Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[NH:15][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>CCO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Yield: 97.3 %

Procedure:
A 95:5 EtOH/H2O solution (5.0 mL) containing methyl 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (120 mg, 0.51 mmol) and NaOH (1.53 mol) was refluxed for 2 h whereupon the EtOH was removed in vacuum. After removal of traces of EtOH by azotroping twice with water, acidification to pH 3 with 1 M HCl generated a white precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuum to give 110 mg (98%) of the title compound as a white solid. MS (ESI) 222 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:16][CH:15]=[CH:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[N:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]OS(C)(=O)=O)=[C:26]([O:37][CH3:38])[CH:25]=1>CN(C)C=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:16]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH:14]=[CH:15]2)=[C:26]([O:37][CH3:38])[CH:25]=1
Reactant: O=c1cc(-c2ccncn2)nc2[nH]ccn12
Reactant: COc1cc(F)ccc1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1CCn1ccn2c(=O)cc(-c3ccncn3)nc12
Temperature: 70 °C

Procedure:
A suspension of 0.4 g (1.88 mmol) of 7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one in 10 ml of anhydrous N,N-dimethylformamide was treated with 337 mg (2.44 mmol) of potassium carbonate and the resulting mixture was heated at 70° C. for 30 min. 605 mg (2.44 mmol) of methanesulfonic acid 2-(4-fluoro-2-methoxy-phenyl)-ethyl ester was added and the reaction mixture was heated at 80° C. during 16 h.
Reaction SMILES: C([O:8][NH:9]C(C1N=CC2N(CC3C=CC(F)=CC=3)C=NC=2C=1)=O)C1C=CC=CC=1.[F:29][C:30]1[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:31]=1[CH2:32][N:33]1[C:37]2=[CH:38][N:39]=[C:40]([C:42]([OH:44])=O)[CH:41]=[C:36]2[CH:35]=[C:34]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]>>[F:29][C:30]1[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:31]=1[CH2:32][N:33]1[C:37]2=[CH:38][N:39]=[C:40]([C:42](=[O:44])[NH:9][OH:8])[CH:41]=[C:36]2[CH:35]=[C:34]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ncc2n1Cc1ccc(F)cc1F
Reactant: O=C(NOCc1ccccc1)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Product: CCOC(=O)c1cc2cc(C(=O)NO)ncc2n1Cc1ccc(F)cc1F

Procedure:
Ethyl 1-(2,4-difluorobenzyl)-5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxyl ate. The title compound can be prepared by alkylation of ethyl 5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (prepared according to J.-F. Rousseau, R. H. Dodd, X. Doisy, P. Potier, Heterocycles 1989, 28, 1101-1113) and 2,4-difluorobenzyl bromide in a manner similar to step (a) in Example 1. (b) 1-(2,4-Difluorobenzyl)-(2-ethoxycarbonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound can be prepared by oxidation of ethyl 1-(2,4-difluoro-benzyl)-5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate according to the procedure by R. H. Dodd, M. Le Hyaric, Synthesis 1993, 295-287. (c) Ethyl 1-(2,4-Difluorobenzyl)-5-hydroxycarbamoyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate. The title compound can be prepared from 1-(2,4-difluorobenzyl)-(2-ethoxycarbonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid following in a manner similar to step (c ) in Example 1.
Reaction SMILES: B.[Na].[C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:25]C(=O)C)=[C:11]([CH:24]=1)[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[O:13])(=[O:5])[CH3:4]>CO>[C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([OH:25])=[C:11]([CH:24]=1)[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[O:13])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(OC(C)=O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Agent: B
Agent: [Na]
Solvent: CO
Product: CC(=O)Nc1ccc(O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Yield: 102.2 %

Procedure:
1.5 g of boron hydride and sodium were added to a suspension of 1.5 g of the product of Step B in 150 ml of methanol and the mixture was refluxed for 2 hours. The methanol was partially removed under reduced pressure at 50° C. and the mixture was diluted with 200 ml of water and 200 ml of ethyl acetate. The mixture was extracted with ethyl acetate and the extracts were dried and evaporated to dryness under reduced pressure at 50° C. to obtain 1.35 g of 5-acetylamino-2-hydroxy-N-(1H-indol-4-yl)-benzamide which was used as is for the next step.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:8].Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]([CH3:29])=[N:27][NH:26][C:25]2=[O:30])=[CH:20][CH:19]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.[Cu](Cl)Cl>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([O:16][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[C:28]([CH3:29])=[N:27][NH:26][C:25]3=[O:30])=[CH:22][CH:23]=2)[CH:13]=[CH:14][CH:15]=1)[CH3:8]
Reactant: CCOc1cccc(O)c1
Reactant: Cc1n[nH]c(=O)n1-c1ccc(Br)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CCOc1cccc(Oc2ccc(-n3c(C)n[nH]c3=O)cc2)c1
Yield: 6.6 %

