Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:34])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[N:22]=3)[C:11]2=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:36]>O>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:34])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([O-:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[N:22]=3)[C:11]2=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:36]
Reactant: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 986.3 %

Procedure:
A suspension of the product of Example 36I (0.77 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.161 mL, 0.160 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.79 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.84 (m, 11 H) 1.45 (m, 7 H) 1.68 (m, 1 H) 2.10 (m, 1 H) 7.31 (m, 3 H) 7.49 (m, 3 H) 7.65 (m, 1 H) 8.05 (m, 1 H) 15.45 (m, 1 H). MS (ESI−) m/z 477 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(O)(=O)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[N+:41]([O-])([OH:43])=[O:42]>>[N+:41]([C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])([O-:43])=[O:42]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 83.9 %

Procedure:
A 50 ml 3-neck round bottom flash was charged with 2.5 gm (6.83 mmol) of 3-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid, 2.18 gm (2.08 ml, 36.19 mmol) of glacial acetic acid, 2.1 gm (20.49 mmol) of acetic anhydride and 70 mg (683 mmol) of concentrated sulfuric acid. The resulting slurry was stirred vigorously while cooling to 0°-5° C. with the aid of an icewater bath. To the cooled slurry was added dropwise a mixture 280 mg (2.73 mmol) of concentrated sulfuric acid and 620 mg (9.56 mmol) to 97% nitric acid (red fuming). The yellow solution was maintained at 0°-5° C. for about 1.5 hours at which time the reaction mixture was poured into stirred ice water. The gummy residue that formed in the bottom of the flask was extracted with 100 ml of ether, the ether layer separated, and the aqueous acid layer reextracted with a second portion of ether. The combined ether layers were washed with brine, dried and evaporated in vacuo leaving a yellow oil. Much of the yellow color was removed by dissolving the oil in 300 ml of chloroform and eluting through a pad of silica gel. Evaporation of the eluent yielded 2.36 gm (83.9%) of a light yellow oil which crystallized on standing. The product had the following elemental analysis, calculated (found): C: 43.76 (44.43); H: 1.71 (2.24); Cl: 8.61 (8.83); F: 23.07 (18.90); N: 3.40 (2.47); O: 19.43.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:7])[Cl:8])[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 34.1 %

Procedure:
13 g of diethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1,1-dicarboxylate were dissolved in 50 g of xylene (technical grade) and 30 g of 1,8-diaza-bicyclo[5.4.0]undec-7-ene were added. The mixture was then heated to the boil for 8 hours. After cooling, ice-cold dilute hydrochloric acid was added so that a neutral or weakly acid pH value resulted. The organic phase was separated off and dried with Na2SO4 and the xylene was distilled off in vacuo. The residue weighed 12.2 g. Fractional distillation gave 3.4 g of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1-carboxylate and also 8.0 g of recovered starting material. The yield was thus 87%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:31][CH2:32][CH2:33][CH2:34]Br>C(#N)C>[Br:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Reactant: BrCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cc(NCCCBr)c3cc(OC)ccc3c2)n1
Temperature: 65 °C
Reaction time: 10 h

Procedure:
A mixture of 4-(4-amino-6-methoxy-2-naphthyl)-N-methylpyrimidin-2-amine (33), synthesized according to General Procedure B Steps 1-3 (1.00 g, 3.2 mmol) and acetonitrile (10 mL) was treated with N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) followed by 1,3-dibromopropane (7.3 mL, 71.4 mmol). The resulting mixture was stirred at 65° C. for 10 h. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated (rotary). The crude compound was purified by column chromatography (silica gel) using 75% ethyl acetate/hexanes as the eluent to afford 4-(4-((3-bromopropyl)amino)-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine (189) (0.55 g). LC/MS (m/z): 402 [M+H]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=O)[NH2:16])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C([O:25][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:36][CH:35]=3)[CH:33]=2)=O)=C(F)C(F)=C(F)C=1F>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:26]([C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)=[CH:36][CH:35]=3)[CH:33]=2)=[O:25])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(N)=O)CC1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-carbamoyl-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (1.01 mmol, 0.25 g) in THF (4.0 mL), was added BH3:THF (2 mL, 1M solution in THF) and stirred for 12 h. All volatiles were removed under reduced pressure. The residue was taken in DCM (2 mL) and 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.29 mmol, 0.15 g) was added followed by TEA (0.5 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with NaOH (0.5 M) solution (2×5 mL) water (2×5 mL), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (3:7) to provide 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:19])C.[NH4+]>C(O)=O.O>[CH3:16][C:13]1[N:12]=[CH:11][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:19])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(COc2ccnc(Cl)c2)cn1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: Cc1ccc(COc2cc[nH]c(=O)c2)cn1
Yield: 77.5 %

