Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>C(OCC)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:30][CH:31]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethane sulfonic anhydride (32.2 mmol) was added dropwise over 5 minutes to a −40° C. pyridine (70 mL) solution of (4-hydroxy-phenyl)-acetic acid methyl ester (5.35 g, 32.2 mmol). The reaction was stirred at −40° C. for 10 minutes and then at 0° C. for 2 hours. The reaction was diluted with diethyl ether and washed with water and 2N hydrochloric acid. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a Biotage Flash 40M column eluting with ethyl acetate/hexanes (1:4) to provide the title compound as a clear, colorless oil, which crystallized upon standing 9.27 g, 97%). 1H NMR (400 MHz, CDCl3) δ7.37-7.34 (m, 2H), 7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4]C=1Cl.[NH4+:10].[C:11](#[N:13])C>>[NH2:10][C:5]1[N:4]=[C:11]([NH2:13])[N:1]=[C:8]([Cl:9])[N:7]=1
Reactant: CC#N
Reactant: [NH4+]
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Nc1nc(N)nc(Cl)n1
Temperature: 0 °C
Yield: 79 %

Procedure:
184.5 g (1.0 mol.) of cyanuric chloride were dissolved in 800 mL of acetonitrile at room temperature. Then, the solution was cooled to 0° C. The cooled solution was dropwise added with 303.7 g (5.0 mol.) of an aqueous 28-% ammonium solution over two hours while vigorously stirring in such a manner that the reaction temperature was kept less than 10° C. After the completion of the dropwise addition, the cooling was stopped and the mixture was stirred at room temperature for one hour. The mixture was gradually warmed and the mixture was further reacted at 45° C. for four hours. After cooling, the obtained product was separated through filtration and then, washed with a large amount of water. The filtered products were dried at 50° C. for six hours under vacuum to obtain 115 g of 2,4-diamino-6-chloro-1,3,5-triazine (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.C(OC(=O)C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
{5-Chloro-2-[(R)-4-(2-1-BOC-piperazin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine prepared in Step A was dissolved in dichloromethane (50 mL). 4N hydrochloric acid ethyl acetate solution (1.3 mL, 5.28 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM and ethylether to give the title compound (125 mg, Yield 55%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=O)(C)(C)C.[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>CO>[CH3:21][S:18]([CH2:16][CH2:17][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:14])[CH3:15])(=[O:20])=[O:19]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: C=CS(C)(=O)=O
Solvent: CO
Product: CC1(C)CNCCN1CCS(C)(=O)=O
Temperature: 65 °C
Reaction time: 96 h

Procedure:
A mixture of 3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.33 mmol) and methyl vinyl sulfone (510 μL, 619 mg, 5.83 mmol) in MeOH (15 mL) was heated to 65° C. for 5.5 h then stirred at room temperature for 96 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%) affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white waxy solid (550 mg, 74%). 1H NMR (CDCl3, 300 MHz): δ 3.47-3.40 (m, 2H); 3.15 (s, 2H); 3.09 (t, J=6.4 Hz, 2H); 3.03 (s, 3H); 2.89 (t, J=6.4 Hz, 2H); 2.58-2.50 (m, 2H); 1.45 (s, 9H); 1.04 (s, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11](=[O:14])(O)[O-:12].[Na+].[Cl-].O1C[CH2:20][CH2:19][CH2:18]1>O.C(OC(=O)C)C>[CH2:20]([O:12][C:11]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:14])[CH:19]=[CH2:18]
Reactant: C1CCOC1
Reactant: O=C([O-])O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 4 °C

