Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=O)=O)=[CH:3][CH:2]=1.C(O)C.[NH2:23][NH2:24]>C(Cl)(Cl)Cl>[C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]2[NH:24][N:23]=[C:10]3[C:11]4[C:16]([CH2:17][C:9]=23)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:3][CH:2]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)C2Cc3ccccc3C2=O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1ccc(-c2[nH]nc3c2Cc2ccccc2-3)cc1

Procedure:
To a warm solution of 3.3 g. of the diketone of Step A in 33 ml. of ethanol and 10 ml. of chloroform is added 4 g. of hydrazine and the resulting solution is refluxed for 1 hr. It is then cooled and evaporated to dryness under reduced pressure. The crude solid residue obtained is crystallized from methanol to yield the product 3-(p-tolyl)-4H-indeno[1,2-c]-pyrazole (m.p. 250°-252°C).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[Cl:22]>CN(C)C=O.O>[Cl:22][C:13]1[CH:14]=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=[CH:17][C:12]=1[CH2:11][CH:5]([C:4](=[O:9])[CH3:3])[C:6](=[O:8])[CH3:7]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: CC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in oil, 0.30 g) was added portionwise to a stirred solution of pentane-2,4-dione (0.92 g) in N,N-dimethylformamide (8.0 mL) at 0-10° C. The resulting mixture was stirred at 0-10° C. for 20 minutes and then a solution of 1-bromomethyl-2-chloro-4-methanesulfonylbenzene (2.0 g) in N,N-dimethylformamide (3.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5 hours, and then diluted with water and this mixture was extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 to 3:7 by volume) gave title compound as a white solid, 1.2 g.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[NH2:15].C(N(CC)CC)C.[CH2:24]([O:26][CH2:27][C:28](Cl)=[O:29])[CH3:25]>ClCCl>[CH2:24]([O:26][CH2:27][C:28]([NH:15][C:6]1[C:7]2[N:8]([N:12]=[N:13][N:14]=2)[C:9]([CH3:11])=[CH:10][C:5]=1[NH:4][CH2:3][CH:2]([CH3:16])[CH3:1])=[O:29])[CH3:25]
Reactant: CCOCC(=O)Cl
Reactant: Cc1cc(NCC(C)C)c(N)c2nnnn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(NCC(C)C)cc(C)n2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of N7-(2-methylpropyl)-5-methyltetraazolo[1,5-a]pyridine-7,8-diamine (8.4 g, 38.1 mmol) in anhydrous dichloromethane (300 mL) was cooled to 0° C. under a nitrogen atmosphere, and triethylamine (5.3 mL, 38.1 mmol) was added. A solution of ethoxyacetyl chloride (4.7 g, 38.1 mmol) in dichloromethane (100 mL) was added dropwise over a period of five minutes, and a homogeneous solution resulted. After the solution was stirred for one hour, it was allowed to warm to room temperature, washed with water (2×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.2 g of 2-ethoxy-N-{7-[(2-methylpropyl)amino]-5-methyltetraazolo[1,5-a]pyridin-8-yl}acetamide as a light tan solid, m.p. 182–185° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[N:17]#[C:18][NH2:19].CC(C)([O-])C.[K+].Br[CH2:27][C:28]([C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)=[O:29]>C(#N)C.C(O)(C)(C)C>[NH2:17][C:18]1[N:19]=[C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[CH:8][CH:9]=2)[S:3][C:27]=1[C:28]([C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)=[O:29]
Reactant: N#CN
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc5c(c4)OCCO5)s3)cc2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
tert-Butanol (4 mL) and then 1-(4-isothiocyanatophenyl)-4-methyl piperazine (of Example 1; 219 mg, 1 mmol) were added to a solution of cyanamide (44 mg, 1.05 mmol) (Aldrich) in acetonitrile (5 mL). Potassium t-butoxide (1 M in tert-butanol; 1 mL, 1 mmol) was added and the solution was stirred for 30 min. 2-Bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (257 mg, 1 mmol) (Maybridge Chemical Company Ltd.) was added, and the solution was stirred at room temperature for 3 days. The yellow solid was filtered off and washed with cold acetonitrile and then ether to give [4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone (280 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH:6]=[CH:7][C:8](OC)=[O:9].[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.CCCCCC.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH:6]=[CH:7][CH2:8][OH:9]
Reactant: COC(=O)C=Cc1cccc(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C=CCO)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
The methyl m-methoxycinnamate was taken up in 50 ml of anhydrous toluene and chilled to -70° under nitrogen. Diisobutylaluminum hydride (54 ml; 83 mM; 1.54M in toluene) was added dropwise through a side-arm addition funnel. Some starting material remained as detected by TLC (35% ethyl acetate/hexane on silica gel) so a further 15 ml of diisobutylaluminum hydride was added. The reaction was allowed to warm to room temperature and then carefully quenched with water at 0° giving an emulsion. The emulsion was taken up in cold 2N aqueous hydrochloric acid and partitioned. The aqueous layer was extracted twice with ether and the combined organic layers were washed with 2.5N aqueous sodium hydroxide and with brine. The organic extracts were then dried over K2CO3 and stripped of volatiles in vacuo. The clear oil was chromatographed on one cartridge in a Water's Prep 500 with 35% ethyl acetate in hexane to give 9.38 g (71% yield) of m-methoxycinnamyl alcohol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8](OC)[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5])[CH3:2].[CH2:20]([Si](C)(C)C)[CH:21]=[CH2:22].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH2:22][CH:21]=[CH2:20])[N:7]1[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:5])[CH3:2]
Reactant: C=CC[Si](C)(C)C
Reactant: CCOC(=O)[C@@H]1CCC(OC)N1C(=O)OC(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C=CCC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of 9.25 g of α-methoxycarbamate 168 (33.8 mmol) in 100 ml of anhydrous CH2Cl2 was cooled to −78° C., added initially with 13.50 ml of allyltrimethylsilane (84.6 mmol, 2.5 eq.), followed by dropwise addition of 8.58 ml of BF3.OEt2 (67.7 mmol, 2 eq.) and stirring for one hour. Thereafter, 10 ml of H2O and 30 ml of saturated NaHCO3 solution were added at low temperature, the batch was allowed to come to 0° C., stirred for 30 min and thawed to RT. After separating the phases, the aqueous phase was extracted with 3×50 ml of CH2Cl2, the combined organic phases were washed with 30 ml of saturated NaCl solution and dried over MgSO4. After removing the solvent, the residue was purified using silica gel column chromatography (EE/CH 1:6) to obtain 6.83 g of allyl substitution product 169 (24.1 mmol, 71%) as a colorless oil (mixture of epimers, cis/trans 4:1).
Reaction SMILES: BrCCC1C(Cl)=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](CCBr)[C:12]=2[Cl:20])[CH:7]=CC=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[ClH:20].[Cl:20][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:6][CH2:7][NH:25][CH:22]([CH3:24])[CH3:23]
Reactant: Clc1c(CCBr)cccc1Oc1cccc(CCBr)c1Cl
Reactant: CC(C)N
Product: CC(C)NCCOc1ccccc1Cl
Product: Cl

