Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])[CH:5]=[C:6]([CH3:30])[C:7]=1[O:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:30][C:6]1[CH:5]=[C:4](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(Oc1c(C)cc(/C=C/C(=O)OCC)cc1C)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC(Oc1c(C)cc(/C=C/C(=O)O)cc1C)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a stirring solution of ethyl (2E)-3-{3,5-dimethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate (35 mg, 0.07 mmol) in THF (5 mL) and MeOH (5 mL) at ambient temperature was added NaOH (2N, 5 mL) and the mixture stirred for 2 h and then left to stand overnight. HCl (2N, 5 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 3:1 to 0:1) the EtOAc:MeOH (gradient 95:5 to 0:1) to give the title compound (28 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH:11]1([C:14]2[C:19](=[O:20])[NH:18][C:17]([CH:21]=[O:22])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1.[Al]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH:11]1([C:14]2[CH:15]=[CH:16][C:17]([CH:21]=[O:22])=[N:18][C:19]=2[O:20][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(C2CC2)c(=O)[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: ClC(Cl)Cl
Product: COc1ccc(COc2nc(C=O)ccc2C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
p-Methoxybenzyl chloride (329 mg) was added to a solution of 5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde (228 mg) in chloroform (10 mL), after which the reaction tube was covered with aluminum foil to provide shading conditions. Silver carbonate (771 mg) was added and the mixture was stirred at room temperature for three hours. The insoluble matter was filtered off and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66) to give 5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridine-2-carbaldehyde as a colorless oil (417 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][C:62]1[C:66]([NH2:67])=[CH:65][O:64][N:63]=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:67][C:66]1[C:62]([CH3:61])=[N:63][O:64][CH:65]=1)=[O:9]
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
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: CN(C)C=O
Product: Cc1nocc1NC(=O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and 3-methyl-4-isoxazolamine (26.8 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 65 mg.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([N:6]3[C:11](=[CH:12]2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)=[N:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:14]=[C:13]2[C:5]([N:6]3[C:11](=[CH:12]2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)=[N:4][CH:3]=1
Reactant: O=C1NCCn2c1cc1cc(O)cnc12
Reactant: ClCCCBr
Product: O=C1NCCn2c1cc1cc(OCCCCl)cnc12
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to example 2, intermediate, from 7-hydroxy-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 84, intermediate a) and 1-bromo-3-chloropropane, to give the desired product as a light yellow solid (80%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1>>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: c1ccc2[nH]ccc2c1
Product: FC(F)(F)c1cccc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3-(trifluoromethyl)benzene: ESMS m/e: 262.0 (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br-].[Li+].Cl[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[CH3:24][N:25]1[C:30](=[O:31])[C:29]2[CH2:32][NH:33][CH2:34][CH2:35][C:28]=2[NH:27][C:26]1=[O:36]>CN(C)C=O>[CH3:24][N:25]1[C:30](=[O:31])[C:29]2[CH2:32][N:33]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:34][CH2:35][C:28]=2[NH:27][C:26]1=[O:36]
Reactant: ClCCCCOC1CCCCO1
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCCCOC1CCCCO1)CC2
Yield: 51 %

Procedure:
27 g of ethyldiisopropylamine, 18 g of lithium bromide and 46 g of 2-(4-chlorobutoxy) tetrahydropyran (86.3% pure according to GC) were added to 36.3 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 1 l of dimethylformamide, with stirring, and the mixture was stirred for 5 h at 70° C. It was concentrated under reduced pressure and 34.5 g of crude 3-methyl-6-[4-(tetrahydropyran-2-yloxy)butyl]-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were obtained after working-up of the residue by extraction with dichloromethane and water and after drying and concentration of the combined dichloromethane phases, and this crude product was purified by column chromatography on aluminum oxide (actiVity grade III) and elution with dichloromethane/ethanol (volume ratio 90:10).
Reaction SMILES: CC(C)[O-].[Al+3:5].CC(C)[O-].CC(C)[O-].[O:14]=[C:15]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[O:18][C:17]2[CH:25]=[CH:26][C:27]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])=[CH:28][C:16]1=2.O>C(O)(C)C>[O:14]=[C:15]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[O:18][C:17]2[CH:25]=[CH:26][C:27]([CH:29]([CH3:33])[C:30]([O-:32])=[O:31])=[CH:28][C:16]1=2.[Al+3:5].[O:14]=[C:15]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[O:18][C:17]2[CH:25]=[CH:26][C:27]([CH:29]([CH3:33])[C:30]([O-:32])=[O:31])=[CH:28][C:16]1=2.[O:14]=[C:15]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[O:18][C:17]2[CH:25]=[CH:26][C:27]([CH:29]([CH3:33])[C:30]([O-:32])=[O:31])=[CH:28][C:16]1=2
Reactant: CC(C(=O)O)c1ccc2oc3ncccc3c(=O)c2c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O
Solvent: CC(C)O
Product: CC(C(=O)[O-])c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A solution of 2 g of aluminum isopropoxide in 30 ml of isopropyl alcohol is added dropwise to a solution of 2.7 g of 2-(5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid in 100 ml of isopropyl alcohol with stirring. The addition is accompanied by immediate formation of white crystals. The mixture is stirred under reflux for 1 hour, and 20 ml of water is added to the reaction mixture, and then the whole mixture is refluxed for an additional hour. After cooling, the crystals are filtered off, washed with isopropyl alcohol, and dried to give aluminum 2-(5-oxo-5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate as white crystals melting at above 250°C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:14]=1)[C:3]([OH:22])=[O:2]
Reactant: C=C(C)C(=O)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)C(=O)c1cc(C(=O)O)cc(C(=O)N(C)CCC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve N-methyl-5-(2-methylacryloyl)-N-propyl-isophthalamic acid methyl ester (50 mg, 0.16 mmol) in methanol (3 mL). Add 2 N NaOH (0.12 mL) and stir overnight at room temperature. Add 2 N NaOH (0.05 mL) and stir for an additional 3 h. Acidify the mixture to about pH=6 using DOWEX® 50WX2-100 ion exchange resin and filter. Concentrate filtrate to give the title compound which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:6]=1[CH2:18][OH:19])([F:4])[CH3:3].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:20][S:21]([O:19][CH2:18][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[N:8][S:9][C:5]=1[C:2]([F:4])([F:1])[CH3:3])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(-c2nsc(C(C)(F)F)c2CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2nsc(C(C)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 28 °C
Reaction time: 0.5 h

