Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[N+:11]([C:9]1[CH:8]=[N:7][N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:10]=1)([O-:13])=[O:12]
Reactant: COC(CCn1cc([N+](=O)[O-])cn1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(3,3-dimethoxypropyl)-4-nitro-1H-pyrazole (1.00 g, 4.65 mmol) in THF (20 mL), a 2N aq. HCl-solution (22 mL, 44 mmol) was added dropwise. After stirring at 80° C. for 10 min, the reaction mixture was allowed to reach rt, then sat. aq. NaHCO3-solution was added to the reaction mixture and the solvent was removed under reduced pressure. The remaining aq. layer was extracted with EtOAc (2×). The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 3-(4-nitro-1H-pyrazol-1-yl)propanal as yellow oil which was used in the next step without further purification. LC-MS conditions B: tR=0.33 min, [M+H]+=no ionization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCC1CCC(CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCC1CCC(CNS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
A solution of 2.37 g of 4-fluorophenylsulfonyl chloride (12.2 mmol) in 30 ml of dichloromethane was added over 10 minutes to a stirred solution of 5.20 g of 1,4-bis-aminomethylcyclohexane (36.6 mmol) and 3.15 g of diisopropylethylamine (24.4 mmol) in 100 ml of dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 16 hours, concentrated, and chromatographed on 200 g of silica packed with 5% MeOH (containing 2M NH3)-CHCl3, eluted with 5%, 7.5%, 10% (1 liter each) to give 3.63 g of the desired product.
Reaction SMILES: [CH3:1][C@H:2]([N:15]=[N+]=[N-])[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[CH3:14]>CCOC(C)=O.[Pd]>[CH3:1][C@H:2]([NH2:15])[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[CH3:14]
Reactant: Cc1ccc(C(F)(F)F)cc1C[C@H](C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(F)(F)F)cc1C[C@H](C)N
Yield: 75.1 %

Procedure:
To a solution of (1S)-1-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethyl azide (1.64 g, 6.74 mmol) in 100 mL of EtOAc was added Pd/C (300 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h. The catalyst was removed by filtration through celite, then passed through silica gel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-1-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]ethylamine (1.10 g, 75%) as pale yellow oil. ESI-MS: m/z (MH+) 218.4. 1H NMR (300 MHz, CDCl3): δ 7.37 (m, 2H), 7.20 (m, 1H), 3.20 (m, 1H), 2.58-2.77 (m, 2H), 2.38 (s, 3H), 1.42 (s, 2H), 1.14 (d, J=6.21 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([Br:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10].C(C1C=CC=C(O)C=1O)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(Br)cc(C(C)O)cc1Br
Agent: CC(C)(C)c1cccc(O)c1O
Product: C=Cc1cc(Br)c(OC(C)=O)c(Br)c1
Yield: 65.3 %

