Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H](C1C=CC=CC=1)C([O:5][CH2:6][C@H:7]([NH2:19])[CH2:8][O:9][C@H:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])=O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[NH2:19][C@@H:7]([CH2:8][O:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH3:11])[CH2:6][OH:5]
Reactant: C[C@H](OC[C@@H](N)COC(=O)[C@H](O)c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@H](OC[C@H](N)CO)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A suspension of (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (R)-hydroxy-phenyl-acetate in EtOAc was treated with aqueous sodium bicarbonate solution and the mixture was stirred at room temperature until all the solid had dissolved. The phases were separated and the organic layer was dried over MgSO4. The solvent was evaporated to afford (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol as the free base.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8]([NH2:10])=O.P(Cl)(Cl)(Cl)=O>C(N(CC)CC)C>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8]#[N:10]
Reactant: NC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CC(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1

Procedure:
(3-Trifluoromethylphenoxy) (4-chlorophenyl)acetamide, (33.0 g., 0.1 mole) is dissolved in 250 ml. of phosphorus oxychloride and triethylamine (22.2 g.) is added over a 45-minute period with stirring while maintaining the temperature of the solution at 0°-2°C. Over a period of an hour the temperature is allowed to rise to 25°C. and then the solution is heated under reflux for 30 minutes. The solution is concentrated in vacuo (about 200 mm.) to remove volatile products and excess phosphorus oxychloride. Toluene (150 ml.) and ice water (250 ml.) are added to the residue. The toluene layer is separated and the aqueous phase is extracted with 3 × 75 ml. of toluene. The toluene solutions are combined and extracted with 0.5 N sodium hydroxide and then with water. The toluene solvent is removed in vacuo and the residue is distilled in vacuo (0.3 mm.). (3-Trifluoromethylphenoxy) (4-chlorophenyl)acetonitrile (27.6 g.) boiling at 144°-145°C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[C:28]([N+:34]([O-])=O)[CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][C:28]=2[NH2:34])[CH2:12]1)=[O:9])=[O:5]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)ccc1CN1CC[C@@H](NC(=O)CNC(=O)c2cc(OC(F)(F)F)ccc2N)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto VarianTM SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd—C (15 mg), and the mixture was stirred under H2 at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]-1-(2-amino-4-chlorobenzyl)pyrrolidine (Compound No. 1921) (2.2 mg, 6%): The purity was determined by RPLC/MS (81%); ESI/MS m/e 486.2 (M++H, C21H23ClF3N5O3).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>C1COCC1.CCOCC>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:11]=2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: NCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reaction time: 24 h
Yield: 0.1 %

Procedure:
121.5 mg of 3-(5-azidomethylfuran-2-yl)-1-benzyl-indazole (0,369 mmol) and 102 mg of triphenylphosphine (0.389 mmol) were stirred in 1 ml of THF for 3.5 hours. 10 μl of water were then added. After 24 hours, ether and aqueous HCl, 0.3M, were added to the reaction mixture. The solid which had been filtered off and the aqueous phase were combined, rendered alkaline with NaOH, 2M, and extracted with ether. The organic phase was washed with a little water and then with a sodium chloride solution, dried over sodium sulphate and concentrated. 79.9 mg of a yellow oil were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]2[C:28]=1[N:27]1[C:29]([CH3:32])=[N:30][N:31]=[C:26]1[CH2:25][CH2:24]2>COCCOC.O>[CH:8]1([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[C:21]2[CH:22]=[C:23]3[C:28](=[C:19]([F:18])[CH:20]=2)[N:27]2[C:29]([CH3:32])=[N:30][N:31]=[C:26]2[CH2:25][CH2:24]3)[CH2:10][CH2:9]1
Reactant: Fc1cncc(Br)c1C1CC1
Reactant: Cc1nnc2n1-c1c(F)cc(B(O)O)cc1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nnc2n1-c1c(F)cc(-c3cncc(F)c3C3CC3)cc1CC2
Temperature: 25 °C

