Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28](=[O:43])[C:29]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[CH:30][C:31]([O:33]C)=O>CO>[F:42][C:39]1[CH:38]=[C:37]2[C:36](=[CH:41][CH:40]=1)[NH:35][C:29]([C:28]([O:27][CH3:26])=[O:43])=[CH:30][C:31]2=[O:33]
Reactant: COC(=O)C=C(Nc1ccc(F)cc1)C(=O)OC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(=O)c2cc(F)ccc2[nH]1
Temperature: 235 °C

Procedure:
250 ml de Dowtherm-A are brought to reflux (about 235° C.) under a nitrogen atmosphere. 41 g (0.16 M) of 2-(4-fluorophenylamino)but-2-enedioic acid dimethyl ester are then introduced dropwise. The methanol formed is separated out. Refluxing is maintained for 10 minutes after the end of introduction. The reaction mixture is then cooled to about 50° C., followed by addition of 250 ml of petroleum ether: a solid precipitates out. It is filtered off by suction, washed three times with petroleum ether and then dried under reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])=[N:15][NH:16][C:17]=1[CH3:18])[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:16]1[C:17]([CH3:18])=[C:13]([CH2:11][CH3:12])[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])=[N:15]1)=[O:10]
Reactant: CCc1c(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]c1C
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn(C(=O)NC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Potassium carbonate (0.50 g, 3.6 mmol) and methyl isocyanate (0.17 g, 3.0 mmol) were added to a solution of 4-ethyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (1.13 g, 3.6 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of N-methyl-4-ethyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.62 g, yield: 55.5%). mp: 81-82° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.14 (t, J=7.6 Hz, 3H), 2.41 (q, J=7.6 Hz, 2H), 2.56 (s, 3H), 2.90 (d, J=5.0 Hz, 3H), 6.50-6.75 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.84 (dd, J=2.1 and 8.7 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H).
Reaction SMILES: F[Sb-](F)(F)(F)(F)F.[CH3:8][O:9][CH2+:10]1[C:13]([F:15])([F:14])[C:12](F)=[C:11]1[F:17].[OH2:18]>C(Cl)Cl>[CH3:8][O:9][C:10]1[C:13]([F:15])([F:14])[C:12](=[O:18])[C:11]=1[F:17]
Reactant: CO[CH2+]1C(F)=C(F)C1(F)F
Reactant: O
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC1=C(F)C(=O)C1(F)F
Temperature: 25 °C

Procedure:
The antimonate (2) solution in SO2 prepared substantially as above was chilled to -78° and added cautiously to 200 ml of vigorously stirred iced water. After warming to room temperature and stirring until all the solid dissolved, 25 ml of methylene chloride was added. The organic phase was withdrawn, washed with saturated aqueous sodium chloride, dried (MgSO4), and distilled to give 3.9 g of 3-methoxy-2,4,4-trifluorocyclobut-2-en-1-one (3): bp 58°(10 mm). ##SPC5##
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>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.COCCOC>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccccc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 100 °C
Yield: 34.6 %

Procedure:
Ethyl 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (2.6 g, 5.76 mmol), phenyltributylstannane (2.24 mg, 6.10 mmol), tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.02 mmol), toluene (15 ml) and anhydrous DME (1.5 ml) were placed in a Schlenk vessel equipped with a magnetic stirring bar. The vessel was purged with argon, sealed and heated at 100° C. overnight. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the tide compound as a white solid (0.8 g, 35%). 1H NMR (CDCl3): δ 8.26 (1H, s); 7.72 (2H, m); 7.56 (1H, s); 7.51-7.36 (4H, m); 7.34-7.28 (2H, m); 4.37 (2H, q, J 7.1 Hz); 1.97 (3H, s); 1.37 (3H, t). APCI-MS m/z: 402.3 [MH+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1.O>C(#N)C.C(Cl)Cl>[N+:27]([C:16]1[CH:15]=[C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:19]=[CH:18][C:17]=1[S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([O-:29])=[O:28]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cc(F)ccc1Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(N2CCNCC2)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a mixture of piperazine (1.0 g, 12 mmol) and potassium carbonate (2.0 g, 14 mmol) in 80 mL of dry acetonitrile is added 4-fluoro-2-nitro-1-(phenylsulfanyl) benzene (2, EXAMPLE 1, step 1, 2.7 g, 9.5 mmol). The mixture is allowed to stir overnight at rt. Water and CH2Cl2 (80 mL each) are added and the layers separated. The aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organic layers are dried over MgSO4, filtered, and concentrated. Purification via column chromatography (50% EtOAc/hexane) gives 1.6 g (47%) of the title compound as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:30])[CH2:17][CH2:16][C:15]([CH2:28][NH2:29])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:15]1([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[CH2:16][CH2:17][C:12]([F:11])([F:30])[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and (4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=433.2, tR (minutes, Method D)=0.78
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]2[NH:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]2[N:12]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1-c1cnc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: COc1c(Br)cccc1-c1cncn1COCC[Si](C)(C)C
Yield: 40.8 %

