Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([F:14])([F:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1>CC(C)=O.CCOC(C)=O>[Cl:21][C:22]1[N:27]=[C:26]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:7][C:8]([F:13])([F:14])[C:9]([O:11][CH3:12])=[O:10])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C(F)(F)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound methyl 3-(cyclopentylamino)-2,2-difluoropropanoate (400 mg, 2 mmol) was solubilized in acetone (20 mL, dry). The solution was cooled in an ice water bath under a nitrogen atmosphere and K2CO3 (552 mg, 4 mmol) added. To this, a solution of 2,4-dichloro-5-nitropyrimidine (407 mg, 2.1 mmol) in acetone (5 mL, dry) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 4 hr. After that, it was diluted with EtOAc and washed by brine and water. The organic extracts were dried over MgSO4, filtered and concentrated to yield the desired product which was used directly for next step without further purification. [M+H] calc'd for C13H15ClF2N4O4, 365. found 365.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N+:11]=[N-:12].C[O-].[Na+]>CO>[N:10]([C:13](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])[C:14]([O:16][CH3:17])=[O:15])=[N+:11]=[N-:12]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccccc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1ccccc1Br)N=[N+]=[N-]
Temperature: 0 °C
Yield: 18636.4 %

Procedure:
A solution of 75 ml (624 mmol) of 2-bromobenzaldehyde and of 252 g (2.2 mmol) of methyl azidoacetate in 160 ml of methanol is added dropwise over 3 h, at a temperature of −10 to −8° C., under nitrogen and with mechanical stirring, to a solution of 476 ml of sodium methoxide (30% in methanol) in 950 ml of methanol. Stirring is maintained for 2 h at a temperature below 5° C. The mixture is poured onto 1.5 kg of ice. The precipitate is collected by filtration, washed with water and dried under reduced pressure with light excluded. 116 g (0.41 mol) of solid are obtained, which solid is used quickly in the following stage.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.C1C[O:33][CH2:32]C1>>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:32]=[O:33])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, n,N-dimethylformamide was added and the resulting mixture was stirred at −78° C. for 20 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with diluted HCl, water and adjusted to pH7.5 and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the tiUe compound. 1H NMR(CDCl3) d 9.93(s,1H), 7.60(s,2H), 6.10(s,1H), 3.75(d,1H), 3.35(m1H), 2.17(s,6H), 2.13(s,3H), 2.12(s,3H), 1.4-1.8(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15](OC3C=CC=CC=3)[C:14]=2[N:13]=[C:12]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:36].[OH-].[K+]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:36])[C:14]=2[N:13]=[C:12]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCOCc1ccccc1
Temperature: 156 °C
Yield: 29.9 %