Procedure:
Into a 25-mL round-bottom flask, was placed [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methanol (32 mg, 0.11 mmol, 1.00 equiv), dichloromethane (2 mL), MsCl (0.0258 g), triethylamine (34.2 mg, 0.34 mmol, 2.99 equiv). The resulting solution was stirred for 0.5 h at 28° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water, the organic phase was collected. The aqueous phase was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.061 g (crude) of [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C15H17F2NO3S2, 362.4 (M+H). found 362.4.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.[C:16](OC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[NH:1][C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Reactant: COC(=O)CC(C)=O
Product: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 4.9 %

Procedure:
A mixture of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (6.66 g) and methyl acetoacetate (5.8 g) was stirred at 170° C. for 2.5 hours, and to the mixture was added methyl acetoacetate (3 g). The mixture was stirred for 1.5 hours and cooled, and precipitated crystals were filtered and washed with ethanol to give 7-(2-chlorophenyl)-4-methyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.42 g) as pale yellow crystals.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([CH3:22])=[C:20]([C:23]([O:25]CC)=[O:24])[CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCOCC1>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([CH3:22])=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of ethyl 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate (40 mg, 0.087 mmol) in dioxane (600 μL) was added lithium hydroxide (300 μL, 1M aqueous, 0.30 mmol). The reaction mixture was stirred at room temperature 16 hours. The reaction mixture was concentrated in vacuo to remove dioxane, then diluted with water. The aqueous mixture was acidified with 1 N aqueous hydrochloric acid. Upon standing for 72 hours, a solid precipitate had formed which was collected by filtration to provide 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid (31 mg, 82%). Rf 0.10 (19:1 dichloromethane:methanol); MS m/z 432 (M+1).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:39]1[CH2:40][CH2:41][N:42]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:18]3[N:17]=[C:16]([C:13]4[CH:14]=[CH:15][C:10]([S:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)(=[O:9])=[O:8])=[CH:11][CH:12]=4)[CH:21]=[CH:20][N:19]=3)=[CH:31][CH:30]=2)=[O:28])[CH2:43][CH2:44]1)=[O:38]
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)cc1)N1CCN(C(=O)c2ccco2)CC1
Reaction time: 12 h
Yield: 51.5 %

Procedure:
4-{4-[4-(Morpholine-4-sulfonyl)-phenyl]-pyrimidin-2-ylamino}-benzoic acid (0.25 g, 0.57 mmol) was dissolved in THF (5 mL). To this solution was added 1-furoylpiperazine (0.123 g), EDCI (0.131 g), and HOBt (0.092 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparatory HPLC (20-70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(furan-2-carbonyl)piperazin-1-yl](4-{4-[4-(morpholine-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.177 g, 52%): HPLC Retention Time; 9.62 min. (Method B) M+H=603.3
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>O1CCCC1.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][S:3][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([Br:10])[N:12]=1)[CH3:9]
Reactant: CCOC(=O)CS
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CSCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.48 g, 11.96 mmol) was suspended in tetrahydrofuran (52.4 mL) and cooled to 0° C. Ethyl mercaptoacetate (0.48 mg, 3.99 mmol) was added and the solution was stirred for 30 minutes at 0° C. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (1.0 g, 3.99 mmol) was added and the solution was allowed to stir until completion. The reaction mixture was then diluted with water and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.C[C:22]([N:24](C)C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH3:9][O:8][C:5]1[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=2[C:2]([C:22]#[N:24])=[CH:7][N:6]=1
Reactant: COc1ncc(Br)c2ccn(COCC[Si](C)(C)C)c12
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ncc(C#N)c2ccn(COCC[Si](C)(C)C)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (1.80 g) in DMA (20.15 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.58 g) and zinc cyanide (0.88 g) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.51 g).
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH2:16][CH:15]=[CH:14][CH:13]=2)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH3:17][C:18]([CH3:20])=O.N1CCCC1>CO>[CH3:1][C:2]1([C:12]2[CH:16]=[CH:15][C:14](=[C:18]([CH3:20])[CH3:17])[CH:13]=2)[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:9]1[CH2:10]3)[CH2:11]2
Reactant: CC1(C2=CC=CC2)C2CC3CC(C2)CC1C3
Reactant: CC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)=C1C=CC(C2(C)C3CC4CC(C3)CC2C4)=C1
Yield: 88.2 %

