Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[O:16])=[CH:12][NH:11][N:10]=1.IC.[C:28](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH3:28])[N:11]=[CH:12][C:13]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3cccnc23)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(-c2c(NC(=O)c3cnn4cccnc34)cnn2C)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.255 g, 0.767 mmol, 1 eq) in 10 mL N,N-dimethylformamide is added iodomethane (60.0 μL, 0.964 mmol, 1.26 eq) and cesium carbonate (0.562 g, 1.72 mmol, 2.25 eq). The reaction mixture is stirred at 40° C. for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The mixture of regioisomeric products was separated and purified by flash chromatography on silica gel (20 to 90% ethyl acetate in dichloromethane) to yield: 84.3 mg (32%) of N-(3-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=347.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 9.30 (d, 1H), 8.65 (s, 1H), 8.47 (d, 1H), 8.27 (s, 1H), 7.27 (d, 1H), 7.23-7.19 (m, 3H), 3.91 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), and 81.8 mg (31%) of N-(5-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=347.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1H), 9.30 (d, 1H), 8.61 (s, 1H), 8.43 (d, 1H), 8.01 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H) 7.20 (m, 2H), 3.62 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:38])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[N:26]=[N:25][C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:28]=4[NH2:37])=[N:23]3)=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42](=[O:49])[CH:41]=[C:40]1[C:50](O)=[O:51]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:38])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[N:26]=[N:25][C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:28]=4[NH:37][C:50]([C:40]4[O:39][C:48]5[C:43]([C:42](=[O:49])[CH:41]=4)=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:51])=[N:23]3)=[CH:20][CH:21]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCc2ccc(-n3nnc(-c4cc(OC)c(OC)cc4N)n3)cc2)cc1OC
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Product: COc1ccc(CCN(C)CCc2ccc(-n3nnc(-c4cc(OC)c(OC)cc4NC(=O)c4cc(=O)c5ccccc5o4)n3)cc2)cc1OC
Yield: 74.3 %

Procedure:
The procedure of Example 2 was repeated except for using 1 g of the compound obtained in Step 2 and 0.97 g of chromone-2-carboxylic acid as starting materials to obtain 0.99 g of the title compound (yield 75%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:10]=[N:9]2)=[CH:5][CH:4]=1.C(C1C=CC(CN2C=C(C=CC(O)=O)N=N2)=CC=1)#N>>[C:2]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([CH:13]=[CH:14][CH:15]=[O:16])[N:10]=[N:9]2)=[CH:5][CH:4]=1)#[N:1]
Reactant: NCc1ccc(Cn2cc(CCC(=O)O)nn2)cc1
Agent: N#Cc1ccc(Cn2cc(C=CC(=O)O)nn2)cc1
Product: N#Cc1ccc(Cn2cc(C=CC=O)nn2)cc1
Yield: 41 %

Procedure:
3-[1-(4-aminomethylbenzyl)-1,2,3-triazol-4-yl]-propionic acid (m.p. 207°-210° c.; prepared by catalytic hydrogenation of 3-[1-(4-cyanobenzyl)-1,2,3-triazol-4-yl]-acrylic acid (m.p. 168°-170° C.) which is obtained by oxidation of the corresponding 3-[1-(4-cyanobenzyl)-1,2,3-triazol-4-yl]-acrolein (m.p. 152°-155° C.))
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[N:15]1([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Solvent: CCO
Product: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (2.00 g; 9.5 mmol) and piperazine (2.50 g; 29 mmol) in absolute ethanol was heated to 100° C. in a sealed tube for 4 h. The mixture was then allowed to cool to room temperature and evaporated. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 1.44 g of yellow colored 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 5 as the trifluoroacetate salt.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1CCCC1=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CCC2)n1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C3CCC3)n2)c(C(N)=O)nn1
Temperature: 120 °C
Yield: 25.1 %

Procedure:
In a 25 mL round bottom flask, a solution of 6-chloro-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxamide (281 mg, 925 μmol) in N-methyl-2-pyrrolidinone (3.5 mL) was treated with tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (397 mg, 1.85 mmol) and the mixture heated to 120° C. for 72 h. After cooling to room temperature the solvent was evaporated in high vacuum and residue was purified by flash column (spherical silica 20-45 μM, 80 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclobutylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (112 mg, 25.1% yield) as a light brown foam. 1H NMR (CHLOROFORM-d) δ: 11.49 (br. s., 1H), 8.38 (s, 1H), 8.12 (d, J=3.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 6.67 (d, J=7.2 Hz, 1H), 6.59 (d, J=7.9 Hz, 1H), 5.89-6.22 (m, 2H), 3.72-4.08 (m, 2H), 3.55 (quin, J=8.6 Hz, 1H), 1.76-2.11 (m, 4H), 1.19-1.74 (m, 19H); LC-MS 482.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH3:3].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[CH3:1][CH:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CC(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 9.9 %

