Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN1CCCC1=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:35][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][O:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[CH:33][CH:32]=2)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1ccc(COC2CCCCO2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=S(=O)(Nc1nccnc1OCc1ccc(COC2CCCCO2)cc1)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28a) (0.1 g), [4-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (0.27 g) and potassium tert-butoxide (2 mL of a 1M solution in tetrahydrofuran) in N-methylpyrrolidinone (1 mL) was stirred at 50° C. After 2 h, aqueous citric acid was added and the mixture extracted with ethyl acetate. The organic solution was washed with water and brine and evaporated to dryness. Used directly.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([O:31][CH2:32][CH2:33]O)=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccnc2ccccc12
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccnc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(4-quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 3 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate-methanol; 20: 1) and crystallized from dichloromethane-hexane to provide 1.2 g of alpha-oxo-4-[[2-(4-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 135°-136° C.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH2:14])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[F:15][C:16]([F:34])([F:33])[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][C@H:25]([C:30](O)=[O:31])[CH2:24][CH2:23][C:22]=2[N:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1C(=O)CCC1>[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH:14][C:30]([CH:25]3[CH2:24][CH2:23][C:22]4[N:21]=[C:20]([C:17]([CH3:19])([CH3:18])[C:16]([F:34])([F:33])[F:15])[CH:29]=[CH:28][C:27]=4[CH2:26]3)=[O:31])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: C[C@@H](N)c1ccc2[nH]ncc2c1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A 2 mL vial was charged sequentially with a solution of (R)-1-(1H-indazol-5-yl)ethanamine dihydrochloride (34 mg, 0.15 mmol) in NMP (0.2 mL, 2 mmol), a solution of (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol) and N,N-diisopropylethylamine (93 μL, 0.53 mmol) in NMP (0.1 mL). A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (61 mg, 0.16 mmol) in NMP (0.3 mL) was added to the resulting mixture and the solution stirred at room temperature. After 30 min the mixture was filtered and purified by reverse-phase HPLC (20-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (44 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 12.98 (br s, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.04 (d, J=0.4 Hz, 1H), 7.66 (s, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.06 (app pentet, J=7.3 Hz, 1H), 2.94-2.76 (m, 4H), 2.68-2.57 (m, 1H), 2.11-2.03 (m, 1H), 1.90-1.78 (m, 1H), 1.54 (s, 6H), 1.43 (d, J=7.0 Hz, 3H); m/z=431.3 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([N:20]([CH3:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CNC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.46 g, 1.59 mmol) in THF (15 ml) was added 1-bromomethyl-4-trifluoromethyl-benzene (0.44 g, 1.86 mmol) and Et3N (0.155 ml, 1.59 mmol). The reaction mixture was stirred overnight at RT and concentrated under vacuo. The product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 500 mg (71%) of the title compound as a colorless oil. ES-MS m/e: 459.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][CH2:22][OH:23])[C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:21][CH2:22][O:23][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:4]2[C:9]([C:10]=1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(=O)c2c(C)n(CCO)c3ccccc23)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2c(C)n(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc23)cc1

Procedure:
Following a procedure similar to that described above in Preparation 4A, 40 g. (0.015 mole) of 2-methyl-3-(4-methoxybenzoyl)indole in 320 ml. of THF was reacted with 61 ml. of a 2.6M solution of butyl lithium in hexane and 45.8 ml. of ethylene oxide to give 33.6 g. (72%) of 2-methyl-3-(4-methoxybenzoyl)-1-(2-hydroxyethyl)-1H-indole. Reaction of 17 g. (0.06 mole) of the latter with 72 g. (0.06 mole) of p-toluenesulfonyl chloride in 250 ml. of pyridine afforded 2-methyl-3-(4-methoxybenzoyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:10][C:11](=O)[NH:12][CH:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[N:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=c1nc(-c2ccncc2)c(-c2ccc(F)cc2)c[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cnc(Cl)nc2-c2ccncc2)cc1