Procedure:
Following the procedure of Example 11, 2-bromoethyl-2-chlorophenyl ether was reacted with isopropyl amine (excess) and the reaction mixture processed to give an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride and the hydrochloride salt recrystallized from methanol-diethyl ether, m.p. 118°-119.5° C. (75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][C@@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([NH2:54])(=[O:53])=[O:52])[CH:46]=1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:27]([S:26][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([CH2:30][C@@H:31]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:16][CH:15]=2)[CH:22]=[CH:21][C:20]=1[C:23]([NH:54][S:51]([C:47]1[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=1)(=[O:53])=[O:52])=[O:24])([CH3:28])[CH3:29]
Reactant: NS(=O)(=O)c1cccnc1
Reactant: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylic acid (500 mg) in N,N-dimethylformamide (5 ml) was added N,N′-carbonyldiimidazole (157 mg) and stirred at room temperature for 30 minutes. To the mixture were added 3-pyridinesulfonamide (153 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (145 μl) and stirred at room temperature for 3 hours. The reaction mixture was poured into 0.1N hydrochloric acid and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [2-[3′-(isopropylthio)-4′-[[(3-pyridylsulfonyl)amino]carbonyl]-4-biphenylyl]-ethyl][(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate (613 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH:9]([OH:11])=O.[C:12](=O)([O-])[O-:13].[Ca+2]>C(O)C>[CH:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH:9]=[O:11])=[O:13]
Reactant: O=CO
Reactant: Nc1ccncc1N
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: O=CNc1ccncc1NC=O