Procedure:
Reaction of 5-(3-bromo-2-methoxy-phenyl)-1H-imidazole (539 mg, 3.10 mmol), NaH (60%, 120 mg, 3.00 mmol), and SEMCl (751 uL, 3.61 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (485 mg, 60%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.93 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=7.5 Hz), 3.93 (s, 3H), 5.31 (s, 2H), 6.82 (d, 1H, J=6.0 Hz), 7.31 (dd, 1H, J=9.0, 3.0 Hz), 7.63 (s, 1H), 7.66 (s, 1H), 8.36 (d, 1H, J=2.1 Hz). ES-MS m/z 385 (M+H).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1OCC(O)CNC(C)(C)C
Solvent: O
Product: Cc1ccc(C2=NNC(=O)CC2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methylbenzoyl]propionate was cyclised with hydrazine hydrate in a manner similar to that described in Example 2(ii) to give 6-[2-(3 -t-butylamino-2-hydroxypropoxy)-4-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone (m.p. 129.5°-130.5° C). The hydrochloride, crystallised from ethanol-ether, had m.p. 206.5°-209.5° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:13]([NH:17][S:18]([CH:21]3[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:12]1[C:13]([NH:17][S:18]([CH:21]2[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][NH:8]2
Reactant: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3CC3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1Nc1ccc(I)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 5-cyclopropanesulfonylamino-4-(2-fluoro-4-iodo-phenylamino)-indazole-1-carboxylic acid tert-butyl ester (206 mg, 0.36 mmol) in DCM (8 mL) was added TFA (1 mL) and the reaction mixture stirred at room temperature for 2 hours. Additional TFA (1 mL) was added and stirring continued for a further 1 hour before the reaction mixture was concentrated in vacuo and the residue azeotroped with DCM, methanol and then DCM again. The resultant residue was triturated with diethyl ether, the solid filtered off and dried under vacuum at 40° C. to give the title compound as a yellow solid (83 mg, 49%). LCMS (Method A): RT=10.03 [M+H]+=437, 1H NMR (DMSO-d6, 400 MHz): 13.14 (1 H, s), 9.07 (1 H, s), 7.80 (1 H, s), 7.57 (1 H, dd, J=10.84, 1.96 Hz), 7.39 (1 H, s), 7.31 (1 H, d, J=8.74 Hz), 7.25-7.20 (2 H, m), 6.45 (1 H, t, J=8.84 Hz), 2.40-2.32 (1 H, m), 0.75-0.62 (4 H, m), −0.05 (1 H, t, J=3.33 Hz).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][S:6][CH:7]=1)#[N:2].Cl.Cl.[C:10]1(N)[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[OH-].[Na+].C1(N)C=CC=CC=1N>O>[CH:14]1[CH:15]=[CH:10][C:11]2[N:16]=[C:1]([C:3]3[N:4]=[CH:5][S:6][CH:7]=3)[NH:2][C:12]=2[CH:13]=1
Reactant: Nc1ccccc1N
Reactant: N#Cc1cscn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(-c3cscn3)nc2c1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a 1 liter four-neck flask equipped with a mechanical stirrer, a condenser, pH probe and thermometer were added 54 grams (0.5 mole) of 4-cyanothiazole, 90.5 grams (0.5 mole) of o-phenylenediamine dihydrochloride and 250 ml of deionized water. Sodium hydroxide pellets were added in sufficient proportion to increase the pH of the reaction mixture to a value of 4.0. The mixture was heated to reflux and held at reflux (100°-102° C.) for 4 hours. The reaction was determined to be complete when the peaks corresponding to o-phenylenediamine and 4-cyanothiazole were absent from the gas chromatogram. The reaction mass was allowed to cool to room temperature before adding 0.1N NaOH to adjust the pH to a value within a range of 8-10. The product was filtered, washed three times with 300 ml portions of deionized water, and then dried overnight in a vacuum oven. A total of 78.0 grams of thiabendazole were obtained which corresponds to a 77.5% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:22])[CH:19]([OH:21])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:11][C:10](=[O:28])[C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([N:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38](O)=[O:39])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[C:32]([O:31][C:29]([N:36]1[CH2:43][CH2:42][CH2:41][CH:37]1[C:38]([O:21][CH:19]([CH3:20])[CH:18]([CH:17]1[CH2:16][NH:15][C:14]2[N:13]=[C:12]([N:23]=[CH:24][N:25]([CH3:26])[CH3:27])[NH:11][C:10](=[O:28])[C:9]=2[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[OH:22])=[O:39])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(O)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Product: CC(OC(=O)C1CCCN1C(=O)OC(C)(C)C)C(O)C1CNc2nc(N=CN(C)C)[nH]c(=O)c2N1C(=O)OC(C)(C)C
Yield: 69 %