Procedure:
3-Bromo-4-cyclopropyl-5-fluoropyridine (462 mg, 2.14 mmol) was dissolved in a mixture of DME (3.55 mL) and water (3.55 mL). Sodium carbonate (226 mg, 2.14 mmol), (9-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)boronic acid (1-6, 176 mg, 0.71 mmol) and tetrakis triphenylphosphine palladium catalyst (4.11 mg, 3.6 mop were added. The mixture was deoxygenated under reduced pressure, flushed with nitrogen and heated under reflux for 18 h. After cooling to room temperature, ethyl acetate (10 mL) and water (10 mL) were added and the organic layer was separated. The water phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered over a short plug of Celite® and evaporated under reduced pressure. The crude compound was purified using preparative thin layer chromatography (ethyl acetate/ethanol 6:4) in order to yield the title compound as a white solid; 1H NMR (CD3SOCD3, 500 MHz) δ 8.49 (d, J=2.5 Hz, 1H), 8.35 (s, 1H), 7.60 (dd, J=1.8, 12.0 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 3.80 (br. s, 4H), 2.54-2.52 (m, 3H), 1.96-1.95 (m, 1H), 0.89-0.87 (m, 2H), 0.68-0.67 (m, 2H); MS (ESI): m/z=338.97 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH3:22]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][S:9][C:4]1[N:5]=[C:6]([NH2:22])[CH:7]=[C:2]([Cl:1])[N:3]=1)[CH3:15]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CSc1nc(N)cc(Cl)n1

Procedure:
A mixture of 10.7 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid, ethyl ester and 4.2 g of sodium carbonate in 150 ml. of saturated ethanolic ammonia solution was stirred at room temperature for 1 week. The reaction mixture was filtered and petroleum ether was added to the filtrate until a precipitate was formed. The precipitate was recrystallized from petroleum ether-ethanol to give 1.2 g of product, mp. 113°-116°C.
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[C:23]([CH3:36])=[N:24][N:25]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[C:26]=4[CH3:27])=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)=[CH:9][C:8]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49].[OH-].[Li+]>C1COCC1.CO.O>[CH3:52][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[C:23]([CH3:36])=[N:24][N:25]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[C:26]=4[CH3:27])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][C:8]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCN(C)C)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(OCCCN(C)C)c(NS(C)(=O)=O)c3)cc12
Yield: 16.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-(3-(dimethylamino)propoxy)-5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (40 mg, 0.05 mmol) was hydrolyzed by lithium hydroxide (4 mg, 0.16 mmol), THF/methanol/water (1/1/0.5 ml) to afford 5 mg (16% yield) of the titled compound after purification by preparative TLC (SiO2)-eluted by 5% methanol in DCM. 1H NMR (CDCl3, 400 MHz): δ 8.88 (s, 1H), 8.54-8.53 (d, 1H), 7.84 (s, 1H), 7.808-7.803 (d, 1H), 7.33-7.23 (m, 3H), 7.05-7.03 (d, 1H), 6.99-6.90 (m, 2H), 6.87-6.852 (d, 1H), 5.31 (s, 2H), 4.16-4.13 (t, 2H), 2.96 (s, 3H), 2.52-2.49 (t, 2H), 2.31 (s, 6H), 2.25 (s, 3H), 2.17 (s, 3H), 2.00-1.97 (m, 2H). MS: m/z=591.4 (M+1), HPLC: 91.28% in method B.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[Br:16]N1C(=O)CCC1=O.Cl>CN(C=O)C>[Br:16][C:4]1[C:3]2[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 22 ml of DMF was cooled to 0° C. A solution of 1.03 g (9.8 mmol) of N-bromosuccinimide in 52 ml of DMF was added dropwise at 0° C. over a period of 1 hour and the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into 400 ml of ice water, acidified with a 1N HCl aqueous solution and extracted with 100 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to provide 510 mg of yellow crystals. Yield: 36%
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH3:13].O1CCCC1.[CH3:20][S:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1)(=[O:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:13][C:7]1[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][CH:3]([N:2]([CH3:1])[C:32](=[O:34])[CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][S:21]([CH3:20])(=[O:22])=[O:23])=[CH:30][CH:29]=1)[CH3:14]
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CNC(C)COc1cc(C)ccc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OCC(C)N(C)C(=O)Cc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution containing 0.52 g (2.7 mmol) of N-methyl-2-(2,5-dimethylphenoxy)-1-methylethylamine (Example 45) in 15 ml of tetrahydrofuran 0.63 g (2.7 mmol) of 4-methanesulfonamido-phenylacetic acid (Example 32) and 0.63 g (3.05 mmol) of dicyclohexylcarbodiimide are added and the reaction mixture is stirred at room temperature for 16 hours. After filtration of the mixture, the filtrate is evaporated under reduced pressure and the pale yellowish resin of about 4.5 g obtained is purified by column chromatography by using a mixture of ethyl acetate and hexane as eluent. Thus, 0.76 g (70%) of the title compound is obtained as an amorphous material.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccccc2c1
Yield: 92.1 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(naphthalen-2-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.090 g; 0.219 mmol), sodium hydroxide 10N (0.219 mL; 2.19 mmol) in methanol (2 mL) to afford 0.080 g (92%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=CC=2O)C=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](I)[CH:32]=1>CN1CCCC1=O.[Cu]=O.C1(C)C=CC=CC=1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1cc[nH]n1
Reactant: Fc1cccc(I)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(C)n1-c1ccn(-c2cccc(F)c2)n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (6.8 g) in N-methyl-2-pyrrolidone (68 ml) were sequentially added cesium carbonate (27.4 g), 8-quinolinol (1.2 g), copper oxide (I) (0.6 g) and 1-fluoro-3-iodobenzene (7.4 ml), and the mixture was stirred at 110° C. for 2 hours. This reaction mixture was cooled to room temperature, and toluene (80 ml) was added thereto, and then the mixture was filtered through Celite. After adding a 1M aqueous solution of sodium hydroxide (80 ml) to the filtrate, the mixture was extracted with toluene. The resulting organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to give the titled compound (10.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16].C[O-].[Na+].[C:22](O)(=[O:24])C.C(OCC)(=O)C>CO.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([O:24][CH3:22])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
256 mg (1.0 mmol) of 2-acetylamino-5-fluoro-4-nitro-benzoic acid methyl ester are dissolved in 5.1 ml of refluxing methanol abs. and cooled to 23° C. whereby some of the material recrystallizes. 81 mg (1.5 mmol) of sodium methanolate are added and the mixture is stirred under argon at room temperature for 16 hours. Acetic acid is added until a pH value of 5 is reached, the resulting mixture is distributed between ethyl acetate and water, the organic phase is separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on 100 g of silica gel (0.04-063 mm) with toluene-ethyl acetate (3:1), fraction size 12 ml. The fractions 37-46 are combined and evaporated, yielding 77 mg (28%) of 2-acetylamino-5-methoxy-4-nitro-benzoic acid methyl ester as yellowish crystals, m.p. 141-143° C.
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>CO.N1CCCCC1>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH2:13][CH:12]([O:23][CH3:24])[O:11][CH3:10])[CH:16]=1
Reactant: Cc1cccc[n+]1C
Reactant: COC(COc1cccc(C=O)c1)OC
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(COc1cccc(C=Cc2cccc[n+]2C)c1)OC
Yield: 85.8 %