Procedure:
To cesium carbonate (641 mg, 1.968 mmol, 2 equiv) was added 3-ethoxyphenol (272 mg, 1.968 mmol, 2 equiv) in 4 mL of NMP. The reaction mixture was degassed and filled with nitrogen 3 times (3 cycles vacuum/nitrogen). 4-(4-bromophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 22, 250 mg, 0.984 mg, 1 equiv), 2,2,6,6-tetramethyl-3,5-heptanedione (18 mg, 0.098 mmol, 0.1 equiv) and copper chloride (58 mg, 0.590 mmol, 0.6 equiv) were added. The reaction mixture was degassed and filled with nitrogen 3 times (3 cycles vacuum/nitrogen) and then warmed to 120 C under nitrogen overnight. The reaction mixture was diluted with dichloromethane and filtered. Volatiles were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (20.2 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[F:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=O.N>>[F:13][C:14]1[C:15]([C:16]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: O=C(Cl)c1cccnc1F
Reactant: N#Cc1cccc(C(N)=NO)c1
Agent: N
Product: N#Cc1cccc(-c2noc(-c3cccnc3F)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 2-fluoronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 1H), 7.95 (m, 1H), 8.17 (m, 1H), 8.17 (m, 1H), 8.43 (m, 1H), 8.6 (m, 1H), 8.8 (m, 1H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]NC3N(C)C4C=NC=CC=4N=3)[CH2:27][CH2:26]2)=[CH:10][CH:9]=1.O1C=CC=C1C[N:50]1C2C=CC=C[C:53]=2[N:52]=[C:51]1[NH:59][CH:60]1[CH2:65][CH2:64][N:63](CCN=C=S)[CH2:62][CH2:61]1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:53][NH:52][C:51]3[NH:59][C:60]4[CH:61]=[CH:62][N:63]=[CH:64][C:65]=4[N:50]=3)[CH2:27][CH2:26]2)=[CH:12][CH:13]=1
Reactant: S=C=NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: Cn1c(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc2ccncc21
Agent: O=C(O)C(=O)O
Product: Fc1ccc(Cn2c(NC3CCN(CCCNc4nc5cnccc5[nH]4)CC3)nc3ccccc32)cc1

Procedure:
N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-3-methyl-3H-imidazo[4,5-c]pyridin-2-amine ethanedioate(1:3) monohydrate; mp. 242.3° C. (compound 123).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.OO.Cl>CO.O>[CH2:1]([O:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](OCc1ccccc1)C(=O)O
Reaction time: 24 h

Procedure:
To the above methyl (2S)-2-benzoxy-4-methylpentanoate (0.69 g, 2.92 mmol) in MeOH/H2O (5 mL/1 mL) was added LiOH.H2O (0.28 g, 11.7 mmol) and 30% H2O2 (0.3 mL, 11.7 mmol). After stirring the reaction mixture for 24 h, the mixture was treated with 1 N HCl (pH=3) and the methanol was removed in vacuo. The aqueous layer was extracted with EA (4×15 mL). The combined organic layers were washed with 1 N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated. (2S)-2-benzoxy-4-methylpentanoic acid was isolated as a colorless oil (0.65 g, 100%): 1H NMR (CDCl3, 300 MHz) δ 0.82-1.60 (m, 6H), 1.53-1.62 (m, 1H), 1.73-1.90 (m, 2H), 3.99-4.50 (m, 1H), 4.46 (d, 1H, J=12.0 Hz), 4.72 (d, 1H, J=12.0 Hz) 7.10-7.26 (m, 5H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[C:26]([C:28]1([C:31](O)=O)[CH2:30][CH2:29]1)#[N:27].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CCOC(C)=O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:31]([C:28]5([C:26]#[N:27])[CH2:29][CH2:30]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C2(C#N)CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (73 mg), 1-cyanocyclopropanecarboxylic acid (25.1 mg) and N,N-diisopropylethylamine (0.11 ml) in DMF (2 ml) was added HATU (86 mg), and the mixture was stirred at room temperature overnight. The mixture was poured into a mixture of EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, and concentrated. Then the resulting residue was heated in AcOH (1 ml) at 90° C. for 1 h. The mixture was concentrated, and poured into saturated NaHCO3. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (8 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=1.C(N(CC)CC)C.O>O1CCCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:12](=[O:13])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH3:15])=[CH:20][CH:19]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Reactant: COc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COC(=O)C(C)c2ccc(CC(C)C)cc2)cc1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a mixture of 2.24 g of 2-(p-isobutylphenyl)propionic acid chloride and 2.10 g of p-methoxybenzyl alcohol in 20 ml of tetrahydrofuran was added 1.50 g of triethylamine under cooling and the whole was stirred for 2 hours. After the reaction was complete, an insoluble matter produced was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. To the residue thus obtained was added water and the resulting mixture was extracted with ether. The ether layer separated was washed with successive, 5% sodium carbonate solution, 5% hydrochloric acid solution and water, and then dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.81 g of 2-(p-isobutylphenyl)propionic acid-p-methoxybenzyl ester as a colorless oil, boiling at 149°-151° C./0.1 mmHg. Analysis-Calculated for C21H26O3 : C, 77.27; H, 8.03. Found: C, 77.11; H, 8.12.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.S1CCC(=O)CC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:21][C:22]([F:33])([F:32])[C:23]1[C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[S:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:29](=[O:30])[C:28]2[C:23]([C:22]([F:33])([F:21])[F:32])=[CH:24][CH:25]=[N:26][CH:27]=2)[CH2:3][CH2:4]1
Reactant: O=C(Cl)c1cnccc1C(F)(F)F
Reactant: NC1CCSCC1
Agent: O=C1CCSCC1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCSCC1)c1cnccc1C(F)(F)F
Yield: 51.3 %