Procedure:
A stirred mixture of 3,4-diaminopyridine (10.0 g, 0.092 mol) and formic acid (20 ml) was neated under reflux for 2.5 hours. The resulting mixture was cooled and the formic acid was evaporated off under reduced pressure to yield a residue. The residue was dissolved in ethanol (300 ml) at 80° C. and the resulting solution was treated with calcium carbonate (lOg) and neutralized by stirring under reflux for 1 hour. The hot mixture was filtered and the residue was washed with hot ethanol (3×300 ml). The filtrate and washings were combined and the ethanol was evaporated off under reduced pressure to yield 3,4-diformylaminopyridine as a colorless solid. The 3,4-diformylaminopyridine was heated at 200-220° C. and 0.5 mm.Hg pressure in a Kugelrohr bulb-to-bulb distillation apparatus to yield a crude product as a distillate which solidified on cooling. The crude product was recrystallized from ethyl acetate to yield imidazo[4,5-c]pyridine as a colorless crystalline solid, having a melting point of 174-176° C. and the following physical characteristics:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:20][C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27]2)[N:23]([CH2:40][C:41]#[C:42][CH3:43])[C:22]=1[C:44](OCC)=[O:45].[C:49]1([CH2:59][NH2:60])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][CH:50]=1>COCCOC>[C:49]1([CH2:59][N:60]2[C:44](=[O:45])[C:22]3[N:23]([CH2:40][C:41]#[C:42][CH3:43])[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:27]4)=[N:25][C:21]=3[NH:20][C:2]2=[O:4])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][CH:50]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc(N)c1C(=O)OCC
Reactant: NCc1cccc2ccccc12
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2[nH]c(=O)n(Cc3cccc4ccccc34)c(=O)c21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.5 g triphosgene and 1.4 ml triethylamine are added successively to an ice-cooled solution of 2.0 g of ethyl 5-amino-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-3-(but-2-ynyl)-3H-imidazole-4-carboxylate in 35 ml dry 1,2-dimethoxyethane. After 2 h stirring at ambient temperature 0.76 ml naphth-1-ylmethylamine and a further 35 ml dry 1,2-dimethoxyethane are added. The reaction solution is stirred for a further 14 h at ambient temperature. Then the solution is evaporated down to approx. 20 ml and diluted with 150 ml dichloromethane. The organic phase is washed with 1 M hydrochloric acid and with aqueous sodium hydrogen carbonate solution and then dried over sodium sulphate. After the solvent has been eliminated the residue is dissolved in 100 ml of ethanol and combined with 0.41 g sodium ethoxide. The solution is stirred for 4 h at 60° C. After cooling to ambient temperature the reaction solution is neutralised with 1 M hydrochloric acid and the ethanol is evaporated off. Water is added and the precipitate is separated off, washed with ether and dried at 60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH3:18])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)c2ccccc2)ccc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(C(C)(O)c2ccccc2)ccc1Br
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-methoxyphenyl)-phenylmethanone (200 mg, 0.687 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.CN[CH:13]([NH:16][CH3:17])[CH2:14][OH:15].[C:18](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][N:16]([CH3:17])[CH2:13][CH2:14][O:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNC(CO)NC
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])cn1

Procedure:
A mixture of 7.93 g (50 mmol) of 2-chloro-5-nitropyridine, 4.9 g (55 mmol) of 2,2-dimethylaminoethanol and 4 g (29 mmol) of potassium carbonate in 50 mL of dimethylformamide was allowed to stand at room temperature with occasional shaking. The mixture was then poured into 200 mL of water and the resulting mixture was extracted three times with 30-mL portions of ethyl acetate. Drying over magnesium sulfate and evaporation of the solvent gave a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:11]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2].Cl.CCOC(C)=O>CO.C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:16]2[C:7]([C:8]3[CH:9]=[C:10]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:11]([C:17]4[CH:18]=[CH:19][C:20]([C:23]5([NH2:27])[CH2:24][CH2:25][CH2:26]5)=[CH:21][CH:22]=4)=[N:12][C:13]=3[CH:14]=[CH:15]2)=[N:6][N:5]=1)[CH3:2]
Reactant: CCOc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3ccn12
Temperature: 25 °C

Procedure:
tert-Butyl {1-[4-(3-ethoxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (9-1) (0.775 g, 0.133 mmol) was dissolved in MeOH (2 mL) and DCM (2 mL), and 4N solution of HCl in EtOAc (10 mL, 40 mmol) was added. The reaction mixture was then permitted to stir at room temperature, capped but not under an atmosphere of nitrogen. After 1 hour the reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were then combined, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1-[4-(3-ethoxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine (1-100) as an off-white solid. HRMS (M+H)+: observed=436.215, calculated=436.2132.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](OCC)(OCC)OCC.[NH2:21][C:22]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][NH:24][N:23]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[CH:11][NH:21][C:22]2[NH:23][N:24]=[CH:25][C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:4](=[O:5])[O:3]1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn[nH]c1NC=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
Meldrum's acid (15.3 g, 106 mmol) was dissolved in toluene (450 mL), triethyl orthoformate (17.6 mL, 106 mmol) was added, and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature, ethyl 3-amino-4-pyrazolecarboxylate (15 g, 96.7 mmol) was added, and the mixture was heated under reflux for 3 hr. The reaction mixture was allowed to cool to room temperature, and stirred at room temperature for 10 hr. The precipitated crystals were collected by filtration, washed with diisopropylether (100 mL), and dried under reduced pressure at 40° C. overnight to give the title compound (26.3 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17](C(OCC3C4C(=CC=CC=4)C4C3=CC=CC=4)=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)CC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1