Procedure:
1-(3',5'-Dibromo-4'-acetoxyphenyl)ethanol (104.86 g, 0.296 mol) KHSO4 (1.0 g) and t-butyl catechol (3.34 g) are mixed in a flask. The flask is equipped with a fractional distillation apparatus and attached to a vacuumpump. Dehydration is conducted at 168°-187° C. under vacuum (0.05-0.10 mm Hg). The product is distilled at 116°-134° C. to yield an oily solid (61.82 g). Recrystallization from hexane gives white crystals, m.p. 76° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:41][N:40]([CH3:42])[CH2:39][CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.12) according to general procedure II. Yellow solid. MS (ISP) 601.3 [(M+H+]; mp 224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C1COCC1>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:18]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a stirring solution of 5-amino-2-chlorobenzoic acid (1.74 g, 10.1 mmol) in anhydrous THF (60 mL), 3-(trifluoromethyl)benzoyl chloride (2.33 g, 11.2 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from acetone/chloroform (v/v 1:1) to afford the title compound as a white solid (1.5 g, 43%).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2>C1COCC1>[CH:1]([O:4][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)([CH3:3])[CH3:2]
Reactant: Cc1ccc2nccc(Cl)c2n1
Reactant: CC(C)O
Solvent: C1CCOC1
Product: Cc1ccc2nccc(OC(C)C)c2n1
Temperature: -20 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a 100 mL flask placed with KH (30%, 2.7 g, 20.15 mmol, pre-washed with nHex) was added a solution of anhydrous isopropanol (2.04 g, 33.59 mmol) in anhydrous THF (15 mL) at room temperature under argon. The reaction mixture was cooled to −20° C. 8-chloro-2-methyl-[1,5]naphthyridine (1.20 g, 6.72 mmol) in THF (20 mL) was added dropwise and the reaction mixture was stirred at −20° C. to r.t for 2 hrs. The reaction mixture was poured into 20 mL ice-water and extracted with AcOEt (100 mL×3). The combined organic layers was dried over Na2SO4 and concentrated to give the crude product which was purified by flash column (AcOEt/Hex=1/3˜3/2) to give 8-isopropoxy-2-methyl-[1,5]naphthyridine as white solid (0.34 g, 25%). HR-MS-EI (+) m/e calcd for C12H14N2O (M+) 202.1106. found 202.1107.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[OH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([N:15]2[CH2:16][CH2:17][C:12]([OH:11])([CH3:18])[CH2:13][CH2:14]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CC1(O)CCNCC1
Reactant: N#Cc1cnc(N)cc1Cl
Solvent: CC(=O)N(C)C
Product: CC1(O)CCN(c2cc(N)ncc2C#N)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 6-amino-4-chloronicotinonitrile (intermediate 16, 31.6 mg, 0.206 mmol) and 4-hydroxy-4-methylpiperidine (47.4 mg, 0.412 mmol) in DMA (0.75 ml) was heated to 100° C. and stirred for 1 h. The resulting brown solution was heated to 120° C. and stirred for 18 h.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([O-:14])=[O:13].[K+].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a mixture of 4-tert-butyl-phenylamine (10.0 g, 67.01 mmol) dissolved in H2SO4 (98%, 60 mL) was slowly added KNO3 (8.1 g, 80.41 mmol) at 0° C. After addition, the reaction was allowed to warm to room temperature and stirred overnight. The mixture was then poured into ice-water and basified with sat. NaHCO3 solution to pH 8. The mixture was extracted several times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10:1) to give 4-tert-butyl-3-nitro-phenylamine (10 g, 77%).
Reaction SMILES: Cl.[C:2]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)N)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][O:20][C:21]([CH:23]1[CH2:29][CH2:28][C:26](=O)[CH2:25][CH2:24]1)=[O:22]>>[C:2]([N:10]1[C:26]2[CH2:28][CH2:29][CH:23]([C:21]([O:20][CH2:19][CH3:18])=[O:22])[CH2:24][C:25]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN(C(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Product: CCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1

Procedure:
Following a procedure similar to that of Example 31 and using 11 g. of 1-benzoyl-1-phenylhydrazine hydrochloride and 7.62 g. of ethyl cyclohexanone-4-carboxylate (prepared in situ from the corresponding ethylene ketal) there was obtained 6.2 g. of the title compound; m.p. 67°-69°C. (ether-pentane).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: Fc1cccc(CBr)c1
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3cccc(F)c3)c12
Yield: 90 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-fluorobenzyl bromide as starting materials, the title compound was obtained in a yield of 90% as an oil.
Reaction SMILES: [BrH:1].C(O)(=O)C.[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH:22]C(OCC3C=CC=CC=3)=O)[CH3:21])=[C:16]([F:33])[CH:15]=2)=[CH:8][CH:7]=1>>[BrH:1].[BrH:1].[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[C:16]([F:33])[CH:15]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccncc2)cc1F
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccncc2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 25% hydrogen bromide-acetic acid solution (8 ml) was added to (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzamide (550 mg), and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained crystals were washed with ether, and recrystallized from methanol to give 350 mg of (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)-3-fluorobenzamide dihydrobromide having a melting point of 294° C. (dec.).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16].P(Br)(Br)[Br:20]>C(OCC)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: BrP(Br)Br
Reactant: C=CC(=O)N(C)CCCCCCCCCCCO
Solvent: CCOCC
Product: C=CC(=O)N(C)CCCCCCCCCCCBr
Temperature: 25 °C
Yield: 53 %

