Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:5][C:6](=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])[CH3:4].[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[OH:29])(=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: O=C(O)c1ccccc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 4.2 mmol), 2-hydroxybenzoic acid (0.57 g, 4.2 mmol) and imidazole (0.29 g, 4.2 mmol) in EtOAc (40 mL) at 0° C. was added a solution of DCC (0.87 g, 4.2 mmol) in EtOAc (40 mL). The mixture was allowed to warm to RT, stirred (16 h) and filtered. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel, eluting with EtOAc-PE (0-50%) to afford N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide (1.07 g, 50.5%) as a light yellow oil. Mass calculated for C32H44N2O3=504.70; found: [M+H]+=505.5.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:8]=[CH:9][C:10]=1[Cl:11])=O.[C:25]1([NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31].CCN(C(C)C)C(C)C>>[Cl:11][C:10]1[CH:9]=[CH:8][C:7]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)=[CH:6][C:5]=1[C:3]1[CH:2]=[N:31][C:26]2[C:25]([N:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(=O)CBr)c2)c1
Reactant: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(-c3cnc4ccccc4n3)c2)c1

Procedure:
Procedure D was performed using N-(3-(2-bromoacetyl)-4-chlorophenyl)-3,5-dimethoxybenzamide (0.029 g, 0.07 mmol), 1,2-phenylenediamine (0.021 g, 0.19 mmol) and DIPEA (0.042 ml, 0.24 mmol) to give N-(4-chloro-3-(quinoxalin-3-yl)phenyl)-3,5-dimethoxybenzamide as a light tan powder.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH2:3][CH:4]=[CH2:5].Cl.C(=O)([O-])O.[Na+]>C(O)C.[C].[Pd]>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: C=CCC(O)(c1ccc(-c2cccc(NC(C)=O)c2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCCC(O)(c1ccc(-c2cccc(NC(C)=O)c2)cc1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 85.5 %

Procedure:
A suspension of N-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)-3-butenyl][1,1′-biphenyl]-3-yl]acetamide (829 mg), 10% palladium carbon (829 mg) and 1N hydrochloric acid (1.41 ml) in ethanol (14 ml) was stirred under a hydrogen atmosphere at room temperature for 9.5 h. Sodium hydrogen carbonate (130 mg) was added and the mixture was stirred. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel chomatography (eluent;chloroform→chloroform:methanol=10:1→7:1→4:1) to give the colorless amorphous title compound (420 mg).
Reaction SMILES: C[O-].[Na+].[C:4]1([CH3:26])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[C:27]1([CH3:56])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]([C:41]1[CH:55]=[CH:54][C:44]([CH2:45]P(=O)(OCC)OCC)=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]>CN(C=O)C>[C:4]1([CH3:26])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[CH:45]/[C:44]2[CH:43]=[CH:42][C:41]([N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:56])=[CH:55][CH:54]=2)=[CH:20][CH:19]=1
Reactant: CCOP(=O)(Cc1ccc(N(c2ccccc2C)c2ccccc2C)cc1)OCC
Reactant: Cc1ccccc1N(c1ccc(C=O)cc1)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N(c1ccc(/C=C/c2ccc(N(c3ccccc3C)c3ccccc3C)cc2)cc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Sodium methoxide (4.9 mmol) was added to a stirring solution of 4-(N,N-di-tolylamino)benzaldehyde (3.78 mmol) and diethyl 4-(N,N-di-tolylamino)-benzylphosphonate (3.78 mmol) in 15 mL of DMF at 25° C. The mixture stirred for 4 h at 25° C., producing a yellow precipitate. The solid was collected, and then slurried in warm water. The solid was collected again, and crystallized from ethanol/toluene to yield 1.5 g of the stilbene, (E)-4,4′-bis-(N,N-di-tolylamino)stilbene (Inv-5). H1 NMR and mass spectra data were consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:19]=1[CH2:20]Cl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C>[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:19]=1[CH2:20][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1CCl
Reactant: CCOC(=O)c1nc2c(N)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nc2c(NCc3c(C)cccc3C)cccn2c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
Ethyl 8-amino-3-methylimidazo[1,2-a]pyridin-2-carboxylate (4.6 g, 21 mmol), 2,6-dimethylbenzyl chloride (3.2 g, 21 mmol), sodium carbonate (4.4 g, 42 mmol) and a cat amount of potassium iodide were added to acetonitrile (50 ml) and refluxed for 3 h., stirred for 20 h. at room temperature and refluxed for 1 h. The solids were removed by filtration and the solvents were evaporated under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent and crystallization from ethyl acetate gave 4.0 g (56%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]Cl)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][N:31]3[CH2:32][CH2:33][N:28]([C:25]4[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=4)[CH2:29][CH2:30]3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1sc2cc(Cl)ccc2n1CCCCl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1sc2cc(Cl)ccc2n1CCCN1CCN(c2ccccc2)CC1
Yield: 61.9 %