Procedure:
Analogously to Example A, equimolar amounts of 4-aminotetrahydrothiopyran (prepared from tetrahydrothiopyran-4-one via the corresponding oxime and subsequent reduction with lithium aluminum hydride in tetrahydrofuran) and 4-trifluoromethylnicotinoyl chloride were reacted in the presence of triethylamine. This gave, after silica gel chromatography (ethyl acetate), the amide as a colorless solid of melting point 161-163° C. (Yield 51.3% of theory).
Reaction SMILES: Cl.[C:2](N)(=[NH:5])[CH2:3][CH3:4].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1>>[NH:5]=[C:2]([N:15]([C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:18][CH:17]=1)[NH2:16])[CH2:3][CH3:4]
Reactant: CCC(=N)N
Reactant: COc1ccc(C(=O)NN)cc1
Agent: Cl
Product: CCC(=N)N(N)C(=O)c1ccc(OC)cc1
Yield: 150.7 %

Procedure:
Prepared from 4.90 g (45 mmol) propioamidine hydrochloride and 5.00 g (30 mmol) 4-methoxy-benzoic acid hydrazide analogously to the method described for intermediate product 1a). After the ethanol has been distilled off, 10.0 g crude product is obtained that is reacted without any further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])(=[O:24])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Oc1cccc(OCC2CCCNC2)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
2-Chlorobenzenesulfonic acid 3-[[N-(tert-butoxycarbonyl)piperidin-3-yl]-methoxy]phenyl ester (482 mg, 1.0 mmol), as prepared in the preceding step, was treated with 30 mL of 4N HCl in 1,4-dioxane and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (5% methanol in methylene chloride to 5% methanol in methylene chloride saturated with NH3) to give the title compound as a white foam (315 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ 1.46 (t, 1H), 1.94 (m, 3H), 2.45 (bs, 1H), 2.79 (q, 2H), 3.51 (dd, 2H), 3.75 (t, 1H), 3.83 (t, 1H), 4.63 (bs, 1H), 6.69 (m, 2H), 6.74 (dd, 1H), 7.16 (t, 1H), 7.39 (t, 1H), 7.62 (m, 2H), 7.95 (dd, 1H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C18H20 NO4SCl: 382.1 (M+H). Found: 382.3.
Reaction SMILES: CN1CCCC1.C=C(OC(=O)[N:12]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[C:29]([NH:31][C:32](OC(C)=C)=[O:33])[C:28]([F:38])=[CH:27][C:26]=3[CH3:39])[C:20]([CH3:24])=[N:21]2)=[CH:16][N:15]=1)[CH3:13])C.[CH2:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCOCC1>[F:38][C:28]1[CH:27]=[C:26]([CH3:39])[C:25]([C:19]2[C:20]([CH3:24])=[N:21][C:22]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:12][CH3:13])[CH:23]=3)=[CH:30][C:29]=1[NH:31][C:32]([NH:49][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:33]
Reactant: NCCc1ccccc1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)C(=O)OC(=C)C)cc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCc4ccccc4)c(F)cc3C)cc2cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Add 1-methylpyrrolidine (0.075 mL, 0.717 mmol) to a solution of prop-1-en-2-yl(3-(4-fluoro-2-methyl-5-(((prop-1-en-2-yloxy)carbonyl)amino)phenyl)-2-methyl-1,6-naphthyridin-7-yl)(methyl)carbamate (0.333 g, 0.717 mmol) and phenethylamine (0.091 g, 0.753 mmol) in dioxane (6 mL) and heat at 50° C. overnight. Cool to RT, add satd. NaHCO3, extract with EtOAc (3×), dry the combined organics over MgSO4 and concentrate to dryness. Dissolve the residue in dioxane (10 mL), add NaOH (1.0M, 2 mL), stir at RT for 2 h, then heat to 50° C. overnight. Add NaOH (3M, 0.5 mL), heat the mixture at 55° C. for 24 h, then add additional NaOH (3M, 0.25 mL) and heat at 60° C. for 24 h. Cool the mixture to RT, add brine, extract with EtOAc (3×), dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford 1-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)-3-phenethylurea (245 mg, 77%). MS(ESI) m/z: 444.2 (M+H+). Add 0.1N HCl (6.08 mL, 0.608 mmol) to a suspension of 1-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)-3-phenethylurea (0.245 g, 0.552 mmol) in MeCN (2 mL), sonicate for 5 min, freeze, lyophilize and dry to afford the title compound (244 mg, 92%) as an orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.32-7.17 (m, 6H), 6.66 (m, 2H), 3.29 (m, 2H), 2.91 (s, 3H), 2.71 (t, J=7.1 Hz, 2H), 2.51 (s, 3H), 2.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@@H:11]2[CH3:25])=[O:9])=[C:4]([C:28]([OH:30])=O)[CH:3]=1.ClC(OCC(C)C)=O.[CH3:39][N:40]1CCOCC1.CN.O1CCCC1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@@H:11]2[CH3:25])=[O:9])=[C:4]([C:28]([NH:40][CH3:39])=[O:30])[CH:3]=1