Procedure:
The title compound (9.4 mg, 8%) was prepared from (4-{[(1-methylethyl)amino]sulfonyl}phenyl)boronic acid (49 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 2H, J=8.6 Hz), 7.66 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.9 Hz), 6.98 (d, 2H, J=8.8 Hz), 4.97-4.87 (m, 1H), 4.28-4.18 (m, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.58-3.45 (m, 1H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.37-1.27 (m, 3H), 1.25 (d, 6H, J=6.4 Hz), 1.11 (d, 6H, J=6.5 Hz); LRMS (ESI), m/z 475 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[S:16]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+]=[N-]>C(O)C.[Pd]>[C:19]1([S:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH2:5][CH2:4][NH2:1])[CH:8]=3)[NH:12][N:11]=2)(=[O:17])=[O:18])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=NCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: [Pd]
Solvent: CCO
Product: NCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reaction time: 1.25 h

Procedure:
To 5-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (1.34 g, 3.41 mmol) in hot ethanol (210 mL) was added 10% palladium on carbon (0.8 g). The reaction mixture was hydrogenated on the Parr apparatus for 1.25 hours, starting pressure 49 psi. It was then filtered over Celite and concentrated. The residue was purified by flash chromatography with 0.5% ammonium hydroxide/5.0% methanol in chloroform. Drying in vacuo at 63° C. for 20 minutes gave 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethylamine as a light yellow foam resulted (0.775 g, 57.0%). Methanol and ethereal hydrochloride were added. Drying in vacuo for 16 hours 68° C. yielded the hydrochloride as a yellow foam (0.825 g). Mass spectrum (−EI, [M−H]−) m/z 366. 1HNMR (500 MHz, DMSO-d6): δ14.22 (s, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.10 (s, br, 3H), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.33 (d, 1H, J=2.19 Hz), 7.13-7.16 (m, 1H), 4.21 (t, 2H, J=5.00 Hz), 3.23 ppm (s, 2H). Elemental Analysis for C19H17N3O3S.1.00 mol HCl.0.55 mol H2O: Calcd: C, 55.15; H, 4.65; N, 10.15; Found: C, 55.54; H, 4.90; N, 10.12.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)[C:22]([C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]=1[NH:35][C:36](OC1C=CC(Cl)=CC=1)=[O:37]>O1CCOCC1>[CH3:30][N:28]1[CH:29]=[C:25]([C:23]2[CH:24]=[C:19]3[C:20](=[CH:21][C:22]=2[C:31]([F:32])([F:33])[F:34])[NH:35][C:36](=[O:37])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]3=[O:17])[CH:26]=[N:27]1
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2cnn(C)c2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 90 °C
Reaction time: 19 h
Yield: 42 %