Procedure:
A solution of L-glutamic acid (6.58 g) in tetrahydrofuran (80 ml) and water (80 ml) containing sodium bicarbonate (11.36 g) is cooled to 4° C. and stirred while adding allykoxycarbonyl chloride (4.25 ml) dropwise during 45 minutes. The mixture is then stirred overnight at room temperature and then diluted with ethylacetate (100 ml). The aqueous phase is separated, acidified with mineral acid and extracted with ethylacetate. The extract is washed with brine, dried and evaporated to give N-allyloxycarbonyl-L-glutamic acid, 8.9 g.
Reaction SMILES: C(CN(CC[N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])CC(O)=O)(O)=O.[N:30]1C=CC=[CH:32][CH:31]=1.[C:36]([O:39][C:40](=[O:42])[CH3:41])(=[O:38])[CH3:37]>>[O:38]=[C:36]1[CH2:37][N:30]([CH2:31][CH2:32][CH:26]([NH:12][CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[C:27]([OH:29])=[O:28])[CH2:41][C:40](=[O:42])[O:39]1
Reactant: CCOC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Product: CCOC(=O)CN(CCNC(CCN1CC(=O)OC(=O)C1)C(=O)O)CC(=O)O
Reaction time: 72 h

Procedure:
A suspension of 21.2 g (50 mmol) of N3,N6 -bis-(carboxymethyl)-N9 -(ethoxycarbonylmethyl)-3,6,9-triazaundecanedioic acid (J. Pharm. Sci. 68, 1979, 194) in 250 ml of acetic anhydride is stirred, after the addition of 42.2 ml of pyridine, for three days at room temperature. Then the precipitate is suctioned off, it is washed three times, each time with 50 ml of acetic anhydride and then stirred up for several hours with absolute diethylether. After suctioning off, washing with absolute diethylether and drying in a vacuum at 40° C., 18.0 g (89% of theory) of a white powder with a melting point of 195°-196° C. is obtained.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.O.C(OCC)(=O)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 24.8 %