Procedure:
A mixture of 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(1H)-pyrimidinone (2.41 mmol) and phosphorus oxychloride (3 ml) was heated at reflux for 45 min. It was evaporated to dryness at a bath temperature of >500° C. The flask was cooled in an ice-bath and ice-water was added. If the pH value was found still acidic, then the mixture was neutralized with aqueous 5% ammonium hydroxide. It was extracted with dichloromethane, followed by washing of the organic solution with aqueous sodium chloride, drying and evaporation to yield the title compound as a yellowish foam which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCc1ncccn1
Product: N=C(NCCNCc1ncccn1)N[N+](=O)[O-]

Procedure:
Reaction of N-(2-pyrimidylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrimidylmethylamino)-ethyl]guanidine. Similarly, from the same starting material, according to the procedure of Example 2(iii), there is produced N-methyl-N'-nitro-N"-[2(2-pyrimidyl-methylamino)ethyl]guanidine.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[N:9]1[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=12>CN(C)C=O>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:25]/[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:10]2[N:9]=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[CH:11]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(-c2cn3ccccc3n2)cc1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 120 °C

Procedure:
Subsequently, N,N-dimethylformamide dimethyl acetal (3.0 mL) was added to a solution of 1-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-ethanone (2.13 g) in N,N-dimethylformamide (50 mL), followed by heating at 120° C. for 8 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was recovered through filtration, followed by washing with ethanol. The filtrate was concentrated under reduced pressure. The thus-obtained solid and the residue were subjected to flash chromatography. Fractions eluted by dichloromethane-methanol (30:1) were concentrated under reduced pressure, and the solid was recovered through filtration by use of ethyl acetate. Through the above procedure, (E)-3-dimethylamino-1-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-2-propen-1-one (2.38 g) was yielded.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.[H-].[Na+].[CH3:18]I.O>C1COCC1>[CH3:18][O:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:12]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]=2[O:9]1
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)OC(CO)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1Cc2cc(C)cc([N+](=O)[O-])c2O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5-methyl-7-nitro-2,3-dihydrobenzofuran-2-yl)methanol (0.70 g, 3.3 mmol) in THF was cooled to 0° C. NaH was added to the mixture at 0° C. It was stirred for 15 min at 0° C. MeI was added dropwise to the mixture at 0° C. It was stirred for 0.5 h at 0° C. The mixture was poured into water (20 mL), extracted with EtOAc (40 mL), washed with water, brine, dried and concentrated to give the title compound (8a) as a yellow oil. MS-ESI (m/z): 224 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[S:6][C:5](=[N:7][CH2:8][CH3:9])[S:4][C:3]1=[N:10][OH:11].[CH3:13][N:14]([S:18][C:19]([Cl:22])([Cl:21])[Cl:20])[C:15](F)=[O:16]>O1CCOCC1.O>[CH3:12][C:2]1([CH3:1])[S:6][C:5](=[N:7][CH2:8][CH3:9])[S:4][C:3]1=[N:10][O:11][C:15](=[O:16])[N:14]([CH3:13])[S:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Reactant: CCN=C1SC(=NO)C(C)(C)S1
Solvent: O
Solvent: C1COCCO1
Product: CCN=C1SC(=NOC(=O)N(C)SC(Cl)(Cl)Cl)C(C)(C)S1
Reaction time: 16 h
Yield: 57.4 %

