Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[OH:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[O:22][CH2:27][CH:26]=[CH2:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: CCN1CCC(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Reaction time: 2.5 h
Yield: 74.3 %

Procedure:
8-t-butyldimethylsilyloxymethyl-4-hydroxy-1-ethyl-1,2,3,4-tetrahydroquinoline (2.19 g) was dissolved in dimethyl formamide (15 ml), followed by addition of sodium hydride (60% in oil, 0.33 g), and allyl bromide (0.99 g) was added thereto under ice-cooling. The mixture was stirred for 2.5 hours at the same temperature. Furthermore sodium hydride (60% in oil, 0.16 g) and allyl bromide (0.48 g) were added to the reaction mixture and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate-toluene and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (6 : 1)]to give 8-t-butyldimethylsilyloxymethyl-4-allyloxy-1-ethyl-1,2,3,4-tetrahydroquinoline (1.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.37 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. 2Methoxyethylamine (1.71 g, 0.023 mole) was added and the reaction mixture was allowed to stir at room temperature overnight.
Reaction SMILES: C(O)C.[C:4]1([S:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=2[N+:38]([O-])=O)[O:21][CH2:22][CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])(=[O:16])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>[Pd].C1COCC1>[NH2:38][C:37]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:26])=[O:27])=[CH:19][C:18]=1[CH2:17][S:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reaction time: 5 h
Yield: 87.6 %

Procedure:
Ethanol (180 mL) and 10% palladium on carbon (5.2 g) were added to a hot solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethyl ester (11.5 g, 21.2 mmol) in THF (180 mL). This mixture was shaken on the Parr hydrogenation apparatus for 5 hours, with a starting pressure of 47 psi. It was then filtered over Celite, concentrated and dried in vacuo at 80° C. for 30 minutes to give toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-ethyl ester as a dark brown gum (9.5 g, 88.0%). Mass Spectrum (+EI, [M+H]+) m/z 512. 1HNMR (500 MHz, DMSO-d6): 88.61 (d, 1H, J=8.41 Hz), 8.25 (d, 1H, J=8.30 Hz), 8.03-8.08 (m, 2H), 7.59-7.75 (m, 5H), 7.43 (d, 2H, J=7.93 Hz), 6.49-6.53 (m, 2H), 6.11 (d, 1H, J=2.68 Hz), 4.65-4.77 (br, 2H), 4.59 (s, 2H), 4.09-4.11 (m, 2H), 3.63-3.65 (m, 2H), 2.38 ppm (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](O)=[CH:17][CH:18]=1)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCc1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 146.5 %

Procedure:
To a solution of THF (50 mL) of 2-(hydroxymethyl)pyridine (1.5 g), methyl p-hydroxybenzoate (2.1 g), and triphenylphosphine (5.0 g) was added diisopropyl azodicarboxylate (3.9 g) at 0° C., which was stirred for 20 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by NH silica gel chromatography (heptane:ethyl acetate=2:1), then purified by silica gel chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (4.9 g).
Reaction SMILES: C([O:8][C:9](=[O:46])[C@H:10]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:11][C:12](=[O:38])[CH2:13][NH:14][C:15](=[O:37])[CH2:16][NH:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:18]([NH:17][CH2:16][C:15]([NH:14][CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:46])=[O:8])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:38])=[O:37])=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
To a solution of 3.6 parts N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanine benzyl ester in 160 parts methanol is added 0.4 part palladium black metal catalyst. The resulting mixture is shaken with hydrogen at room temperature at atmospheric pressure for about 5 hours. The catalyst is then removed by filtration, and the solvent removed by evaporation under reduced pressure. The resulting crude material is purified using low-pressure chromatography to afford N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanine.
Reaction SMILES: [OH:1][CH:2]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Zn].O>[C:2]1(=[O:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCCCCCCC=CCCCCCCCCC1O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCCC=CCCCCCCCCC1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
In a 50 ml four neck reactor equipped with a thermometer, a dripping funnel and a refrigerant, zinc powder (2.3 g), 2-hydroxy-11-cycloeicosenone (1.4 g) and toluene (10 ml) were mixed, stirred and heated at 90° C. under a nitrogen flow. A 20N sulphuric acid aqueous solution (2.8 ml) was added thereto dropwise over 2.5 hours, and the resulting mixture was stirred under heating for 30 minutes. After the reaction, the mixture was supplemented with toluene and water, and allowed to stand to separate into two phases. The organic phase thus obtained was washed twice with water and then with a saturated sodium chloride aqueous solution. The solvent was removed under reduced pressure to give 1.4 g of crude product. This latter was purified on a silica gel column chromatography (hexane/ethyl acetate=10/1, v/v) to give 1.2 g of 10-cycloeicosenone (yield 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([N:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:31]([N:20]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:21]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@@H:22]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:23])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Brc1ccccn1
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O[C@H](c1ccccn1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C