Procedure:
A solution of 3.03 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 45 mL of trifluoroacetic acid was stirred for 1 hour and 30 minutes at room temperature. The reaction mixture was cooled with ice, added with 30 mL of water and 30 mL of ethyl acetate, and adjusted to pH 10 with a 2 mol/L sodium hydroxide aqueous solution. The organic layer was separated and the aqueous layer was extracted 7 times with ethyl acetate. The organic layer was combined therewith and the solvent was concentrated to 10 mL under reduced pressure, whereby insoluble matter was filtered out. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [eluate; chloroform:methanol=92:8], recrystallized from 3 mL of ethyl acetate to give 0.611 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one (anhydrate) as a light yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[CH:18]=[CH2:19].Cl.CCOCC>O1CCCC1.CCCCCC>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:19][CH:18]=[CH2:17])[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: C=CCBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C=CCC(C(=O)O)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of diphenylacetic acid (250 g., 1.17 mol ) in 2.4 L of tetrahydrofuran was stirred at 0° C. under argon while 0.94 L of a 2.5M solution on n-butyllithium in hexane was added dropwise. After 1 hour, allyl bromide (142.5 g, 1.17 mole) was added in one portion. After 15 minutes, 500 mL of 10% hydrochloric acid was added, along with ether (2 L). The layers were separated, the aqueous layer extracted with ethyl ether (1×250 mL), the organic layers combined, washed with brine, dried (MgSO4), and filtered. Concentration afforded 296 g (99%) of an off-white solid, mp 134°-137° C. 1H NMR (CDCl3)δ 7.3 (m, 10H), 5.6 (m, 1H), 4.9 (bs, 2H), 3.2 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH:16]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1)[CH:17]=O>C(O)(C)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:16]([C:19]4([C:22]5[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=5)[CH2:20][CH2:21]4)=[CH:17][N:14]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(C(Cl)C=O)CC2)cc1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc(C2(c3cnc4ncc(-c5ccc(F)cc5)nn34)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine (20.1 mg, 0.106 mmol) and chloro[1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (53 mg, 0.24 mmol) in isopropyl alcohol (0.6 mL) was heated to 90° C. overnight. After cooling, the mixture was diluted with methanol and was purified by mass-guided RP-HPLC to afford the desired product. LCMS: (M+H)=361.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][C:38]=1[CH3:39].O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:37][C:38]=2[CH3:39])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3nc(-c4ccccc4)oc3C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (260 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (622 mg, yield: 88%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[OH:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][NH2:41]>>[OH:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][NH:41][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: CC(C)(CN)CO
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: CC(C)(CO)CNC(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 3-hydroxy-2,2-dimethylpropylamine according to Procedure K: mp>230° C.; Anal. Calcd for C20H23N5O5S: C, 53.92; H, 5.20; N, 15.72. Found: C, 54.04; H, 5.17; N, 15.77.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1.O>C(O)CCC>[N:23]1[CH:3]=[C:2]([CH2:5][C:6]2[CH:16]=[CH:15][C:9]3[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=3[CH:7]=2)[N:18]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:17]2
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: Nc1cccnn1
Solvent: O
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4cccnn34)cc2s1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (500 mg, 1.8 mmol) from Step 4 of Example 117 and pyridazin-3-amine (350 mg, 3.6 mmol) in 1-butanol (20 mL) was heated at reflux for 15 h. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL×3) and the combined organic layers were washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 5% MeOH in DCM to afford 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (460 mg, 80%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ 8.32 (dd, J=4.5, 1.5 Hz, 1H), 7.94 (dd, J=9.3, 1.5 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (m, 1H), 4.45 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1.[NH3:15].O>CCO>[CH:11]1([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([NH2:15])[CH:3]=[C:4]3[CH:10]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Clc1cc2cc(C3CCC3)[nH]c2cn1
Reactant: N
Solvent: CCO
Solvent: O
Product: Nc1cc2cc(C3CCC3)[nH]c2cn1
Temperature: 180 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To the solution of 5-chloro-2-cyclobutyl-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.97 mmol) in EtOH (10 mL) and NH3.H2O (30 mL) was added CuSO4.5H2O (30 mg, 0.12 mmol). The reaction mixture was stirred under 3 MPa at 180° C. for 16 h. The mixture was extracted with ethyl acetate (3×30 mL). The extract was dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% MeOH in ethyl acetate as eluant) to afford the pure 2-cyclobutyl-1H-pyrrolo[2,3-c]pyridin-5-amine (40 mg, 22% yield). 1H NMR (300 MHz, MeOH) δ: 8.02 (s, 1H), 6.72 (s, 1H), 6.11 (s 1H), 3.72-3.60 (m, 1H), 2.47-1.90 (m, 6H). MS (ESI): m/z [M+H+] 188.1.
Reaction SMILES: [CH3:1][C:2]1[O:9][C:7](=[O:8])[CH:6]([C:10]([CH3:12])=O)[C:4](=[O:5])[CH:3]=1.[NH2:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1.C1(C)C=CC=CC=1>O>[CH3:12][C:10]1[N:13]([CH:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(=O)c(C(=O)O)c(C)n1C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C