Procedure:
CH3SO2NHNH2 (130 mg, 2.4 equiv) and i-Pr2NEt (169 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-5-(1-methyl-1H-pyrazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (224 mg, 0.49 mmol) in dioxane (11 mL). The mixture was stirred for 19 h (TLC control) at 90° C. The mixture was evaporated to dryness. The crude product was triturated with hexanes and DCM. The formed precipitate was filtered and washed with hexanes to give N-[6-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (83 mg, 42%) as a white solid. ESI-MS: m/z 404 [M+H]+, 1H-NMR (DMSO-d6, 400 MHz) 7.91 (s, 2H), 7.57 (s, 1H), 7.54 (s, 1H), 3.88 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH2:15][CH2:14]C(C)(C)[CH2:12][CH:11]=2)[C:7]([NH:18][C:19]([C:21]2[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:28][Mg]Br.[CH2:31]1[CH2:35]OC[CH2:32]1>>[CH3:32][CH:31]1[CH2:35][CH2:14][CH2:15][C:10]([C:8]2[C:7]([NH:18][C:19]([C:21]3[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=3)=[O:20])=[CH:6][CH:5]=[C:4]([C:1]([OH:3])([CH3:28])[CH3:2])[N:9]=2)=[C:11]1[CH3:12]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1
Reactant: C1CCOC1
Product: CC1=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CCCC1C
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 5-cyano-1H-imidazole-2-carboxylic acid [6-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step, 6 mg, 0.016 mmol) in THF (1 mL) was added methylmagnesium bromide (MeMgBr) (3 M in THF, 41 μL, 0.072 mmol). After 20 min another 2.5 equivalents of MeMgBr was added and the reaction was allowed to warm to room temperature and quenched with saturated aqueous NaHCO3 (2 mL). The slurry was filtered through a 5-g Sep-Pak and concentrated in vacuo. The crude product was purified by silica gel chromatography (250-mg, 3-mL Supelco Si-tube, gradient CHCl3-2% CHCl3-MeOH) to afford 2.6 mg (43%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.44 (d, 1H, J=8.5 Hz), 7.90 (s, 1H), 7.42 (d, 1H, J=8.5 Hz), 5.86 (s, 1H), 2.39-2.37 (m, 2H), 1.99-1.94 (m, 2H), 1.51 (t, 1H, J=6.3 Hz), 1.43 (s, 6H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H25N5O2, 380.2 (M+H). found 380.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][CH:35]([C:37]([O:39]CC)=[O:38])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][CH:35]([C:37]([OH:39])=[O:38])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)COc1ccc(Br)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 52.7 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.3 mmol), NaOH (40 mg, 1 mmol), H2O (5 mL) and THF (5 mL) was heated at 80° C. for 2 h. Then THF was removed in vacuum. The water solution was acidified by concentrated hydrochloric acid (1.5 mL) to “pH” 2. The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 100 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH2:23]([N:30]1[C:40]([CH3:42])([CH3:41])[CH2:39][O:38][C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:30]1[C:40]([CH3:42])([CH3:41])[CH2:39][O:38][C:32]2([CH2:33][CH2:34][N:35]([C:9]([C:8]3[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH3:14])[CH:7]=3)=[O:11])[CH2:36][CH2:37]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: CC1(C)COC2(CCNCC2)CN1Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)C(C)(C)CO3)ccc1OC(C)C
Reaction time: 0.08 h
Yield: 70.3 %

Procedure:
A solution of 4-isopropoxy-3-methylbenzoic acid (31.0 mg, 0.161 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (61.3 mg, 0.161 mmol) in acetonitrile was treated with triethylamine (67 μL, 0.48 mmol) and stirred for 5 min. 8-Benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride (56.0 mg, 0.161 mmol) was added and the reaction mixture stirred for 3 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by chromatography (0-80% of ethyl acetate/hexanes) to provide (8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (51.0 mg, 70%) as colorless oil. ESI-MS m/z calc. 450.6. Found 451.3 (M+1)+; Retention time: 1.54 minutes (3 min run).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[C:19]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])[CH:18]=[C:17]([CH2:33]Br)[N:16]=1)=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([CH2:33][N:1]2[CH2:9][CH2:8][N:7]([CH2:33][C:17]3[CH:18]=[C:19]([C:21]4[C:22]([O:31][CH3:32])=[CH:23][C:24]([O:29][CH3:30])=[CH:25][C:26]=4[O:27][CH3:28])[CH:20]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[N:16]=3)[CH2:6][CH2:5][N:4]([CH2:33][C:17]3[N:16]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH:20]=[C:19]([C:21]4[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=4[O:31][CH3:32])[CH:18]=3)[CH2:3][CH2:2]2)[CH:18]=[C:19]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1)=[O:14])[CH3:11]
Reactant: C1CNCCNCCN1
Reactant: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CBr)n1
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CN2CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CC2)n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
1,4,7-triazacyclononane (31.5 mg) and compound 14 (0.3 g, 0.76 mmol) were dissolved in dry acetonitrile (20 mL) Potassium carbonate (0.17 g) was added and the mixture was refluxed overnight. The mixture was allowed to cool to room temperature, filtered and concentrated. Purification on silica gel (eluent CH2Cl2:EtOH:HOAc; 80:20:1, v/v/v) yielded the title compound (0.17 g, 62%). ESI-MS: [M+H]+ 1117.5 calc. for C60H73N6O15+ 1117.5
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:23]O>C(OCC)(=O)C>[CH3:23][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
3-Benzoyl-benzoic acid (5.12 g, 22.6 mmol) was stirred in methanol (45 mL) with conc. H2SO4 (2.0 mL) for 18 h at 60° C. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated to provide 3-benzoyl-benzoic acid methyl ester (5.4 g, 22.6 mmol) in quantitative yield as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[O:9][C@@H:10]1[O:18][C@H:17]([C:19]([O:21]C)=O)[C@@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12])(=[O:3])[NH2:2].[NH3:23]>CO>[C:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[O:9][C@@H:10]1[O:18][C@H:17]([C:19]([NH2:23])=[O:21])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12])(=[O:3])[NH2:2]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2nc[nH]c2C(N)=O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: N
Solvent: CO
Product: NC(=O)c1[nH]cnc1O[C@@H]1O[C@H](C(N)=O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.55 g of methyl 1-O-(5-carbamoyl-1H-imidazole-4-yl)-β-D-glucopyranuronate in 50 ml of dry methanol was saturated with ammonia (gas) cooling in an ice bath and the reaction mixture was stirred for 1.5 hours. Then the reaction mixture was heated to room temperature and was concentrated to a residue under reduced pressure. The residue was washed with methanol and ether, and then separated crystals were filtered off and dried to give 0.5 g of 1-O-(5-carbamoyl-1H-imidazole-4-yl)-β-D-glucopyranuronamide which was recrystallized from water-ethanol. m.p. 206° C. (dec.)
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C(C3C(C)=NN(C)C=3C)N=CC=4)=CC=2)CCC1.[OH:37][CH2:38][CH2:39][O:40][C:41]1[N:42]=[CH:43][CH:44]=[C:45]2[C:50](=[O:51])[C:49]([C:52]3[CH:57]=[CH:56][C:55]([C:58]4([NH:62]C(=O)OC(C)(C)C)[CH2:61][CH2:60][CH2:59]4)=[CH:54][CH:53]=3)=[C:48]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[O:47][C:46]=12>>[NH2:62][C:58]1([C:55]2[CH:54]=[CH:53][C:52]([C:49]3[C:50](=[O:51])[C:45]4[C:46]([O:47][C:48]=3[C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)=[C:41]([O:40][CH2:39][CH2:38][OH:37])[N:42]=[CH:43][CH:44]=4)=[CH:57][CH:56]=2)[CH2:59][CH2:60][CH2:61]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OCCO)nccc4c3=O)cc2)CCC1
Agent: Cc1nn(C)c(C)c1-c1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OCCO)nccc4c3=O)cc2)CCC1