Procedure:
The product of Example 5, step b) was treated by the same method as that described in Example 5, step c) except N-Boc-L-Proline (13.6 g, 63.1 mmol) was used to give the sub-title compound as a tan solid (5.2 g, 69%). MS: ESI (positive): 594 (M+H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:28]([CH3:30])([CH3:29])[CH2:27][C:26]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:25][C:24]2([CH3:36])[CH3:35])[N:12]=1>O.C1(C)C(C)=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:11]1[N:16]=[C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:14]=[C:13]([N:23]2[C:24]([CH3:36])([CH3:35])[CH2:25][C:26]3([O:31][CH2:32][CH2:33][O:34]3)[CH2:27][C:28]2([CH3:30])[CH3:29])[N:12]=1
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(N3CCOCC3)n1)OCCO2
Reactant: OCCNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(C)CC2(CC(C)(C)N1c1nc(N(CCO)CCO)nc(N3CCOCC3)n1)OCCO2
Reaction time: 14 h

Procedure:
5.3 g of diethanolamine and a solution of 1 g of NaOH in 3 ml of water are added to a solution of 20 g of 2-chloro-4-morpholino-6-(4,4-ethylenedioxy-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 44) in 50 ml of xylene. 1 g of NaOH in 3 ml of water is again added after 1.75 hours with stirring under reflux. After 14 hours, 7.9 g of diethanolamine are added, after which the mixture is stirred under reflux for a further 28 hours. It is then allowed to cool and washed with water, and the organic phase is separated off. After drying over Na2SO4, evaporating and recrystallizing twice from toluene, the above product is obtained as a white powder which melts at 135°-140°.
Reaction SMILES: NC1C2N(C3C=CC(N)=CC=3)N=C(C3CCN(C(OC(C)(C)C)=O)CC3)C=2N=CN=1.CN1C2C(=CC=CC=2)C=C1C(Cl)=O.[NH2:44][C:45]1[C:46]2[N:53]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][C:61]([C:63]4[N:64]([CH3:72])[C:65]5[C:70]([CH:71]=4)=[CH:69][CH:68]=[CH:67][CH:66]=5)=[O:62])=[C:56](OC)[CH:55]=3)[N:52]=[C:51]([CH:75]3[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]3)[C:47]=2[N:48]=[CH:49][N:50]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[NH2:44][C:45]1[C:46]2[N:53]([C:54]3[CH:55]=[CH:56][C:57]([NH:60][C:61]([C:63]4[N:64]([CH3:72])[C:65]5[C:70]([CH:71]=4)=[CH:69][CH:68]=[CH:67][CH:66]=5)=[O:62])=[CH:58][CH:59]=3)[N:52]=[C:51]([CH:75]3[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]3)[C:47]=2[N:48]=[CH:49][N:50]=1
Reactant: COc1cc(-n2nc(C3CCNCC3)c3ncnc(N)c32)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(C)(C)OC(=O)N1CCC(c2nn(-c3ccc(N)cc3)c3c(N)ncnc23)CC1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Cn1c(C(=O)Cl)cc2ccccc21
Solvent: CC#N
Product: Cn1c(C(=O)Nc2ccc(-n3nc(C4CCNCC4)c4ncnc(N)c43)cc2)cc2ccccc21

Procedure:
The title compound was prepared from tert-butyl 4-[7-amino-1-(4-aminophenyl)-1H-pyrazolo[4,3-d]pyrimidine-3-yl]-1-piperidinecarboxylate and 1-methylindole carbonyl chloride in the manner described for the preparation of N2-{4-[7-amino-3-(4-piperidyl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide: 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.28 (s, 1H), 8.03 (d, 2H), 7.74 (d, 1H), 7.58 (d, 1H), 7.53 (d, 2H), 7.37 (s, 1H), 7.34 (t, 114), 7.15 (t, 1H), 6.5 (bs, 1.4H), 4.04 (s, 3H), 3.19 (m, 1H), 3.10 (m, 2H), 2.70 (m, 2H), 1.84-2.0 (m, 4H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 14.42 min; MS: MH+ 467.1, M−H+ 465.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][N:12]=[N+]=[N-])=[O:8])=[CH:5][CH:4]=1.C(Cl)Cl.C(OCC)(=O)C>[Pd].C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][NH2:12])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)N[C@@H](CN=[N+]=[N-])c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N[C@@H](CN)c2ccccc2)cc1
Yield: 83.8 %