Procedure:
A 1-liter, 3-neck, round-bottom flask was equipped with a mechanical stirrer, thermometer, and a Dean-Stark water trap topped with a water cooled condenser. The flask was charged with a mixture of 80.5 g (0.479 mol) dehydroacetic acid, 75.0 g (0.479 mol) 4-amino-2,2,6,6-tetramethylpiperidine, and 600 ml toluene. The stirred mixture in the flask was heated to the boiling point by means of an oil bath and the water formed during the reaction was collected in the trap. After 6 hours of reflux a total of 7.0 ml water had been collected and the flask and its contents cooled to room temperature. The mixture deposited crystals on standing which were collected by vacuum filtration. Reduction of volume of toluene in the filtrate caused a deposit of a second crop of crystals. The combined crystals were recrystallized from a 65/35 mixture of hexane/benzene to give 111 g (75.6%) of a white to colorless crystalline solid (M.P. 174° C.). The chemical structure and purity of these crystals were verified by mass spectroscopy, nuclear magnetic resonance spectroscopy; and by elemental analysis.
Reaction SMILES: ClC1C=CC(C(O)=O)=CC=1[N+]([O-])=O.[CH3:14][C:15]1([CH3:23])[CH2:20][CH:19]([CH3:21])[CH2:18][CH:17]([NH2:22])[CH2:16]1.[Cl:24][C:25]1[CH:62]=[CH:61][C:28]([C:29]2[C:34]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:45]5N(CC)[C:48]6[CH:52]=[CH:53][C:54]([C:56]([OH:58])=[O:57])=[CH:55][C:47]=6[N:46]=5)[CH:41]=4)[N:36]=3)=[CH:33][C:32]([O:59][CH3:60])=[CH:31][CH:30]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]2[C:34]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:45]5[N:22]([CH:17]6[CH2:18][CH:19]([CH3:21])[CH2:20][C:15]([CH3:23])([CH3:14])[CH2:16]6)[C:48]6[CH:52]=[CH:53][C:54]([C:56]([OH:58])=[O:57])=[CH:55][C:47]=6[N:46]=5)[CH:41]=4)[N:36]=3)=[CH:33][C:32]([O:59][CH3:60])=[CH:31][CH:30]=2)=[CH:61][CH:62]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: CC1CC(N)CC(C)(C)C1
Agent: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CC(C)CC(C)(C)C4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and 3,3,5-trimethylcyclohexylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][NH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][C:11]([NH2:13])=[O:12])=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(NNC(N)=O)cn1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(NC(N)=O)c2ccc(OC)nc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a suspension of 2-(6-methoxypyridin-3-yl)hydrazinecarboxamide (17 g, 93.3 mmol) in 100 mL of toluene, pyridine (15.1 mL, 187 mmol) and then a solution of 4-methoxybenzoyl chloride (15.9 g, 93.3 mmol) in 50 mL of toluene were added. The mixture was refluxed with stirring for 1 hour. After cooling at 80° C., 75 mL of water was added to the mixture. After vigorous shaking, an insoluble material was isolated by filtration, washed with water and toluene, dried in vacuo to give 2-(4-methoxybenzoyl)-2-(6-methoxypyridin-3-yl)hydrazinecarboxamide (8.5 g, 28.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[N:30]1([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[CH:42][CH:41]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: Nc1ccc(CN2CCOCC2)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCOCC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.28 g, 0.068 mmol) and 4-morpholin-4-ylmethyl-phenylamine (0.013 g, 0.068 mmol) were combined in i-PrOH (1 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 22 mg (62%) of 8-indan-5-yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.38 (br s, 1H), 8.55 (s, 1H), 7.44 (d, 2H, J=7.6 Hz), 7.05-7.30 (m, 5H), 4.40 (q, 2H, J=7.1 Hz), 3.71 (br s, 4H), 3.43 (s, 2H), 3.09 (t, 2H, J=7.5 Hz), 3.02 (t, 2H, J=7.2 Hz), 2.42 (br s, 4H), 2.21-2.31 (m, 2H), 1.40 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NNc1ccccc1Cl
Solvent: CCN(CC)CC
Product: Clc1nc(NNc2ccccc2Cl)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-(2-chlorophenylhydrazino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-chlorophenylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: CO[C:3]1[C:4](C)=[C:5](C)[C:6]2[O:11][C:10](CCN3CCNCC3)(C)[CH2:9][CH2:8][C:7]=2[C:21]=1C.O1CCCC1.C([Li])CCC.O>CCCCCC>[O:11]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:21][C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCNCC1)O2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C

Procedure:
A solution composed of 2 g (6.02 mmol) of the 3,4-dihydro-6-methoxy-2-[2-(piperazin-1-yl)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained by the process of Example 12 and 50 ml of tetrahydrofuran was cooled to -40° C. in a nitrogen atmosphere and, to this solution, 4.7 ml of a 15% solution of n-butyllithium in hexane was added gradually. The resultant mixture was stirred at -40° C. for 30 minutes. Then, 6.65 millimoles of the halogenated terpene compound (X') was added gradually thereto, and the resultant mixture was stirred at -40° C. for 30 minutes. After raising the temperature gradually to room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The ether layer was dried over anhydrous sodium sulfate, and low-boiling substances were distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the corresponding 3,4-dihydrobenzopyran derivative. The yield and physical characteristics for each derivative thus obtained are shown in Table 19.