Procedure:
Diethylether (250 ml) was added to N-(11-hydroxy-undecyl)-N-methyl acrylamide (38.31 g, 0.150 mol) and BHT (10 mg). Phosphorus tribromide (13.53 g, 50.0 mmol) was added dropwise. The initially undissolved solid dissolved completely and a yellowish oil precipitated. The reaction mixture was stirred at ambient temperature. After 24 h water (100 ml) and dichloromethane (200 ml) were added and the phases were separated. The aqueous phase was extracted with dichloromethane (2×100 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated on the rotary evaporator and dried on the fine vacuum. The yellowish oil was dissolved in dichloromethane (100 ml) and filtered via a fritted-glass filter filled with diatomaceous earth (n-hexane/ethyl acetate 1:1). The eluent was concentrated on the rotary evaporator and dried under a fine vacuum. 25.25 g (79.3 mmol; 53% yield) of a yellowish oil was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].[OH-].[Na+].CCO.CCOCC>O>[CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: Cc1cc(C)c(C)c(OCCCC(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C)c(C)c(OCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 4-(2,3,5-trimethylphenoxy)butyrate (9.09 g), 1N NaOH (58 ml), and EtOH (80 ml) was stirred at room temperature overnight. The reaction mixture was poured into a mixture of Et2O and water. The separated water phase was washed with Et2O, and was acidified by 6N HCl. After extraction by AcOEt, the AcOEt was washed with water and brine, and dried over MgSO4, and then evaporated. The resulting precipitate was collected by filtration, and dried to give 4-(2,3,5-trimethylphenoxy)butyric acid (4.91 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:12]=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(F)cc1
Solvent: ClCCl
Product: O=C=NC(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
1.5 g of 4-fluorobenzamide was dissolved in 20 ml of dichloromethane and 2.3 ml of oxalyl chloride was slowly added thereto at room temperature, and then the mixutre was heated and refluxed for 16 hours. When the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was distilled under reduced pressure to produce the titled compound as a oil. Without purification processes, next process was proceeded.
Reaction SMILES: B(Cl)(Cl)Cl.[C:5]1([OH:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+].CS[C:24]#[N:25]>ClCCCl>[C:24]([C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[OH:15])#[N:25]
Reactant: CSC#N
Reactant: Oc1cccc2ccccc12
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#Cc1ccc2ccccc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To 6 ml of a solution of 2.02M of boron trichloride in 1,2-dichloroethane were added a solution of 1.44 g of α-naphthol in 30 ml of 1,2-dichloroethane, 0.82 ml of methyl thiocyanate and 1.33 g of aluminium chloride under ice-cooling. After stirring at room temperature for 3 hr., the reaction mixture was poured into 33 ml of 4N aqueous NaOH and stirred at 75°-78° C. on an oil bath for 30 min. After cooling the aqueous layer was washed with methylene chloride, acidified with 25 ml of 6N HCl and extracted with ether. After drying the ether layer over anhydrous magnesium sulfate, the solvent was distilled off. The residue (1.51 g) was purified on a column of 30 g of silica gel. Then 1.26 g of the eluate with 10% ethyl acetate-methylene chloride was recrystallized from ether-petroleum ether to give 1.04 g of 2-cyano-1-naphthol as crystals melting at 182°- 183° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH:16]=O)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH2:16][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(N2CCC(CN3CCCC3)CC2)c1
Product: c1cc(CN2CCCCC2)cc(N2CCC(CN3CCCC3)CC2)c1

Procedure:
Prepared from the product of Example 20 and piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([CH:15]=[C:16](OCC)[NH:17][CH3:18])#[N:14]>>[C:13]([CH:15]=[C:16]([NH:17][CH3:18])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:14]
Reactant: NCCCCc1ncccc1Cl
Reactant: CCOC(=CC#N)NC
Product: CNC(=CC#N)NCCCCc1ncccc1Cl
Reaction time: 5 h

Procedure:
3-Chloro-2-(4-aminobutyl)pyridine is added to a solution of 1-cyano-2-ethoxy-2-methylaminoethylene and stirred at 100° for 5 hours. Chromatographic purification of the reaction mixture yields the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1CC(O)=O.N1C2C(=CC=CC=2)C(C[CH2:24][C:25]([OH:27])=[O:26])=C1.CC1NC2C(C=1CC(O)=O)=CC=CC=2.C1OC2C=C(CC(O)=O)C=CC=2O1.C1C(/C=C/C(O)=O)=CC2OCOC=2C=1.N1C2C(=CC=CC=2)C(CCCC(O)=O)=C1.COC1C=C2C(=CC=1)NC=C2CC(O)=O.O1C2C(=CC=CC=2CC(O)=O)C(=O)C=C1C1C=CC=CC=1.C1C(CCCC(O)=O)=CC=C(N(CCCl)CCCl)C=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:24][C:25]([OH:27])=[O:26])=[CH:2]1
Reactant: O=C(O)Cc1cc2ccccc2[nH]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: Cc1[nH]c2ccccc2c1CC(=O)O
Agent: O=C(O)/C=C/c1ccc2c(c1)OCO2
Product: O=C(O)Cc1c[nH]c2ccccc12

