suspended in diethylene glycol dimethyl ether (0.1 ml), and the suspension was stirred at 180° C. for 1.5 hr. The reaction solution was cooled to room temperature, and an aqueous sodium hydroxide solution was then added to the reaction solution. The mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel using acetone-chloroform to give 4-(2,4-dimethylphenoxy)-6,7-dimethoxyquinoline (127 mg, yield 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1.CCCCCC>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Cl)c3)ncnc2cc1F
Reaction time: 0.25 h

Procedure:
A solution of 2.76 ml of 3-chloroaniline in 7 ml of dioxan is added dropwise to 5.0 g of 4-chloro-7-fluoro-6-nitro-quinazoline in 40 ml of methylene chloride at 15° C. within 15 minutes. The reaction mixture is stirred for a further 15 minutes at this temperature before being poured onto 100 ml of n-hexane for working up. The mixture is stirred for about one hour while cooling with an ice bath, then the precipitate formed is filtered off. The hydrochloride thus obtained is suspended in 30 ml of methanol, made alkaline with triethylamine while cooling with an ice bath and combined with 100 ml of water. The precipitate formed is suction filtered and washed with water. The crude product is purified by chromatography on a silica gel column with methylene chloride/methanol (20:1) as eluant. Yield: 3.50 g (50% of theory), Melting point: 223-225° C. Mass spectrum (ESI*): m/z=319, 321 [M+H]*
Reaction SMILES: C([Li])CCC.Br[C:7]#[C:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[S:19][CH3:20].BrC(Br)=CC1C=CC(C(F)(F)F)=CC=1SC.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.[Cl-].[NH4+]>C1COCC1>[CH:37]1([C:40](=[O:41])[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[S:19][CH3:20])[CH2:39][CH2:38]1
Reactant: O=C(Cl)C1CC1
Reactant: CSc1cc(C(F)(F)F)ccc1C#CBr
Agent: CSc1cc(C(F)(F)F)ccc1C=C(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(C(F)(F)F)ccc1C#CC(=O)C1CC1
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M, 1.45 ml) was added to a stirred cooled solution of 1-bromo-2-[2-(methylsulphenyl)4-trifluoromethylphenyl]acetylene and 1,1-dibromo-2-[2-(methylsulphenyl)4-trifluoromethylphenyl]ethene (1.0 g) in THF, maintaining the temperature below -70°C. The mixture was stirred for 30 minutes and cyclopropanecarbonyl chloride (0.75 g) was added. The temperature was allowed to rise to room temperature and the mixture was stirred for 2 hours, aqueous ammonium chloride was added and the mixture was extracted with ether, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromotography eluted with a mixture of hexane and ether to give 3-cyclopropyl-1-[2-(methylsulphenyl )-4-trifluoromethylphenyl]prop- 1-yn-3one (0.64 g) as yellow oil, NMR (CDCl3) 1.15(m,2H), 1.45(m,2H), 2.2(m,1H), 2.6(s,1H), 7.35(d,1H) 7.4(s,1H), 7.6(d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[NH2:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[NH2:24][C:25]1[C:30]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])=[C:2]([F:1])[CH:14]=2)=[N:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Nc1nccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2nccnc2N)cc1F
Temperature: 100 °C
Yield: 86.3 %

Procedure:
A 2 L round-bottomed flask was charged with tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (54 g, 151 mmol), 2-amino-3-chloropyrazine (19.54 g, 151 mmol), 2 N sodium carbonate (158 mL, 317 mmol) and DME (600 mL). The reaction mixture was degassed for 10 min using argon, and then PdCl2(dppf)-CH2Cl2 (6.16 g, 7.54 mmol) was added. The reaction mixture was heated to 100° C. and maintained at this temperature for 4 h. After cooling down, the reaction mixture was poured into water (400 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with brine (3×200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified using flash chromatography on silica gel (0 to 70% EtOAc in heptane over 50 min), giving tert-butyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate (37.7 g, 86%) as a solid. LCMS (m/z): 290 (MH+), 0.80 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 (d, 1H) 7.91-7.81 (m, 2H) 7.65-7.46 (m, 2H) 6.35 (br. s., 2H) 1.54 (s, 9H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[C:15]2C=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[ClH:21].[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([Cl:22])=[CH:15][C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH:6]=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=CN1CCN(c2cc(Cl)ccc2Cl)CC1
Reaction time: 0.25 h
Yield: 196.1 %