Procedure:
1-[2-(Benzyloxy)ethyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (6.6 g, 15.8 mmol) and ammonium acetate (66 g) were combined in a dried glass pressure flask under nitrogen with stirring. The flask was sealed with a teflon screw cap and heated to 156° C. for 44 hours. The reaction was complete as determined by HPLC and LC/MS, and the resulting solution was cooled and basified to a pH of about 14 with 1 N potassium hydroxide. The basic solution was extracted with dichloromethane (5×), and the organic layers were combined, washed with 1 N potassium hydroxide (3×), water (1×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate/diethyl ether, and the resulting solids were filtered off and dried. NMR analysis of the solids indicated impurities. The solids were recrystallized from isopropyl alcohol and dried. Impurities were found in the resulting solids (3.2982 g), which were then recrystallized from ethyl acetate/hexane and again dried. The resulting solids (2.4076 g), still with impurities, were dissolved in ethanol, and the resulting solution was treated with 1 M hydrochloric acid in diethyl ether (10 mL). The resulting hydrochloride salt was filtered off, dissolved in water, and the aqueous solution was basified with 1N potassium hydroxide to a pH of about 14. The resulting aqueous mixture was extracted with dichloromethane (5×), and the combined organic layers were washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was dried to provide 1.5999 g of 1-[2-(benzyloxy)ethyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 99.5–100.0° C.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:5]([OH:7])=O)=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([F:56])[C:30]=1[CH2:31][CH2:32][C@H:33]1[O:38][CH2:37][C@H:36]([CH2:39][O:40][C:41]([NH:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[O:42])[N:35]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:34]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([NH:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([F:56])[C:30]=1[CH2:31][CH2:32][C@H:33]1[O:38][CH2:37][C@@H:36]([CH2:39][O:40][C:41](=[O:42])[NH:43][CH2:44][C:45]([F:48])([F:46])[F:47])[N:35]([C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50])[CH2:34]1)=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1cc(F)cc(F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2cc(F)cc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (105 mg, 0.31 mmol) and the product from step 4 of Example 89 (150 mg, 0.31 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.035 mL, 0.38 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-70% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=800.6.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH3:14])[CH:9]=[CH:8][N:7]=1.[Li+].[BH4-].O>C1COCC1.Cl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:13]([CH3:14])[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][OH:2])[CH:11]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCCO)c1)C(F)(F)F
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
{4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridin-2-yloxy}-acetic acid methyl ester (Example 120, 70 mg) was dissolved in THF (5 mL) and treated with LiBH4 (10 mg). After 2 h stirring at 45° C. another portion of LiBH4 (5 mg) was added and the reaction mixture further stirred at 45° C. for 2 h. After cooling down to r.t., 3 drops of 1N aqueous HCl were added, followed by water (5 mL). The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 30:70) to give the title compound as colorless foam (52 mg). MS (m/e)=410.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34].N>N1C=CC=CC=1.CN(C=O)C>[NH2:30][C:31]1[C:32]([C:33]([NH2:35])=[O:34])=[CH:36][CH:37]=[CH:38][C:39]=1[NH:40][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)c1cccc(N)c1N
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-2-methylpropanoic acid (5.18 g, 21.83 mmol) in a mixture of pyridine (25 mL) and DMF (25 mL) was treated with 1,1′-carbonyldiimidazole (3.72 g, 22.92 mmol) and heated at 40° C. for 2 hours. 2,3-Diaminobenzamide dihydrochlolide (4.89 g, 21.83 mmol), prepared as described in WO0026192, was added and the mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The formed slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1A. MS (DCI/NH3) m/z 371 (M+H)+.
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][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:30][CH2:29]1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[C:35]2[N:36]([N:37]=[CH:38][N:39]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: c1nnc(NC2CCOCC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.1 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.57 g, 81%). 1H NMR (300 MHz, CHLOROFORM-d) δ1.07 (t, J=7.4 Hz, 3H), 1.62-1.79 (m, 4H), 2.90-3.10 (m, 4H), 3.55 (td, J=12.0, 1.8 Hz, 2H), 4.03 (s, 2H), 4.08-4.17 (m, 2H), 5.30 (tt, J=12.2, 4.1 Hz, 1H), 7.23-7.28 (m, 2H), 7.36-7.51 (m, 3H), 7.63 (dd, J=7.5, 1.1 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.93 (s, 1H)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-:21]#[N:22].[Na+]>CS(C)=O>[F:20][C:16]1([F:19])[CH2:15][CH2:14][CH:13]([CH2:12][C:21]#[N:22])[CH2:18][CH2:17]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1CCC(F)(F)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of Example 370B (4.5 g, 15 mmol) in dimethylsulfoxide (100 mL) was added sodium cyanide (Aldrich, 2.2 g, 45 mmol). The reaction mixture was stirred at 80° C. for 14 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% pentane in ether) to afford the title compound. MS (ESI+) m/z 177 (M+NH4)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[CH2:19][CH:18]([CH3:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[C:16]1=[NH:29]>C1C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[CH2:19][CH:18]([CH3:20])[N:17]([C:21]2[C:22]([CH3:28])=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:27])[C:16]1=[N:29][C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(C)c1N1CC(C)N(c2c(C)cccc2C)C1=N
Solvent: c1ccccc1
Product: CCOC(=O)N=C1N(c2c(C)cccc2C)CC(C)N1c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
A solution of 1.0 ml (1.38 g, 10.5 mmoles) of ethyl chloroformate in 10 ml of dry benzene is added dropwise at room temperature to a stirred solution of 6.15 g (20 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine, obtained as described in Example 7, in 60 ml of dry benzene. The mixture is stirred for additional 5 hours at room temperature, and then washed thrice with 50 ml of water each. The benzene solution is dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The thick, yellow oily residue is crystallized from diisopropyl ether to obtain 2.7 g (71.2%) of 1,3-bis(2',6'-dimethylphenyl)-2-carbethoxyimino-4-methyl-imidazolidine; m.p.: 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][C:31]([C:33](=O)[CH3:34])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:15][CH2:14]1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:33]([C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[O:21])=[CH:27][CH:26]=2)=[CH:29][CH:30]=1)[CH3:34]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=C1C(=O)Nc2ccc(Cl)cc21)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Yield: 19.4 %

Procedure:
A solution of 5-chlorooxindole (362 mg, 2.17 mmol), 1-(5-(4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethanone (800 mg of oil) and piperidine (214 μL, 2.17 mmol) in toluene (10 mL) was heated at reflux with a Dean-Stark receiver for 16 hours. After evaporation of the solvent, purification by silica column chromatography (methanol gradient in dichloromethane, 0 to 5% vol) gave 5-chloro-3-(1-(5-(4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethylidene)indolin-2-one (200 mg) as an E:Z mixture. LCMS (ES): m/z 476 [M+1]+.
Reaction SMILES: Br[CH:2]([CH2:5]Br)[C:3]#[N:4].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][O:12][NH2:13]>>[C:3]([CH:2]1[CH2:5][N:13]1[O:12][CH2:11][C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([F:7])[CH:9]=1)#[N:4]
Reactant: NOCc1cccc(F)c1
Reactant: N#CC(Br)CBr
Product: N#CC1CN1OCc1cccc(F)c1