Procedure:
Dissolve 2-bromopyridine (2.73 mL, 28.63 mmol) in THF (150 mL) and cool to −78° C. Add n-butyllithium (12.0 mL, 2.5 M in hexanes). Slowly add 2-(S)-dibenzylamino-3-phenyl-propionaldehyde (4.71 g, 14.31 mmol) in THF (15 mL) and stir 30 min. Quench reaction with saturated aqueous ammonium chloride. Remove cold bath and warm to room temperature. Wash organic layer twice with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with dichloromethane and ethyl acetate) to give the title compound as a residue (3.654 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]2([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10]2)=[C:4]([F:28])[C:3]=1[O:29][CH3:30].[CH2:31]([SH:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]([CH2:11][S:33][CH2:31][CH3:32])([C:12]([F:13])([F:15])[F:14])[OH:10])=[C:4]([F:28])[C:3]=1[O:29][CH3:30]
Reactant: COc1c(Cl)ccc(C(Nc2cccc3nc(C)ccc23)C2(C(F)(F)F)CO2)c1F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(Cl)c(OC)c1F)C(F)(F)F

Procedure:
Analogously to example 45 100 mg (0.25 mmol) {[4-chloro-2-fluoro-3-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-(2-methylquinolin-5-yl)amine (example 13) are reacted with 0.24 ml of the 1 M ethanthiol solution under the presence of 148 mg Caesium carbonate in DMF. The typical work up after 2 hours yields 54 mg of the title compound after preparative thin layer chromatography on silica gel (aceton in hexane 50%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:17]=[C:16]2[N:7]([C:8](=[O:19])[N:9]([CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1.[CH3:20]I>C(COC)OC.CN(C)P(=O)(N(C)C)N(C)C>[CH3:20][O:3][CH2:4][C:5]1[CH:17]=[C:16]2[N:7]([C:8](=[O:19])[N:9]([CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1
Reactant: Cn1c(=O)n2nc(CO)cc2c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCc1cc2c3ccccc3n(C)c(=O)n2n1
Reaction time: 0.25 h

Procedure:
To a suspension of 32 mg (0.0013 mole) of oil-free sodium hydride in 25 ml of glyme is added 227 mg (0.001 mole) of 2-(hydroxymethyl)-6-methylpyrazolo[1,5-c]quinazolin-5(6H)-one. The suspension is stirred for 15 minutes and then a solution of 0.66 ml (0.0107 mole) of methyl iodide in 2 ml of hexamethylphosphoric triamide added. The reaction mixture is stirred for 18 hours at room temperature. The solution is filtered and the filtrate stripped to an oil which is partitioned between dichloromethane and aqueous sodium thiosulfate. The organic phase is washed with water and stripped to an oil which is dissolved in acetone and applied to a Merck silica gel plate (20 cm × 20 cm × 2 mm thick). The chromatogram is developed with chloroform-methanol (9:1) and the product is eluted off with acetone. Evaporation of the acetone gives an oil that solidifies on standing under pentane at 5°. The yield of title compound is 100 mg (41%), m.p. 98°-100°.
Reaction SMILES: [Br-].C[O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:7]=1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1>>[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][CH2:21][C:7]2[O:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=3)=[CH:10][C:6]=2[CH2:4][OH:3])=[CH:44][CH:43]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: Cc1ccc(CCc2oc(-c3ccc(C(F)(F)F)cc3)cc2CO)cc1