Procedure:
(R)-2-(4-methoxybenzoylamino)-2-phenylethyl azide (46.3 g) was combined with 10% palladium on carbon in THF (400 mL), methanol (100 mL) and was stirred under a hydrogen atmosphere. Analysis by TLC (70% methylene chloride, ethyl acetate) indicated absence of starting material after stirring overnight. The solution was filtered through diatomaceous earth, rinsed with THF, and evaporated. The resulting solid was recrystallized with ethyl acetate, and dried under vacuum at 60° C. for 1 h to afford 35.4 g (84%) of a white crystalline solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu+2].CC(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N:30]5[CH:34]=[CH:33][N:32]=[CH:31]5)[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8]
Reactant: c1c[nH]cn1
Reactant: O=C(NC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)n1)(C3)C2)c1ccccn1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: O=C(NC12CC3CC(C1)CC(NC(=O)c1cccc(-n4ccnc4)n1)(C3)C2)c1ccccn1
Temperature: 180 °C
Yield: 20.3 %

Procedure:
To a microwave vial was added a stir bar, 6-chloro-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide (Intermediate 4, 20 mg, 0.05 mmol), copper (II) acetoacetonate (20 mg), DMA (1 mL), imidazole (50 mg, 0.73 mmol) and cesium carbonate (60 mg, 0.15 mmol). The mixture was heated at 180° C. under microwave irradiation for 15 minutes. Solvent was removed in a high performance solvent evaporation system HT-4X (Genevac, Inc., supra). The residue was dissolved in DCM (2 mL), washed with aq. 1 N NaOH (2 mL), and water (2×2 mL). After removing the solvent, the residue was purified on a RP-HPLC/MS system (Gradient: acetonitrile in water with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan) to afford 4.5 mg of the title compound, 6-imidazol-1-yl-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. ESI-MS m/z: 443.5 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7](O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P(Br)(Br)[Br:12]>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([Br:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](O)CC1
Reactant: BrP(Br)Br
Product: CCCC1CCC(Br)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 176 %

Procedure:
142 g (1.0 mol) of trans-4-propylcyclohexanol was stirred at room temperature and 136 g (0.5 mol) of PBr3 was added drop-wise. The reaction was exothermic and reached about 80° C. The product of the reaction was stirred over a hot water bath at 70° C. for 1 hour, cooled to room temperature, and poured into ice water to decompose the excess PBr3. The oily layer was separated out and the aqueous layer was extracted with chloroform. The oily layers were combined and washed with water. The chloroform was distilled off the washed mixture. The oily residue was distilled in a vacuum (b.p. 97° C./14 mmHg) to yield 180 g (0.88 mol) of 4-propyl-1-bromocyclohexane.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][C:53]1[CH:58]=[C:57]([C:59]2[S:60][CH:61]=[CH:62][CH:63]=2)[CH:56]=[CH:55][C:54]=1[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C.CN(C)C1C=CN=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([NH:52][C:53]3[CH:58]=[C:57]([C:59]4[S:60][CH:61]=[CH:62][CH:63]=4)[CH:56]=[CH:55][C:54]=3[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:17])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1ccc(N2CCOCC2)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)/C=C/c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 164 (0.275 g, 1.17 mmol) in DMF (10 mL) was added triethylamine (0.168 mL, 1.21 mmol) and BOP reagent (0.563 g, 1.27 mmol) and the mixture was stirred at room temperature for 30 min. Then amine 4 (0.309 g, 1.06 mmol) and excess triethylamine (0.443 mL, 3.18 mmol) were added and the reaction mixture was allowed to stir for 18 h at room temperature. Then 4-(dimethylamino)pyridine (catalytic amount) was added and the reaction mixture was heated to 50-60° C. for 24 h. The solution was concentrated, diluted with AcOEt, washed with saturated NaHCO3, H2O, brine, dried over MgSO4, filtered and concentrated. The resulting yellow solid was triturated from ethyl ether to give compound 165 (0.435 g, 81% yield).
Reaction SMILES: C(OC([N:8]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[C:15]([N:17]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:32][C:30]1[CH:29]=[C:14]([CH:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH:31]=1)[C:15]([N:17]([CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Yield: 734.7 %

Procedure:
A solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-cyclopentyl-amino)-butyric acid (0.015 g) in trifluoroacetic acid (3 ml) was stored at room temperature for 2 h and then the solvent removed under reduced pressure. The residue was purified by preparative hplc to give title compound (0.09 g) as a colourless gum.