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-2-phenyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl 1-(4-(8-(2-hydroxyethoxy)-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate was reacted to give the title compound. (10 mg, 62%). 1H NMR (400 MHz, CD3OD): δ 8.15 (d, 1H), 7.55 (d, 1H), 7.49-7.31 (m, 9H), 4.68-4.65 (m, 2H), 3.95-4.01 (m, 2H), 2.82-2.75 (m, 2H), 2.63-2.52 (m, 2H), 2.30-2.19 (m, 1H), 2.03-1.92 (m, 1H). LCMS (Method I): RT=3.83 min, [M+2]+=430.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[CH2:39]([N:46]=[C:47]=[S:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([NH:46][C:47]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:20]=[C:19]([CH2:21][O:22][C:23]5[CH:24]=[CH:25][C:26]([CH2:27][CH:28]6[S:32][C:31](=[O:33])[NH:30][C:29]6=[O:34])=[CH:35][CH:36]=5)[N:18]([CH3:37])[C:17]=4[CH:38]=3)[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[S:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Reactant: S=C=NCc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(NC(=S)NCc5ccccc5)c4c3)cc21
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) in anhydrous tetrahydrofuran (10 ml) was added benzyl isothiocyanate (0.24 g) and the mixture was stirred at room temperature for 5.5 hours and then at 50° C. for 9 hours. The reaction mixture was concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:1→3:1 as the eluant to afford the title compound (0.36 g, Rf=0.53: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=3:1).
Reaction SMILES: Cl[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][O-].[K+].S(=O)(=O)(O)O.[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][N:18]=1>C(O)C>[OH:23][C:21]1[CH:20]=[CH:19][N:18]2[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:16]=[C:17]2[CH:22]=1
Reactant: Nc1cc(O)ccn1
Reactant: CCOC(=O)C(Cl)=C[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(O)ccn12
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a chilled (0° C.) solution of potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (16.4 g, 86.3 mmol) in concentrated sulfuric acid (43.5 mmol) and ethanol (50 mL) was added 2-aminopyridin-4-ol (3 g, 27 mmol). The resulting mixture was warmed to ambient temperature and refluxed for 10 hours. The reaction was concentrated and suspended in EtOAc. The solids were isolated to afford 829 mg of pure product. The supernatant was concentrated, and subjected to chromatography on silica with 30% EtOAc/Hexanes as eluent to afford a second batch of desired product (5.8 g, 80% purity) as a brown, viscous oil.