Procedure:
In 6 ml of methanol, 1.50 g of 1,2-dimethyl pyridinium iodide and 1.50 g of m-(2,2-dimethoxyethoxy)-benzaldehyde were dissolved. The resultant solution, with two drops of piperidine added thereto, was refluxed for five hours and thereafter cooled off. Consequently, crystals were deposited. When the crystals were collected and washed thoroughly with acetone, there was obtained 2.34 g of 1-methyl-2-[m-(2,2-dimethoxyethoxy)-styryl]pyridinium iodide. In water, this product showed the highest absorption at 336 nm (ε=2.13×104). The infrared absorption spectrum (KBr) showed peaks at 1620, 1600, 1580, 1268, 1137, 1068, 965, 840, 772 and 680 cm-1. The yield was 86%.
Reaction SMILES: C(N(CC)CC)C.C(P(Cl)(CC)=O)C.[CH:15]1[C:28]2[CH:27]([CH2:29][C:30](O)=[O:31])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.[C:33]([C:37]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:47])=[CH:40][C:38]=1[NH2:39])([CH3:36])([CH3:35])[CH3:34].C(OC(C)C)(C)C>C(OCC)(=O)C.N1(C2C=CN=CC=2)CCCC1.C1C=CC=CC=1>[C:33]([C:37]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C:46]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:47])=[CH:40][C:38]=1[NH:39][C:30](=[O:31])[CH2:29][CH:27]1[C:28]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[O:20][C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)c1ccc(CCC(=O)c2ccccc2)cc1N
Reactant: O=C(O)CC1c2ccccc2Oc2ccccc21
Agent: CCP(=O)(Cl)CC
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CCC(=O)c2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 1 h
Yield: 88.7 %

