Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(CO)ncn2-c2cccc(Cl)c2C1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
18.0 g (64.8 mmol) of 7-chloro-4,5-dihydro-3-hydroxymethyl-5methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 75 g of manganese dioxide and 700 ml of methylene chloride are stirred at room temperature for 1.5 hours. The reaction mixture is filtered and the filtrate is evaporated. By recrystallization of the residue from alcohol there is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde of melting point 204°-205°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:19][Si](C)(C)C>O1CCOCC1>[Br:19][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1
Reactant: C[Si](C)(C)Br
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
A solution of (4′-methanesulfonyl-biphenyl-4-yl)-methanol (129 mg, 0.49 mmol) in 1,4-dioxane (5 mL) was treated with bromotrimethylsilane (0.2 mL, 1.5 mmol) and stirred at 25° C. for 16 h. The reaction mixture was concentrated and purified by flash column chromatography to yield 4.15-B (152 mg, 95%) as a yellow solid. LCMS found for C14H14BrO2S (M+H)+: m/z=326.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:31])[C:6]([CH3:8])=[CH2:7])=[O:4].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:31])=[C:6]([CH3:8])[CH3:7])=[O:4]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(=C(C)C)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
A mixture of 2.25 g (5 mmoles) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one (prepared as described in Example 2) and 1.4 ml (10 mmoles) of triethylamine in 100 ml of tetrahydrofuran was stirred at 65°C for 25 minutes. The reaction mixture was evaporated, treated with 25 ml of ethyl acetate and evaporated once more. The residual foam was dissolved in 50 ml of ethyl acetate, treated with charcoal and concentrated to a small volume. The desired product crystallized upon cooling. There was obtained 1-(1-methoxycarbonyl-2-methylpropenyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:32])[C:30]=1[F:31])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([F:32])[C:30]=1[F:31]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(F)c(F)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-4,5-difluorobenzoic acid: MS (APCl) m/z 440 (M+1).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[CH:17]=[O:18].[Mn]([O-])(=O)(=O)=[O:20]>O.CC(C)=O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[C:17]([OH:20])=[O:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1c(Br)ccc2c1OCO2
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1c(Br)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Potassium permanganate (1.03 g, 6.55 mmol) was dissolved in water (25 mL). 5-Bromo-1,3-benzodioxole-4-carboxaldehyde (0.60 g, 2.62 mmol) was dissolved in acetone (25 mL) and slowly added to the permanganate solution and the reaction mixture was stirred at ambient temperature for 24 h at which time TLC analysis indicated the reaction complete. The reaction mixture was quenched with 5% sodium sulfite (100 mL). Concentrated HCl (10 mL) was added and the mixture turned a pale yellow color. The solution was extracted with ethyl acetate and the organic layers were dried with magnesium sulfate and concentrated by rotary evaporation to afford 0.34 g of product (1.39 mmol, 53% yield) as an off-white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.[CH:22]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH2:23]>O1CCCC1>[Cl:3][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH2:17][C:18]([CH3:21])([O:20][CH2:23][CH2:22][S:24]([CH3:27])(=[O:26])=[O:25])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(Cn1cnc2c(Cl)nc3ccccc3c21)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 58 mg, 1.45 mmol) was added to a stirred solution of 1-(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (described in U.S. Pat. No. 4,689,338 Example 189, Part D, 4.00 g, 14.5 mmol) in tetrahydrofuran (58 mL). After 5 minutes, methyl vinyl sulfone (3.10 g, 29.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 17 hours. The volatiles were removed under reduced pressure and the resulting oil was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield 4.3 g of 4-chloro-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)=[O:4].C([C@@H](NC([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1NC(C1NC2C(C=1)=CC=C(C1C=CC=CC=1)C=2)=O)=O)CC(C)C)#N>>[CH3:15][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:8]=2)[CH:13]=[C:5]1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1cc2ccc(Br)cc2n1C
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(-c3ccccc3)cc2[nH]1
Product: Cn1c(C(=O)O)cc2ccc(-c3ccccc3)cc21

Procedure:
Similarly, 1-methyl-6-phenyl-1H-indole-2-carboxylic acid was prepared from 6-bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester and was used to prepare 6-Phenyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[CH2:27][CH3:28])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>O1CCCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:27][CH3:28])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