Procedure:
2-indolylacetic acid; (N-methyl)-2- or -3-indolylacetic acid; 3-(3-indolyl)propionic acid; 3- or 2-indolylacrylic acid (also (N-methyl)); (2-methyl-3-indolyl)acetic acid, 3,4-(methylenedioxy)phenylacetic acid; 3,4-(methylenedioxy)cinnamic acid; indole-3-butyric acid; (5-methoxyindol-3-yl)acetic acid; naphthyl-1- or -2-acetic acid; flavone-8-acetic acid; 5,6-dimethylxanthone-4-acetic acid (L. L. Thomsen et al.: Cancer Chemother, Pharmacol. 31, 151ff. (1992) demonstrate that the corticoid 21-carboxylic esters prepared from this could also have an antitumorigenic effect, likewise the abovementioned chlorambucil).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH:17][CH3:18])[C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH3:18])[C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2]
Reactant: CC=Cc1cccc(NC(=O)OCC)c1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cccc(NC(=O)OCC)c1C(=O)O
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of 2-ethoxycarbonylamino-6-propenylbenzoic acid (220 mg) in ethanol was hydrogenated at 50 psi hydrogen over 10% palladium on charcoal. After 3 hours, the catalyst was filtered through Celite and the filtrate evaporated to give an oily solid (194 mg). IR νmax =1680-1740 (br), 2500-3200 (br).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[O:12][CH2:13][C:14](=[O:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCCCC1>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]4[N:1]=[CH:2][NH:3][C:4]=4[CH:9]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: CCOC(=O)C1=C(Nc2ccc3nc[nH]c3c2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc3nc[nH]c3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 3.6 %

Procedure:
To a solution of ethyl 2-[(5-benzimidazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0 mL), piperidine (0.20 mL, 3.1 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.015 g, y. 4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][C:18]3[CH:19]=[N:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:13]2=[O:25])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11].[CH:26](O)([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=3)[C:13]2=[O:25])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11]
Reactant: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(O)nc4)C3=O)cc21
Reactant: CC(C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)Oc1ccc(O[C@@H]2CCN(c3cc(F)c4c(c3)C(=O)CC4)C2=O)cn1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a mixture of (R)-1-(7-fluoro-3-oxo-indan-5-yl)-3-(6-hydroxy-pyridin-3-yloxy)-pyrrolidin-2-one (60 mg), isopropanol (30 mg) and solvent (THF/DCM/NMP 4:4:1, 5 mL) under argon was added triphenyiphosphine (polymer, 0.4 mmol). After 5 minutes DIAD (51 mg) was added. The mixture was shaken at 40° C. for 12 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to provide Example 2-24. 1H-NMR (400 MHz, DMSO) δ 7.99 (1H, dd, J=11.1, 1.8 Hz), 7.97 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.51 (1H, dd, J=9.0, 3.1 Hz), 6.71 (1H, d, J=9.0 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 5.14 (1H, m), 3.96 (1H, m), 3.85 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.69 (1H, m), 2.14 (1H, m), 1.27 (6H, d, J=6.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(-c2ccccc2Cl)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
300 mg (0.8 mmol) of 8-bromo-1-(2-chloro-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one [see under B)] are dissolved in 5 ml of anhydrous N,N-dimethylformamide and 35 mg (0.8 mmol) of NaH are added portionwise. The suspension is stirred for 90 min at room temperature and 113 mg (0.8 mmol) of methyl iodide dissolved in 3 ml of N,N-dimethylformamide are added. After stirring for 18 h at room temperature, the solution is cooled at 0° C. and 20 ml of water are added slowly to the stirred suspension. The suspension is extracted with ethyl acetate and the water phase is discarded. The organic phase is washed with brine, dried with Na2SO4 and evaporated to dryness. The crude compound is purified by flash-chromatography (dichloromethane with 2% methanol) to provide the title compound: Analytical HPLC: tret=7.64 min (Grad. 2); ES-MS: m/e0=388.0, 390.0.