Procedure:
A flask containing 19.45 grams (90.74 mmol) of 2-methyl-2-adamantylcyclopentadiene was charged with 30 mL acetone, 100 mL methanol, and 10 mL pyrrolidine (120 mmol). The solution formed a yellow precipitate over 96 hours which was collected by suction filtration and rinsed with 50 mL methanol. The material was dried in vacuo to provide 20.36 grams of product as a yellow powder (88.2%).
Reaction SMILES: OO.[C:3]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([OH:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1)=[O:9].S([O-])([O-])=O.[Na+].[Na+].[C:41]([OH:45])([CH3:44])([CH3:43])[CH3:42]>>[OH:45][C:41]([CH3:44])([CH3:43])[CH2:42][O:19][N:14]1[C:15]([CH3:18])([CH3:17])[CH2:16][CH:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:23][CH:24]2[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH2:42][C:41]([OH:45])([CH3:44])[CH3:43])[C:28]([CH3:31])([CH3:30])[CH2:29]2)=[O:22])[CH2:12][C:13]1([CH3:21])[CH3:20]
Reactant: CC1(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethyl-pieridin-4-yl) adipate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH:24](OC)[O:25]C)[CH:20]=[CH:19][C:18]=3[N+:29]([O-:31])=[O:30])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:19][C:18]=3[N+:29]([O-:31])=[O:30])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(Cc1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1)OC
Solvent: O=CO
Solvent: O
Product: NC(=O)c1sc(Nc2cc(CC=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 0.200 g (0.43 mmole) of 4-(3-chloro-phenyl)-2-[5(2,2-dimethoxy-ethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.9a) and 3 mL of 96% formic acid was stirred at room temperature for 1 hour. The solution was poured into water and the resulting precipitate was collected by filtration, washed with water and air-dried to give 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b) as an orange solid. A mixture of 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b), 0.10 mL of N-methylpiperazine, 0.10 mL of glacial acetic acid, 0.50 g of sodium triacetoxyborohydride and 10 mL of dichloromethane was stirred at room temperature for 16 hours. To the mixture was carefully added 1 mL of 1M hydrochloric acid and stirring was continued at room temperature for 30 minutes. The mixture was partitioned between 30 mL of dichloromethane and 30 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed once with 30 mL of water, then 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 15:85-20:80) to give an orange foam. Trituration with diethyl ether gave 0.100 g of 4-(3-chlorophenyl)-2-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-2-nitro-phenylamino}-thiazole-5-carboxylic acid amide (VI.9c) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCBr
Reactant: O=c1[nH]cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Br)cccn1CCCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 3-bromo-2(1H)-pyridinone (commercial source: Alfa Aesar) (5 g, 28.7 mmol) in DMF (130 ml) was added K2CO3 (4.8 g, 34.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, then 1-bromo-4-chlorobutane (3.3 ml, 28.7 mmol) was added and the reaction mixture was stirred for 18 hours at room temperature. DMF was evaporated, water was added to the crude and the organic layers were extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with a gradient of methanol in DCM (from 0 to 5%) to afford the title compound (4.82 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:17](#[N:21])[CH2:18][C:19]#[N:20].[O-]CC.[Na+]>C(O)C>[NH2:21][C:17]1[C:18]([C:19]#[N:20])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[C:13]([Cl:16])[CH:12]=2)[N:1]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N#CCC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(N)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a yellow solution of 2-amino-5-chlorobenzophenone (2.31 g, 10.0 mmol) in warm (82° C.) dry ethanol (20 ml) was added malononitrile (1.98 g, 30.0 mmol) followed by a solution of sodium ethoxide (9.6 ml of a 3.08 M solution in ethanol, 30.0 mmol). The reaction was heated at reflux for 48 hours, then cooled to room temperature, and the solid filtered off, which was washed with water, ethyl acetate, and dried under reduced pressure to provide 2-amino-6-chloro-4-phenylquinoline-3-carbonitrile as a yellow powder (2.44 g, 87% yield). TLC Rf=0.62 using 1:1 ethyl acetate:hexanes on a silica gel glass backed plate. 1H NMR (DMSO-d6; 400 MHz) δ 7.70-7.58 (m, 5H); 7.56-7.5 (m, 2H); 7.22-7.12 (m, 3H). LC MS (CI) shows M+H 280.