Procedure:
A solution of 4-(2,5-dichloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (390 mg, 1.08 mmol) in 1,4-dioxane (1 mL) was cooled to 0° C. Dioxane.HCl (1 mL) was then added and the resulting mixture stirred for 15 minutes. The reaction mixture was then concentrated under reduced pressure to afford a solid, which was washed with ether and dried to afford 313 mg (97%) of 4-(2,5-dichloro-phenyl)-piperazin-1-yl-methanone.hydrochloride, LCMS: 296.01 (M+1)+, 96.09%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[ClH:21].[H][H]>C(O)C.[Pd]>[ClH:21].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cccc3cncn23)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 2.0 g of 5-(p-ethoxycarbonylphenyl)imidazo[1,5-a]pyridine in 120 ml of anhydrous ethanol containing 30 ml of concentrated hydrochloric acid, is hydrogenated with 1.0 g of 10% palladium on charcoal at 40 psi hydrogen and 60° for 4 h. The catalyst is filtered and the solvent is evaporated to yield a solid which is recrystallized from isopropanol and ether to provide the title compound, m.p. 164°-166°.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH:15][S:24]([C:21]4[CH:20]=[CH:19][C:18]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)(=[O:26])=[O:25])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1nc2c(s1)CCc1ccc([N+](=O)[O-])cc1-2
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=[N+]([O-])c1ccc2c(c1)-c1nc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)sc1CC2

Procedure:
The title compound was prepared from 8nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 7-nitrotetralone) and 4-biphenylsulfonyl chloride (122 mg) as described in the synetic METHOD A to give a yellow powder (4.4 mg) with a purity of >90%: MS-ES (neg) m/z 462.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C1([Li])C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21]>O1CCCC1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:20]([C:19]2[CH:30]=[CH:31][CH:32]=[C:17]([O:16][CH3:15])[CH:18]=2)([OH:21])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C(=O)c2cccc(OC)c2)c1
Reactant: Cc1ccncc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(C(O)(Cc2ccncc2)c2cccc(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred solution of 4-picoline (32,5 g) in tetrahydrofuran (140 ml), was added dropwise under argon a solution of phenyl lithium in 7:3 cyclohexane-ether (1.9M; 184 ml) at such a rate that the reaction temperature could be maintained at 10°-20° by means of an external cooling bath. After the addition was completed, the reaction was cooled to -5°, and then a solution of 3,3'-dimethoxybenzophenone (77.4 g) in dry tetrahydrofuran (140 ml) was added so that the reaction temperature did not exceed 0°. The cooling bath was removed and the mixture was stirred at room temperature for two hours, whereupon water (140 ml) was added slowly followed by tetrahydrofuran (140 ml). The layers were separated, and after sodium chloride (~30 g) was added to the aqueous phase, it was reextracted with tetrahydrofuran (2×100 ml). The combined organic layers were washed with brine (50 ml), then were dried (over sodium sulfate) and evaporated. The crude product was triturated with hot hexane (2×300 ml) and the resulting solid was filtered to give 93.5 g of alpha,alpha-bis(3-methoxyphenyl)-4-pyridineethanol, mp 134°-135°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13]C([O-])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[CH:13]/[C:12]([O:18][CH2:19][CH3:20])=[O:17])/[O:6]1)=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C1\OC(=O)c2ccccc21
Yield: 75 %

Procedure:
59.2 g (0.4 mol) of phthalic anhydride, 26.4 g (0.2 mol) of monoethyl malonate, and 15.8 g (0.2 mol) of pyridine are added to 200 ml of toluene, and the reaction mixture is heated under reflux for 4 hours. After terminating the reaction, 100 ml of water is added to the reaction mixture, and an organic layer is separated out. The organic layer is washed with 100 ml of 5%-aqueous acetic acid solution, and toluene is distilled off under a reduced pressure. The residue thus obtained is recrystallized from ethanol, to give 32.7 g (0.15 mol) of ethyl (Z)-3-phthalidylideneacetate. The yield is 75.0%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2>ClCCl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2)=[O:1]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CO)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a solution of 4-[(2-hydroxymethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (295 mg) in dichloromethane (8.0 ml) was added manganese(IV) oxide (196 mg) and the mixture was stirred at ambient temperature for 3 hours. The resulting mixture was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was triturated with diethyl ether-n-hexane (1:3) to give 4-[(2-formylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (255 mg).