Procedure:
Analogously to Example 4, by the reaction of 2,3-dibromopropionitrile with O-(3-fluorobenzyl)-hydroxylamine, there is obtained 2-cyano-1-(3-fluorobenzyloxy)-aziridine (see Example 4d). The two invertomers can be separated by column chromatographic separation on silica gel (elution agent diethyl ether/ligroin 1/1 v/v) to give:
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.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:19]([CH:20]=[O:21])[C:18]=1[OH:25].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:18]1[C:17]([F:16])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1cccc(F)c1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3c(F)cccc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 3-fluorosalicylaldehyde (280 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].N.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[Cl:23])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cl
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 6-chloro-4-hydroxy-2-isopropyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 20 step A, 2 g, 7.15 mmol) and phosphorous oxychloride (10 ml) under nitrogen was refluxed for 1 h. After cooling the reaction mixture to room temperature, the mixture was poured onto ice cold water and the pH of the aqueous phase was adjusted to 7 with aqueous ammonia solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 5-10% EtOAc in hexane) to afford pure 4,6-dichloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (1.3 g, 61%) as pale yellow solid. LC-MS: 298 (M+H)+.
Reaction SMILES: [CH:1]([Li])(CC)C.[CH2:6]([C:8]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[C:15]2[C:9]=1[C:10](=[O:23])[NH:11][S:12]2(=[O:14])=[O:13])[CH3:7].CI>O1CCCC1>[CH2:6]([C:8]1[C:18]([O:19][CH3:20])=[C:17]([CH3:1])[C:16]([O:21][CH3:22])=[C:15]2[C:9]=1[C:10](=[O:23])[NH:11][S:12]2(=[O:13])=[O:14])[CH3:7]
Reactant: CCc1c(OC)cc(OC)c2c1C(=O)NS2(=O)=O
Reactant: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(OC)c(C)c(OC)c2c1C(=O)NS2(=O)=O
Reaction time: 0.25 h
Yield: 32 %

Procedure:
s-Butyllithium (0.87M in cyclohexane, 20.4 mL) was added dropwise during one hour with stirring at -78° C. to a solution of 4-ethyl-5,7-dimethoxysaccharin (Example 22L, 2.2 g) in tetrahydrofuran (100 mL). After continued stirring at -78° C. for one hour methyl iodide (1.5 mL) was added. Stirring was continued at -78° C. for 15 minutes, the temperature was allowed to rise to room temperature, and the mixture was quenched in water. Aqueous sodium hydroxide (0.5%, 200 mL) was added. The mixture was washed with ethyl acetate (200 mL), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (200 mL). The ethyl acetate extract was washed with aqueous sodium thiosulfate (10%, 50 mL) and saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and stripped of ethyl acetate affording 4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.73 g, 32% yield).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11](C)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:13](Cl)Cl>>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][N:10]([CH3:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Cn1nccc1-c1ccc(Br)s1
Product: Cn1ccc(-c2ccc(Br)s2)n1

Procedure:
To a stirred solution of 1-(5-bromothiophen-2-yl)-3-dimethylaminopropenone (0.70 g, 2.7 mmol) in EtOH (15 mL) was added methylhydrazine (0.16 mL, 3.0 mmol) and then acetic acid (0.45 mL, 8.0 mmol). The resulting mixture was heated at reflux for 2 h, allowed to cool to ambient temperature and then concentrated under reduced pressure. The residue was diluted with DCM (50 mL), washed with H2O and brine, then dried (Na2SO4), concentrated and purified by chromatography (silica, DCM) to yield the title compound 10a (0.21 g) as a white solid and regioisomer, 5-(5-bromothiophen-2-yl)-1-methyl-1H-pyrazole, 11a (035 g) as a pale yellow solid. 10a: Rf 0.42 (DCM); 1H-NMR (CD2Cl2): δ 7.36 (1H, d), 7.01 (2H, m), 6.41 (1H, d), 3.87 (3H, s); 11a: Rf 0.19 (DCM); 1H-NMR (CD2Cl2): δ 7.42 (1H, d), 7.10 (1H, d), 6.94 (1H, m), 6.36 (1H, d), 3.92 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1([CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][O:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Cl)cc2C=O)COC1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (4.5 g, 29 mmol), toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester in Example 13c (6.4 g, 25 mmol) and K2CO3 (8 g, 58 mmol) in anhydrous N,N-dimethylformamide (40 mL) was heated at 100° C. for 1 h. Then the mixture was filtered and the filtrate was concentrated. The residue was dissolve in EtOAc (50 mL). The solution was washed with water, dried and concentrated to give title compound as a yellow oil (5.2 g).