To a solution of 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D51) (313 mg) in tetrahydrofuran (THF) (20 mL) stirred under nitrogen at room temperature was added 14 drops 2M hydrochloric acid. The reaction mixture was stirred at 70° C. for 4 h. After cooling the reaction, the solution was condensed under reduced pressure to give [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D52) (300 mg), which was used directly in the next step without further purification. MS (ES): C21H21 ClN2O2S requires 400. found 401.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([CH:17]([C:23](OCC)=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1>OS(O)(=O)=O>[OH:24][C:23]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:15](=[O:16])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(OC)cc2)CCOCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cc(OC)ccc2C2(CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
Diethyl 2-(4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (2.2 g) in 1 mL IPAc was added to 20 mL of concentrated H2SO4, and the resulting mixture was stirred at room temperature for 2 hours, M+1=333, M−1=331. The mixture was then poured into 200 g of ice. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-50% EtOAc/hexane to give 0.66 g of the title product as a yellow oil. MS (m/z)=333 (M+H)+.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].O(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>CO.CCCCCC>[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:13]=1[N:14]=[C:1]([C:7]([O:9][CH3:10])=[O:8])[CH:2]=[C:3]2[OH:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1Br
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(O)c2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
27 ml of dimethyl acetylenedicarboxylate was added to a solution of 34.4 g of 2-bromoaniline in 200 ml of MeOH placed in a 1 L-flask at room temperature. The mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo to afford a yellow oil. The crude product was added to 200 ml of Ph2O placed in 1 L-flask heated at 250° C. The mixture was stirred for 15 min at the same temperature and then cooled to room temperature. 200 ml of toluene and 200 ml of hexane was added to the mixture. The slurry was stirred for 1 h with cooling at 0 deg C. The resulting solid was filtered, washed with hexane, and dried under vacuum to afford methyl 8-bromo-4-hydroxyquinoline-2-carboxylate as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-cyanopyridine (0.500 g, 4.2 mmol) was suspended in dry dichloromethane (10 mL) and triethylamine (0.635 g, 6.3 mmol) was added to it under stirring at 0° C. To the reaction mixture 2,2-dichloroacetyl chloride (0.800 g, 6.3 mmol) was added dropwise under stirring at 0° C. and stirring was further continued for about 10 minutes at about 0° C. and then at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified using column chromatography (silica gel, 30% ethyl acetate in petroleum ether as an eluent) and further crystallized from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][S:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[C:30](=[O:44])[CH2:29][C@@:28]2([CH3:45])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1>CO>[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][S:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[C:30](=[O:44])[CH2:29][C@@:28]2([CH3:45])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1.[OH:4][C:3]([C:5]([O-:7])=[O:6])([CH2:8][C:9]([O-:11])=[O:10])[CH2:2][C:1]([O-:13])=[O:12]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCSC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
A solution of citric acid (576 mg) in methanol (70 ml) was added to (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-thiomorpholinyl)pregnane-11,20-dione (1.39 g). The mixture was warmed to effect solution and the solvent was removed under reduced pressure to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-thiomorpholinyl)pregnane-11,20-dione 2-hydroxy-1,2,3-propanetricarboxylate (1:1) salt (1.96 g). [α]D +92.2° (c 0.5).
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([C:40]([O:42]C)=[O:41])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH:34]=3)[C:40]([OH:42])=[O:41])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C(=O)c3cccs3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1ccc(C)c(C(=O)O)c1)CN2C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
1-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea (0.70 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml), aqueous lithium hydroxide hydrate (0.23 g) solution (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N HCl and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(chloroform:methanol=30:1), to thereby obtain 224 mg of the title compound as a white crystal.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1.[C:32](Cl)(=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:12]1[N:11]=[C:10]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:9]=[C:8]([NH:7][C:32](=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:13]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Nc1cc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Pyridine (0.014 mol) was added to a mixture of 4-[[4-amino-6-[(2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile (0.0013 mol) in CH2Cl2. A solution of octanoyl chloride (1.5 equiv) in CH2Cl2 (0.5 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. More octanoyl chloride (3.5 equiv) in CH2Cl2 was added dropwise. The mixture was stirred. The solvent was then evaporated. The residue was treated with a saturated aqueous NaHCO3 solution and the mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated to give the crude product. The residue was recrystallized from CHCl3 and hexane, yielding 0.443 g (68.6%) of N-[6-[(2,6-dichloro-phenyl)-methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]octanamide (mp. 135–137° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:23][C:14]3=[N:15][C:16]4[C:21]([N:22]=[C:13]3[N:12]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:10]=1)=[O:5])C.[OH-].[K+]>C1COCC1>[NH:23]1[C:14]2=[N:15][C:16]3[C:21]([N:22]=[C:13]2[N:12]=[C:11]1[N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: CCOC(=O)c1cnn(-c2nc3nc4ccccc4nc3[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3nc4ccccc4nc3[nH]2)c1