Reactant: CN1CCOCC1
Reactant: C[C@@H]1CN(C(=O)COc2ccc(Cl)cc2C(=O)O)[C@@H](C)CN1Cc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@@H](C)N(Cc2ccc(F)cc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
To a solution of (trans)-1-((4-chloro-2-carboxyphenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine (0.217 g, 0.50 mmol) in a solution of tetrahydroduran (5 mL) at 0° C. was added isobutyl chloroformate (0.075 g, 0.55 mmol) and N-methylmorpholine (0.0556 g, 0.55 mmol). The resulting mixture was stirred at 0° C. for 20 min, resulting in formation of a white precipitate. A solution of methylamine in tetrahydrofuran (0.25 mL, 2.0 M, 0.50 mmol) was then added and the mixture stirred for 30 min more, at which time it was concentrated of volatiles in vacuo. The resulting residue was dissolved in ethyl acetate and washed with water, then brine, dried over MgSO4, filtered and concentrated to 0.208 g of a foam. This was dissolved in ethyl acetate and treated with 1 M ethereal HCl solution (excess). The resulting solid was collected by filtration and washed with ethyl acetate. Drying in vacuo afforded 0.19 g of (trans)-1-((4-chloro-2-(methylaminocarbonyl)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine as a white solid; NMR (DMSO-d6) 10.8 (br d, 1), 9.2 (br s, 1), 7.8 (s, 2), 7.7 (m, 1), 7.6 (m, 1), 7.3 (m, 3), 5.4 (d, 1), 5.0 (m, 2), 4.7 (m, 1), 4.3 (m, 3), 4.0 (m, 1), 3.6 (m, 2), 2.8 (s, 3), 1.4 (m, 3), 1.3 (m, 3) ppm.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH:30]=[CH:29]2)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 4-((6-bromopyridin-3-yl)amino)piperidine-1-carboxylate and 5-(methylsulfonyl)-1H-indole; MS: 415.2 (M−56).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-phenylalanine methyl ester hydrochloride (4.31 g), p-anisaldehyde (2.45 ml), anhydrous magnesium sulfate (5.19 g) and triethylamine (2.9 ml) were added to methylene chloride (200 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, ethyl acetate (150 ml) was added to the residue. The solid was separated again by filtration, and the solvent was distilled off under reduced pressure to quantitatively obtain desired N-(p-methoxyphenylmethylene)-L-phenylalanine methyl ester (5.94 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)CCC>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:28]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCCC2
Solvent: CCCCO
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCCCC4)cc1

Procedure:
A mixture of 2.24 g of ethyl 4-chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-carboxylate and 1.16 g of 4-methoxyphenylhydrazine is stirred and heated at reflux under a nitrogen atmosphere for 20 hours in 20 ml of n-butanol. The solvent is then evaporated under reduced pressure and the residual material stirred with 20 ml of 1N sodium hydroxide, ether, and water. The layers are separated, the aqueous phase is extracted with ether and then treated with an aqueous solution of 1.07 g of ammonium chloride. The precipitate is filtered off and washed with water to give 2-(4-methoxyphenyl)-2,3,6,7,8,9,10,11-octahydrocycloocta[b]pyrazolo[3,4-d]pyridin-3(5H)-one, m.p. 275°-277°, the compound of formula II wherein n represents the integer 6, R4 and R5 represent hydrogen, and R1 represents p-methoxyphenyl. Further purification gives m.p. 283°-285°.