Procedure:
4-(1-Fmoc-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.61 mmol) was stirred with 20% piperidine in methylene chloride for 40 min. The mixture was concentrated to dryness to give 4-piperidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester. It was then dissolved in tetrahydrofuran (5 mL), and triethylamine (308 mg, 3.05 mmol) and acetic anhydride (86 mg, 0.9 mmol) were added, respectively. After the reaction mixture was stirred for 2 h, water and ethyl acetate were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated to give 4-(1-acetyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester. It was dissolved in methylene chloride (7 mL), cooled with an ice bath and trifluoroacetic acid was added. The reaction mixture was stirred for 30 min, and the solvent was removed. The residue was triturated with diethyl ether and the solvent was removed to give 1-(4-piperazin-1-yl-piperidin-1-yl)-ethanone trifluoroacetate as a light-yellow foam (151 mg, 76%). LR-MS: 212 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:12])[CH:4]=1.[CH:13]([C:16]1[N:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=1)([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:12][C:21]([C:18]1[S:19][CH:20]=[C:16]([CH:13]([CH3:15])[CH3:14])[N:17]=1)=[O:22])(=[O:8])[NH2:9]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: COc1ccc(C(N)=O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 4-methoxy-2-aminobenzamide (5.6 g, 33.7 mmol), 4-isopropylthiazole-2-carboxylic acid (7.1 g, 42 mmol) and Hobt-hydrate (6.4 g, 42 mmol) in DMF (150 ml) was added EDAC (8.6 g, 45 mmol) and TEA (6.4 ml, 45 mmol) and the mixture was stirred overnight at room temperature. A 2.5% aqueous solution of citric acid (600 ml) was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine and saturated sodium hydrogencarbonate. The solution was dried over sodium sulphate and evaporated under reduced pressure. Yield: 9.0 g, 91%.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C.[CH:13]1(Br)[CH2:16][CH2:15][CH2:14]1.[C:18]([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>C(O)C.CN(C=O)C>[CH:13]1([CH2:18][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:12])=[CH:10][CH:9]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: BrC1CCC1
Agent: [Cs+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(OCC2CCC2)cc1

Procedure:
4-Hydroxybenzoic acid ethyl ester was alkylated with cyclobutyl bromide by standard methods (DMF, Cs2CO3), and the resulting ester was hydrolyzed by boiling with sodium hydroxide in aqueous ethanol. The product with the molecular weight of 206.24 (C12H14O3); MS (ESI): 207 (M+H+) was obtained in this way.
Reaction SMILES: [OH-].[Li+].[C:3]([C:6]1[CH:37]=[CH:36][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]3[C:19](=[O:30])[CH2:20][C:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])([CH3:23])[O:22][C:17]=3[C:16]=2[CH2:33][CH2:34][CH3:35])=[C:8]([CH2:38][CH2:39][CH3:40])[C:7]=1[OH:41])(=[O:5])[CH3:4]>O.O1CCCC1.CO>[C:3]([C:6]1[CH:37]=[CH:36][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]3[C:19](=[O:30])[CH2:20][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])([CH3:23])[O:22][C:17]=3[C:16]=2[CH2:33][CH2:34][CH3:35])=[C:8]([CH2:38][CH2:39][CH3:40])[C:7]=1[OH:41])(=[O:5])[CH3:4]
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)OC)CC3=O)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)O)CC3=O)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
A solution of 0.5 g (19.5 mmole) of lithium hydroxide in 10 ml of water was added to a solution of 2.2 g (3.9 mmole) of the title compound of Example 6 in 25 ml of tetrahydrofuran and 20 ml of methanol. After the reaction mixture was stirred for 3 hours at room temperature, the solvent was evaporated and water was added to the residue. After extracting with a small amount of diethyl ether, the aqueous layer was acidified with dilute hydrochloric acid and allowed to stand in the cold overnight. The solid was filtered, washed with water and recrystallized from ethyl acetate/hexane to yield 1.83g of the title compound, mp. 80°-83°. Structure assignment was confirmed by nmr and infrared spectra and by elemental analysis.