Reaction time: 4 h
Yield: 88.2 %

Procedure:
A mixture of 1-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.110 g, 0.360 mmol), aqueous KOH (1M, 3.0 mL) and THF (3.0 mL) was stirred for 4 h. The mixture was concentrated and the aqueous residue was acidified to pH 2 with 1M aqueous HCl. The resulting precipitate was collected by filtration to yield the titled compound (89.0 mg, 89%). MS (ESI/CI): mass calcd. for C13H8N6O2, 280.2; m/z found, 281.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.32-12.37 (br m, 1H), 9.03 (s, 1H), 8.19 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C([Mg]Cl)(C)C.C(OCC)C.[O:23]1[CH2:26][C:25](=[O:27])[CH2:24]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:25]2([OH:27])[CH2:26][O:23][CH2:24]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: O=C1COC1
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2cc(Cl)nc(C(F)(F)F)c2)COC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (1.00 g, 3.25 mmol, European Journal of Organic Chemistry, (18), 3793-3798, 2004) in tetrahydrofuran (20 mL) at 0° C. was added dropwise 2.0 M isopropylmagnesium chloride in diethyl ether (1.95 mL, 3.90 mmol, Aldrich). After stirring for 30 minutes at 0° C., a solution of oxetan-3-one (0.281 g, 3.90 mmol, Synthonix) in Tetrahydrofuran (5 mL) was added. After stirring for 1 hour, the reaction was quenched by the addition of water and ammonium chloride. The product was extracted with two portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes on a 40 g silica gel cartridge afforded purified product (0.31 g, 38%). LCMS (M+H)+: 254.1.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.O1CCOCC1.[O:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1>ClCCl>[O:17]1[CH2:22][CH2:21][CH:20]([O:23][C:2]([NH:1][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])[CH2:19][CH2:18]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.600 ml (4.80 mmol) of ethyl isocyanatoacetate was dissolved in dichloromethane. 0.06 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution, and they were stirred at room temperature for 5 minutes. 0.503 ml (5.28 mmol) of tetrahydro-4H-4-pyranol was added to the reaction mixture, and they were stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the residue was purified by the silica gel chromatography (hexane:ethyl acetate=9:1 to 1:4), the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:19]([F:22])([F:21])[F:20])[N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]([O:18][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:19]([F:22])([F:20])[F:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C1CC(c2ccc(Cl)cc2)=Nc2cccc(C(F)(F)F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(COc1cc(-c2ccc(Cl)cc2)nc2cccc(C(F)(F)F)c12)N1CCOCC1
Yield: 79.2 %

Procedure:
The procedure is as in Example 1, but starting with 2-(4-chlorophenyl)-5-trifluoromethyl-4-quinolone (2.9 g), 4-(2-chloroacetyl)morpholine (1.62 g) and anhydrous potassium carbonate (2.5 g) in 2-butanone (60 cc). After recrystallization in acetonitrile, 4-{[2-(4-chlorophenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morphline (3.2 g), m.p. 179° C., is isolated.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][CH:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4]
Reactant: O=C(CCl)c1ncccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)c1ncccn1
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
2-Chloro-1-pyrimidin-2-ylethanone (6.15 g, 39.3 mmol) was dissolved in ethanol (125 ml) and CeCl3.7H2O (14.64 g, 39.3 mmol) was added. Stirring was continued for 10 min then sodium borohydride (1.49 g, 39.3 mmol) was added over 2 min. After 1 hr the solid was filtered and the filtrate evaporated. Sat. ammonium chloride solution (25 ml) was added followed by brine (250 ml) and the mixture adjusted to pH3-4 with 1N.HCl. Extraction with ethyl acetate (3×250 ml) afforded an amber oil which was chromatographed over silica gel (150 g) to give the product as a pale yellow oil (3.85 g)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5]([C:11]#[N:12])=[CH:4][NH:3]1.C(O)(=O)C.[I:17]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O.CN(C=O)C>[I:17][C:9]1[S:10][C:6]2[C:5]([C:11]#[N:12])=[CH:4][NH:3][C:2](=[O:1])[C:7]=2[CH:8]=1
Reactant: N#Cc1c[nH]c(=O)c2ccsc12
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c[nH]c(=O)c2cc(I)sc12
Temperature: 80 °C
Reaction time: 21 h
Yield: 84.7 %

Procedure:
To 4-oxo-4,5-dihydro-thieno[3,2-c]pyridine-7-carbonitrile 24 (5 g, 28.4 mmol) in a 1:1 solution of acetic acid and DMF (18.4 mL) was added N-iodosuccinimide (12.8 g, 56.8 mmol). The reaction was warmed to 80° C. and stirred for 21 h. The reaction was diluted 10 fold with water and neutralized with aqueous sodium bicarbonate. The precipitate was filtered, washed with water and dried to provide 7.27 g of 25. 1H NMR (400 MHz, d6-DMSO) δ 12.45 (s, 1H), 8.25 (d, J=5 Hz, 1H), 7.77 (s, 1H).