Procedure:
prepare from intermediate 62 and 4-methylbenzaldehyde
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1
Reactant: COCCNCCOC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(CCOC)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of N,N-bis(2-methoxyethyl)amine (2.40 g) and triethylamine (2.27 g) in dichloromethane (30 ml) was added 3-nitrobenzoyl chloride (2.78 g) in an ice-water bath. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified with column chromatography eluting with dichloromethane-methanol to give N,N-bis(2-methoxyethyl)-3-nitrobenzamide (4.12 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][OH:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1.Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][O:43][S:52]([C:49]4[CH:50]=[CH:51][C:46]([CH3:45])=[CH:47][CH:48]=4)(=[O:54])=[O:53])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CCO)C(=O)OCC)CC2)c2ncnn12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CCOS(=O)(=O)c3ccc(C)cc3)C(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate (0.54 g), 4-methylbenzenesulfonyl chloride (0.70 g) and pyridine (6 mL) was stirred at room temperature for 75 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 65%).
Reaction SMILES: C[O:2][C:3](=[O:32])/[C:4](/[O:30][CH3:31])=[CH:5]/[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.O>[CH3:31][O:30]/[C:4](=[CH:5]\[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1)/[C:3]([OH:32])=[O:2]
Reactant: COC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
To a suspension of 45.81 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid methyl ester (100.9 mmol) in 920 ml of methanol, a solution of 40.15 g of potassium hydroxide (615.3 mmol) in 92 ml of water was added within 5 minutes. The white suspension was stirred for 90 min at 100° C. The formed yellowish reaction solution was cooled to 60° C., 54 ml of conc. hydrochloric acid were added dropwise within 5 min (pH 3-4) and the resulting thick suspension was cooled to 0° C. The solid was filtered off and washed with 1000 ml water in four portions. The filter cake was suspended in 920 ml of ethanol at 80° C. for 1 h and after at 0° C. for 2 h. The white crystals were filtered off, washed with 300 ml of cold (−15° C.) ethanol in two portions and dried to constant weight (20° C./5 mbar/16 h) to afford 41.66 g (95%) of the title compound with a purity of >99.9% according to HPLC (method described in Example 10). m.p.: 189-190° C. MS: 434.2 (M−H)−. 1H-NMR (CDCl3): 2.41 (s, 3H); 3.11 (t, J=6.6, 2H); 3.79 (s, 3H); 4.47 (t, J=6.8, 2H); 6.88 (d, J=8.8, 1H); 7.30-7.40 (m, 2H); 7.40-7.47 (m, 3H); 7.49 (d, J=5.6, 1H); 8.00-8.10 (m, 2H); 8.12 (d, J=8.4, 1H); COOH very br.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.[F:14][C:15]1[C:16]([N+:27]([O-:29])=[O:28])=[C:17]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:18][CH2:19][CH:20]1[CH2:22][O:21]1>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:17]3[CH:23]=[C:24]([F:26])[CH:25]=[C:15]([F:14])[C:16]=3[N+:27]([O-:29])=[O:28])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1OCC1CO1
Reactant: Clc1ccc(OC2CCNC2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1c(F)cc(F)cc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1