Procedure:
0.58 ml (4.20 mmol) of triethylamine and 0.31 ml (2.10 mmol) of diethylphosphoryl chloride were added to 20 ml of a benzene suspension containing 505 mg (2.10 mmol) of 2-(9H-xanthen-9-yl)acetic acid, and then the mixture was stirred for 1 hour. At the end of this time, 5 ml of a benzene solution containing 587 mg (2.09 mmol) of 2-t-butyl-5-(3-phenyl-3-oxopropyl)aniline (prepared by a procedure similar to that described in Preparation 7), followed by 10 mg of 4-pyrrolidinopyridine, were added to the reaction suspension, and the resulting mixture was heated under reflux for 4.5 hours. The reaction mixture was then diluted with ethyl acetate, washed with dilute aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogen carbonate solution and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure, and the resulting residue was subjected to column chromatography through silica gel. Elution with a 4:1 by volume mixture of methylene chloride and cyclohexane yielded 934 mg (yield 86%) of the title compound as crystals, melting at 116°-118° C. (after crystallization from diisopropyl ether).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 4-bromobenzaldehyde (10.00 g, 54.08 mmol) and triphenylphosphine (0.500 g, 1.91 mmol) in anhydrous triethylamine (80 mL) under Angon, were added ethynyltrimethylsilane (6.00 g, 61.09 mmol) and palladium (II) acetate (0.100 g, 0.445 mmol). The final mixture was heated to reflux for 2 hours, and then it was cooled down to room temperature and filtrated. The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (dichloromethane/petroleum ether 1:4) and recrystallized from cold cyclohexane to give 10.5 g (96.1% yield) of 4-(trimethylsilylethynyl)benzaldehyde; MS m/e 187.2 (M+); 1H-NMR (CDCl3) δ ppm: 0.27 (s, 9H, SiMe3), 7.60 (d, 2H, ArH, J=8.1 Hz), 7.82 (d, 2H, ArH, J=8.1 Hz), 10.00 (s, 1H, CHO)]. This compound (8.00 g, 39.59 mmol) was treated with K2CO3 (0.500 g) in methanol (50 mL) at 25° C. for 2 hours, under Argon. The solvent was removed under vacuum and the residue dissolved in dichloromethane (100 mL). This solution was washed once with an aqueous saturated solution of NaHCO3 and once with water, before being dried over anhydrous Na2SO4 and the solvent evaporated under vacuum. The yellow residue was purified by column chromatography using dichloromethane/petroleum ether 1:4 for elution and recrystallization from cold cylohexane to give 4.40 g (85.5% yied) of the title compound; MS (EI) m/e 130.0; (M+). 1H-NMR (CDCl3) δ ppm: 3.30 (s, 1H, CH), 7.64 (d, 2H, ArH, J=8.1 Hz), 7.84 (d, 2H, ArH, J=8.1 Hz), 10.02 (s, 1H, CHO).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:27])[O:5][CH2:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:8][NH:9]C(OC(C)(C)C)=O)[CH3:2].[ClH:28]>O1CCOCC1>[ClH:28].[CH2:1]([NH:3][C:4](=[O:27])[O:5][CH2:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=1)[CH2:8][NH2:9])[CH3:2]
Reactant: CCNC(=O)OCC(CNC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)OCC(CN)c1cccc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
105 mg (0.27 mmol) of the compound of Example 19A were dissolved in 2 ml of a 4 N solution of hydrogen chloride in dioxane, and the mixture was stirred at 60° C. until the reaction had gone to completion (about 2 h). The volatile components were then removed on a rotary evaporator and the residue was dried under high vacuum. This gave 91 mg of the title compound in a purity of about 83% according to LC/MS (about 86% of theory); this material was reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([OH:18])[CH:4]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]([F:19])([F:20])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH3:21])[CH:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 88.4 %

Procedure:
This compound was prepared using the procedure of Example 8, 12.0 g (0.038 mol) of product of Example 5, 5.8 g (0.042 mol) of K2CO3, 12 ml (0.190 mol) of methyl iodide in 200 ml of acetone were reacted affording 11.21 g of solid which was purified by HPLC using 25% ethyl acetate/cyclohexane as eluting solvent to give 9.33 g (73.6%) of product as a white solid; mp 62°-64° C.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH:36](Br)([CH3:38])[CH3:37]>>[CH:36]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])([CH3:38])[CH3:37]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: CC(C)Br
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC(C)C)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with isopropyl bromide