Procedure:
2-Chloro-4-((6-methylpyridin-3-yl)methoxy)pyridine (4.20 g, 17.9 mmol) and ammonium acetate (6.91 g, 89.7 mmol) were heated at 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO3 solution. The solid was filtered off to provide the title compound (3.0 g, 77%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.27-11.04 (br s, 1H), 8.51 (s, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.29-7.24 (m, 2H), 5.89 (d, J=7.2 Hz, 1H), 5.82 (s, 1H), 5.05 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22]Cl)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)C=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-adamantan-1-yl-5-(chloromethyl)-4-(trifluoromethyl)pyrimidin-2-amine (170 mg) and N,N-dimethyl formamide (4 mL) were added morpholine (0.21 mL) and potassium carbonate (136 mg) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain N-adamantan-1-yl-5-(morpholin-4-ylmethyl)-4-(trifluoromethyl)pyrimidin-2-amine (160 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([OH:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:20][CH2:22][C:23]2[CH:28]=[N:27][C:26]([O:29][CH2:30][C:31]3[N:32]=[C:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:34][C:35]=3[CH3:36])=[CH:25][CH:24]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A mixture of ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (411 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg), potassium carbonate (414 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]propionate (748 mg, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.[C:14](#[N:18])[CH:15]([CH3:17])[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[F:12][C:10]1[CH:11]=[C:2]([C:15]([CH3:17])([CH3:16])[C:14]#[N:18])[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2
Reactant: CC(C)C#N
Reactant: O=C1NCCc2cc(F)cc(F)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(F)c2c(c1)CCNC2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
To a flask containing a solution of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one (4 g, 21.8 mmol) and isobutyronitrile (6.04 g, 87.4 mmol) in dry tetrahydrofuran (45 ml) was added a solution of potassium bis(trimethylsily)amide (50.4 ml, 0.91M in tetrahydrofuran) and the mixture was placed in an oil bath and heated to 70° C. On heating a red-brown homogeneous solution was obtained within 5 minutes. After 1 hour at 70° C., additional potassium bis(trimethylsily)amide (5 ml of 0.91 M) was added and was stirring continued for another 30 minutes. The flask was cooled to ambient temperature and the reaction was quenched with water (125 ml). Ethyl acetate (100 ml) was added and the material was transferred to a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×70 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane to provide a semi-pure component (710 mg, 33% purity) as well as pure product as a white powder (316 mg). (M+H)+=233 m/e.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][C@@H:3]1[CH2:23][NH:24]C(=O)OCC1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:24][CH2:23][C@@H:3]1[C@H:2]([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4]1
Reactant: COc1ccc2ncc(=O)n(CCN3CC[C@@H](O)[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(n1)N(CCN1CC[C@@H](O)[C@@H](CN)C1)C(=O)CN2
Reaction time: 8 h

Procedure:
To a solution of phenylmethyl [((3S,4R)-4-hydroxy-1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-3-piperidinyl)methyl]carbamate (234 mg; 0.502 mmol) in EtOH was added 20% Pd(OH)2/C (100 mg). The mixture was hydrogenated at 1 atm of H2 at ambient temperature overnight. The crude product was filtered through Celite, washed with ethanol and concentrated under reduced pressure to obtain the product (170 mg; 100%)
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH:24]([C:25](O)=[O:26])[CH2:23][S:22](=[O:29])(=[O:28])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:25]([CH:24]1[CH2:23][S:22](=[O:29])(=[O:28])[CH2:21][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])(=[O:26])[NH2:3]
Reactant: CC(C)(C)OC(=O)N1CS(=O)(=O)CC1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CS(=O)(=O)CC1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Carbonyldiimidazole (520 mg, 3.21 mmol) was added to an ice cold solution of 3-tert-butoxycarbonyl-1,1-dioxo-1,3-thiazolidine-4-carboxylic acid (Example 127 b, 304 mg, 1.15 mmol) in DMF (1 mL). After 5 min. the mixture was warmed to ambient temperature and stirred for 2 h. Gaseous NH3 was bubbled for 10 min through the solution while the temperature was kept below 20° C. Stirring was continued for 12 h at ambient temperature. The reaction mixture was poured into 30 mL ice/water/1N HCl and extracted with EtOAc (2×30 mL). The combined extracts were washed with ice/brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (197 mg, 65%) as white solid, MS (ESI) m/e=263.1 [M−H−].
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4](=[O:34])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(N[C:40]1[CH:45]=CC=[CH:42][CH:41]=1)C>>[CH2:35]([N:3]([C:1]1[CH:42]=[CH:41][CH:40]=[CH:45][CH:2]=1)[C:4](=[O:34])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:36]
Reactant: CCN(CC)C(=O)C(Cc1ccc(OC(F)(F)F)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCNc1ccccc1
Product: CCN(C(=O)C(Cc1ccc(OC(F)(F)F)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 40.3 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (1.18 g) obtained in Example 117 (4) and N-ethylaniline (305 mg). This was purified by silica gel column chromatography to give the title compound (519 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=1)[N:3]=[C:2]([NH:17][CH:18]([C:19](=[O:20])[NH:21][CH3:22])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: CNC(=O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Product: CNC(=O)C(Cc1ccccc1)Nc1nc2c(Cl)cc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-methyl-3-phenyl-propionamide to provide the title compound in moderate yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]
Reactant: Cn1c(=O)[nH]c(=O)n(-c2ccc(F)cc2Cl)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Nitric acid (70% real, 8.3 mL, 0.131 mol) is added to a solution of 1-(2-chloro-4-fluorophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (32.4 g, 0.119 mol) in concentrated sulfuric acid while maintaining the reaction mixture temperature below 10° C. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes, cooled to 10° C and diluted with ice-water. The resultant aqueous mixture is filtered to obtain a solid which is washed with water and air-dried to give the title product as a white solid (28.5 g, mp 135°-139° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([Cl:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:12][Br:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Cl)cc(CBr)c1