Procedure:
A solution of 3-(4-chlorophenoxy)pyrrolidine and 2-[(3,5-difluoro-2-nitrophenoxy)methyl]oxirane (50 mg, 0.21 mmol) in ethanol was refluxed for 3 hrs. The solvent was distilled off under reduced pressure and the resulting residue purified by silica gel column chromatography (dichloromethane/methanol 20:1) to give 45 mg (0.105 mmol) of the title compound as solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]2=[O:43])[CH:29]=[CH:30][C:31]=1[F:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:28]6[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=6)[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)c(F)c1
Yield: 85.6 %

Procedure:
Using a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol) and 1-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (244 mg, 0.919 mmol) in N,N-dimethylacetamide (2.0 mL), HATU (350 mg, 0.919 mmol) and N,N-diisopropylethylamine (160 μL, 0.919 mmol) and in the same manner as in Example 44, the title compound (301 mg, 86%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:13][C:14]1[CH:21]=[N:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.CS(C)=O>O>[F:13][C:14]1[CH:21]=[N:20][CH:19]=[CH:18][C:15]=1[C:16]1[S:12][C:3]2[C:2]([N:1]=1)=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=2
Reactant: O=Cc1ccncc1F
Reactant: Nc1cc(C(F)(F)F)cnc1S
Solvent: CS(C)=O
Solvent: O
Product: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 170 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A mixture of 0.90 g of 3-amino-5-(trifluoromethyl)-pyridine-2-thiol, 0.58 g of 3-fluoroisonicotinaldehyde and 5 ml of DMSO was stirred at 170° C. for 2 hours. The reaction mixture was cooled down to room temperature, then, to the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.55 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 9).
Reaction SMILES: C[O:2][C:3]([C:5]([S:18]([CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:19])=[CH:6][NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:25][C:22]([F:23])([F:24])[CH2:21][S:18]([CH:5]1[C:3](=[O:2])[C:9]2[C:8](=[C:17]3[C:12](=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[N:16]3)[N:7]=[CH:6]1)(=[O:19])=[O:20]
Reactant: COC(=O)C(=CNc1cccc2cccnc12)S(=O)(=O)CC(F)(F)F
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: O=C1c2ccc3cccnc3c2N=CC1S(=O)(=O)CC(F)(F)F
Temperature: 260 °C
Reaction time: 2 h

Procedure:
8-[2-Methoxycarbonyl-2-(2,2,2-trifluoroethylsulfonyl)-ethenylamino]quinoline (4 g) was added to diphenyl ether (100 ml) with stirring at 260° C., and stirring was continued for 2 hours. The mixture was allowed to cool to ambient temperature and hexane (100 ml) was added. The mixture was filtered, and the residue purified by flash chromatography on silica using increasingly polar mixtures of methanol and chloroform as eluant. The product so obtained was recrystallised from acetic acid to give 3-(2,2,2-trifluoroethyl-sulfonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline, mp 272-274° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]#[N:10])=[C:6]([NH:24][CH2:23][CH2:21][OH:22])[N:7]=1
Reactant: NCCO
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(Cl)nc1NCCO
Reaction time: 18 h
Yield: 25 %

Procedure:
A solution of 3.0 g (14.4 mmol) of 2,4,6-trichloro-5-cyano-pyrimidine (example 38a) and 2.51 ml (14.4 mmol) of N-ethyl-diisopropylamine in 90 ml of dioxane was treated at room temperature with 0.88 ml (14.4 mmol) of ethanolamine and stirred during 18 hours. For the working-up, the yellow solution was evaporated and the residue dissolved in 300 ml dichloromethane. The organic phase was washed twice with 50 ml of water, and the two aqueous phases were re-extracted with 50 ml of dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure. For purification and separation of the two isomers, the crude material (3.2 g) was chromatographed (2×) on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent giving 0.85 g (3.6 mmol, 25% of theory) of the 2,4-dichloro-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (less polar isomer); MS: [M]+=232; 1.51 g (6.5 mmol, 45% of theory) of the 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (more polar isomer); MS: [M]+=232; and 0.26 g (1.1 mmol, 8% of theory) of a mixture of the two isomers.