Procedure:
To a solution of 3.5 grams (0.017m) of 5,5-dimethyl-2-ethylimino-4-oximino-1,3-dithiolane (XXIII) and 3.84 grams (0.017m) of N-methyl-N-trichloromethanesulfenyl carbamoyl fluoride in 75 ml of dioxane, was added dropwise with stirring 1.71 grams (0.017m) of triethylamine. After allowing the reaction mixture to stand at room temperature for 16 hours it was diluted with 250 ml of cold water and was extracted in ethylacetate. The organic extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to a residual oil which crystallized on the addition of isopropyl ether and hexane, to afford 4.0 grams of a white solid. m.p. 69°-71° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:19]=[C:18]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=3[O:25][CH3:26])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:23]([S:20]([C:18]1[CH:17]=[CH:16][C:15]([O:25][CH3:26])=[C:14]([NH:13][C:11]2[O:12][C:8]([C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=4)[CH:7]=[CH:6][CH:5]=3)=[CH:9][N:10]=2)[CH:19]=1)(=[O:22])=[O:21])[CH3:24]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Br)c3)o2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4ccc(C#N)cc4)c3)o2)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
A mixture of the title compound of Example 100 (250 mg, 0.57 mmol), 4-cyanophenyl boronic acid (108 mg, 0.74 mmol), 2M aqueous sodium carbonate solution (0.5 mL, 1.0 mmol), and (bistriphenylphosphine)palladium(II) chloride (50 mg, 0.071 mmol) was suspended in DMF (2 mL) and stirred at 100° C. After 20 min, the reaction was determined to be complete by TLC analysis. After cooling to RT, the DMF was evaporated under reduced pressure. The crude product was partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (1:1) to afford the title compound (152 mg, 58%) as a solid white powder. 1H NMR (400 MHz, d6-DMSO): δ 9.82 (s, 1H), 8.81 (d, J=2.2, 1H), 7.95–8.05 (m, 5H), 7.68–7.74 (m, 3H), 7.63 (d, J=7.8, 1H), 7.53 (dd, J1=2.2, J2=8.7, 1H), 7.31 (d, J=8.5, 1H), 4.01 (s, 3H), 3.24 (q, J=7.3, 2H), 1.14 (t, J=7.3, 3H). MS (ES+, m/z)=459 (m+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[N:12]=3)=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CN1CCCC1C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CN1CCCC1C

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 9 using 2-(4-Bromo-phenyl)-5-methyl-4-(2-methyl-pyrrolidin-1-ylmethyl)-oxazole (See Example 99) and 4-methylsulfonylphenylboronic acid. MS (m/e) 411.2 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[N:31]=[N:32][N:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:37]2)[C:34]=1I)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]1(B2OC(C)(C)C(C)(C)O2)[CH2:46][CH2:45]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>O>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[N:31]=[N:32][N:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:37]2)[C:34]=1[CH:44]1[CH2:46][CH2:45]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CC(C)CC1CC(n2nnc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CC1CC(n2nnc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-[5-iodo-1-(3-isobutylcyclobutyl)-1H-[1,2,3]triazol-4-yl]valerate (340 mg), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.16 mL), tripotassium phosphate (403 mg), N,N-dimethylacetamide (3.4 mL) and water (0.85 mL) were mixed. The mixture was degassed by bubbling argon gas. To the mixture was added PdCl2(PPh3)2 (50 mg). The mixture was stirred at 80° C. for 1 hr. To the reaction mixture was added ethyl acetate at ice temperature, and then the mixture was filtered. The filtrate was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/20) to give the title compound (238 mg).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1>CN(C=O)C>[CH:18]1([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:19]1
Reactant: BrC1C=CCCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CC=CCC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 234.7 %

Procedure:
A mixture of potassium phthalimide (1.85 g, 3 mmol) and 3-bromocyclohexene (1.79 g, 3 mmol) in DMF (15 mL) was stirred in a 100° C. oil bath for 12 h. The cooled reaction mixture was poured into ice water. The solid was collected by filtration and purified by flash chromatography with CH2Cl2 as the eluent to afford compound 221 (1.6 g, 72%) as pink crystals; mp 114° C.; 1H NMR (CDCl3) δ 7.73-7.69 (m, 2H), 7.62-7.58 (m, 2H), 5.85-5.82 (m, 1H), 5.47-5.44 (m, 1H), 4.80-4.78 (m, 1H), 2.14-2.00 (m, 3H), 1.86-1.78 (m, 2H), 1.64-1.58 (m, 1H).
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].[Al+3:14].[Cl-].[Cl-].[Cl-]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Al+3:14]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
combining the AlCl3 solution with an aqueous solution of citric acid containing up to about 50 weight % citric acid, while vigorously agitating the resultant solution to form an aluminum citrate solution having a mole ratio of aluminum ion to citric acid molecule of from about 1.5:1 to about 2:1, said AlCl3 solution being provided in an amount sufficient to form an aluminum citrate solution containing from 1 up to about 3 weight % aluminum; and
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]2=[N:22][N:21]=1)[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[N:22]1[N:21]=[C:20]([CH:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nnc3ccccn23)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(N)c2nnc3ccccn23)cc2cn[nH]c12
Reaction time: 1 h