Procedure:
3-t-Butyl-5-chlorotoluene (5.7 g) was dissolved in carbon tetrachloride (80 ml) and N-bromosuccinimide (5.56 g) was added followed by benzoyl peroxide (750 mg). This mixture was heated at reflux for 6 h. The mixture was cooled, filtered through celite and the flitrate was concentrated in vacuo. The residue was purified by chromatography on silica using hexane as eluant. This afforded the title compound as a colourless liquid. 1H NMR (360 MHz, CDCl3) δ 1.31 (9H, s, (CH3)3), 4.42 (2H, s, CH2), 7.20 (1H, t, J=1.5 Hz, ArH), 7.26 (1H, t, J=1.5 Hz, ArH), 7.28 (1H, t, J=1.5 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27]>C1(C)C=CC=CC=1>[N:25]1[NH:26][N:27]=[N:18][C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1

Procedure:
The title compound was prepared from 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.273 g, 0.86 mmol), azidotributyl tin (0.314 g, 0.260 mL, 0.95 mmol) in toluene (10 mL). The reaction mixture was heated to reflux temperature for 12 hours resulting in partial conversion to the desired product along with partially and fully deprotected final products. An additional amount of azidotributyl tin was added (0.260 mL) and the reaction was heated to reflux temperature for 18 hours. Toluene was removed under reduced pressure and the crude was dissolved in 5 mL of 1,4-dioxane, 5 mL of 6.0 N aqueous hydrogen chloride, and 2 mL of methanol. The reaction was then heated to 60° C. for 2 days. The reaction was concentrated under reduced pressure and the pH was made basic by adding 2.0 N aqueous NaOH. The aqueous phase was washed with ethyl acetate (3×10 mL). The aqueous phase was then acidified using 6.0 N aqueous hydrogen chloride. The compound was filtered and purified by preparative HPLC (10–100% acetonitrile in H2O, 20 min) (0.050 g, 0.18 mmol, 21% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.8 (br s, 1H), 8.9 (s, 1H), 8.1 (d, 1H), 8.0 (d, 2H), 7.8 (d, 1H), 7.6 (t, 1H), 7.3 (d, 1H); ES-MS (m/z) 278 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](O)=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O=P(Cl)(Cl)[Cl:38]>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([Cl:38])=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1

Procedure:
6.6 g of 1-benzyl-3-(2-furyl)-4-hydroxypyrazolo[3,4-d]pyrimidine are boiled for 12 h in 100 ml of POCl3. The mixture is evaporated in vacuo, the residue is stirred with aqueous K2HPO4 solution and the mixture is extracted with ethyl acetate. After drying using Na2SO4 and concentrating in a rotary evaporator, 7.47 g of a solid are obtained which can be reacted directly for the next stage (Rf=0.8, SiO2, toluene/ethyl acetate=1:1).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)=O>C(O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:4]
Reactant: NN1CCOCC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C=O
Solvent: CCO
Product: Nc1ccccc1C(=O)NN1CCOCC1
Temperature: 70 °C

Procedure:
33 g isatoic anhydride are suspended in 200 cc ethanol heated to 70° C.; 20.5 g 4-amino-morpholine are slowly added thereto. After completion of the addition, the temperature is maintained at the same level until carbon dioxide is no longer evolved. The ethanol is partly removed (100 cc) and the reaction product is crystallized by addition of 100 cc benzene. It may be purified by recrystallization from a benzene-ethanol mixture. M.P.=172° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=[C:8]2[C:16]([O:18]CC)=O)[CH:2]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1>>[CH3:30][C:28]1[S:29][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:16]([C:8]3[N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:11]4=[N:12][CH:13]=[CH:14][CH:15]=[C:10]4[CH:9]=3)=[O:18])=[CH:31][C:26]=2[N:27]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: CCOC(=O)c1cc2cccnc2n1-c1cccnc1
Product: Cc1nc2cc(NC(=O)c3cc4cccnc4n3-c3cccnc3)ccc2s1

Procedure:
This compound was prepared according to the experimental protocol described in Example 6.2, starting with ethyl 1-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate obtained according to the protocol described in step 7.1 and 5-amino-2-methylbenzothiazole. A yellow solid is obtained.