Procedure:
tert-Butyl-1-([1,2,4]triazolo[4,3-a]pyridine-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethylcarbamate (43.2 mg, 0.11 mmol) was dissolved in a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) and stirred under nitrogen for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cationic exchange column. After washing the column with several volumes of methanol, the desired amine was obtained by washing the column with 2M ammonia in methanol. Concentration afforded 33 mg (93%) of the crude product which was used without purification. 1H-NMR (CD3OD, 300 MHz) δ 2.41 (s, 3H), 3.50-3.66 (m, 2H), 5.50 (bs, 2H), 6.63 (dd, J=6.6, 6.2, 1H), 6.95 (s, 1H), 7.11-7.20 (s, 1H), 7.38 (s, 1H), 7.71 (d, J=9.2, 1H), 7.88 (d, J=7.0, 1H), 7.91 (s, 1H). Mass spec.: 293.02 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[N:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=[O:27])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(CC(=O)OC(C)(C)C)cc1NC(=O)c1cnn2cccnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1nn(CC(=O)O)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetate (1.85 g, 3.83 mmol) in 50 mL dichloromethane was added 30 ml of TFA. The mixture was stirred 2 h at ambient temperature, then concentrated and recrystallized from EtOAc to furnish 1.4 g (86%) of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetic acid as a colorless solid. LCMS (ESI) m+H=427.1. 1H NMR (400 MHz, CD3OD) δ 9.95 (s, 1H), 9.08 (m, 1H), 8.69 (m, 1H), 8.63 (s, 1H), 8.34 (s, 1H), 7.47 (m, 2H), 7.21 (m, 2H), 5.03 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [OH-].[Na+].C(O[C:6]([C:8]1[NH:9][C:10]([CH3:37])=[C:11]([C:14]2[NH:15][C:16]3[CH:22]=[C:21]([S:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][C:17]=3[N:18]=2)[C:12]=1[CH3:13])=[O:7])C.[CH2:38]([N:40]=[C:41]=NCCCN(C)C)C.CNC>CN(C)C=O.C(O)C>[CH3:38][N:40]([CH3:41])[C:6]([C:8]1[NH:9][C:10]([CH3:37])=[C:11]([C:14]2[NH:15][C:16]3[CH:22]=[C:21]([S:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:19][C:17]=3[N:18]=2)[C:12]=1[CH3:13])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1[nH]c(C)c(-c2nc3cc(Oc4ccccc4)c(Sc4ccncc4)cc3[nH]2)c1C
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1[nH]c(C(=O)N(C)C)c(C)c1-c1nc2cc(Oc3ccccc3)c(Sc3ccncc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 17 h
Yield: 34.3 %

Procedure:
Five milliliters of ethanol and 3.5 ml (3.5 mmol) of a 1 N sodium hydroxide aqueous solution were added to 0.48 g (1.0 mmol) of the 4-(5-(4-pyridylsulfenyl)-6-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid ethyl ester obtained in Comparative Example 1, and the reaction mixture was stirred at 60° C. for 17 hours. The reaction mixture was allowed to cool and concentrated, and the insoluble material was filtered off by adding water. The filtrate was neutralized with a 2 N hydrochloric acid solution, and the precipitate was collected by filtration, washed with water, and dried at reduced pressure to afford crude carboxylic acid (0.22 g). 0.2 g (0.4 mmol) of the crude carboxylic acid was dissolved in 3 ml of N,N-dimethylformamide, and then 92 mg (0.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.25 ml (2.2 mmol) of a 40% dimethylamine aqueous solution were added to the solution. The reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated at reduced pressure. The obtained residue was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:100 to 1:10) to afford (N,N-dimethyl)-4-(5-(4-pyridylsulfenyl)-6-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide (83 mg, 43%) as an amorphous.