Procedure:
A solution of compound (X) (3.71 g, 20 mmol), K2CO3 (3.31 g, 24 tool), phenylpiperazine (XIb) (3.24 g, 20 mmol), and KI (3.98 g, 24 mmol) in DMF (20 ml) was stirred at 100° C. for 5 hours and concentrated in vacuo. The residue was extracted with dichloromethane, washed with a saturated saline solution and dried over MgSO4. The dichloromethane layer was subjected to column chromatography on silica gel. The eluate eluted with dichloromethane/ethyl acetate (4/1) was recrystallized from ethyl ether to obtain compound (XIIb) (4.8 g, yield=61.9%) as colorless prism-shaped crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C[O:20][C:21](=[O:31])[C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][C:25](=O)[CH2:26][CH3:27]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][CH2:23][C:22]([CH3:30])([CH3:29])[C:21]([OH:31])=[O:20])=[CH:5][CH:4]=1
Reactant: CCC(=O)CCC(C)(C)C(=O)OC
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1c(CCC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-[4-fluorophenyl]hydrazine hydrochloride and methyl-2,2-dimethyl-5-oxoheptanoate as starting materials, in t-butanol as solvent, the title compound was prepared.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]=[C:11]([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([NH:10][CH:11]([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)C(C)=NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C)NCc1ccccc1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
3.95 g sodium borohydride was added to 18.9 g benzyl-(2,2-dimethoxy-1-methyl-ethylidene)-amine in 100 mL methanol at 0-5° C. The reaction was stirred over night at RT. The solvent was removed, dissolved in toluol and washed with water and saturated ammoniumchloride solution. The organic layer was evaporated and the residue was purified by column chromatographie on silica gel (cyclohexane/ethylacetate) to give 10.7 g of the desired product.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[CH:14]=[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[CH:11][N+:10]=2[CH:9]=[CH:8][CH:7]=1.COC1C=CC(CN2C=CC(C(C3C=CN(CC4C=CC(OC)=CC=4)N=3)=C)=N2)=CC=1>[N+](C)([O-])=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][N+:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c[n+]3ccccc3cc2c1
Agent: C=C(c1ccn(Cc2ccc(OC)cc2)n1)c1ccn(Cc2ccc(OC)cc2)n1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C[N+](=O)[O-]
Product: c1ccc2c(c1)Cc1cccc[n+]1C2

Procedure:
A reaction mixture containing benzo[b]quinolizinium perchlorate (9.5 g; 6.8 mmol) and 1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)ethylene (14.9 g; 0.034 mol) in 300 mL of nitromethane was refluxed for 16 h under nitrogen. The reaction mixture was concentrated in vacuo, the residue was triturated with 400 mL of methanol, and the solid was filtered, and dried (60° C.) to afford 22.1 g (85.6%) of 6,11-ethano-12,12-di-[(1-p-methoxybenzyl) pyrazol-3-yl)]-6,11-dihydrobenzo[b]quinolizinium perchlorate (Formula I: R1 =R2 =R3 =R4 =R7 =H ;R5 =R6 =1-p-methoxybenzyl-3-pyrazolyl;X- =ClO4-), as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:18][CH2:19][N:20]([S:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:38])=[O:37])[CH2:21][CH2:22]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(S(=O)(=O)c3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and pyridine (18 μl, 0.23 mmol) in DMF (1 ml) was added benzenesulfonyl chloride (21 μl, 0.17 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 80:1) to yield the title compound as a white solid (32 mg, 45%).
Reaction SMILES: C(O)(=O)C(C1C=CC=CC=1)O.[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.Cl[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[O:36]=[C:33]1[CH2:34][CH2:35][CH:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:15]3[CH2:16][CH2:17][CH2:18][C@H:13]([CH3:12])[CH2:14]3)=[CH:29][CH:28]=2)[CH2:31][CH2:32]1
Reactant: O=C1CCC(c2ccc(OCCCCl)cc2)CC1
Reactant: C[C@H]1CCCNC1
Agent: O=C(O)C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C[C@H]1CCCN(CCCOc2ccc(C3CCC(=O)CC3)cc2)C1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of (3S)-3-methylpiperidine mandelate (1.57 g), 4-[4-(3-chloropropoxy)phenyl]cyclohexanone (1.33 g), potassium carbonate (2.0 g) and a catalytic amount of potassium iodide in N,N-dimethylformamide (20 mL) is stirred overnight at a temperature close to 100° C., cooled back to room temperature and filtrated. The precipitate is rinsed with ethanol, the filtrate concentrated under reduced pressure and purified by chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 90/10). Fractions containing the expected product are pooled and concentrated under reduced pressure to give 1.04 g of (3S)-1-{3-[4-(4-oxocyclohexyl)phenoxy]propyl}-3-methylpiperidine as an orange coloured oil used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[C:4]([NH2:17])[N:3]=1.[Cl:18][CH:19]([CH:23]1[O:27][CH2:26][CH2:25][O:24]1)[CH2:20][CH2:21][CH3:22].N(CC)(C(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[ClH:18].[O:24]1[CH2:25][CH2:26][O:27][CH:23]1[CH2:19][CH2:20][CH2:21][CH2:22][N:10]1[C:5]2[C:4]([NH2:17])=[N:3][C:2]([CH3:1])=[N:7][C:6]=2[CH:8]=[C:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC(Cl)C1OCCO1
Reactant: Cc1nc(N)c2nc(-c3ccccc3)cc-2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(N)c2c(cc(-c3ccccc3)n2CCCCC2OCCO2)n1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of 2-methyl-4-amino-6-phenylpyrrolo[3,2-d]pyrimidine (Example 22) (0.079 g, 0.35 mmol), 2-(1-chlorobutyl)-1,3-dioxolane (Fluka Chemika) (0.14 g, 0.85 mmol), and iso-Pr2NEt (0.3 mL, 1.7 mmol) in toluene/DMF (2.5:1.0 mL) was heated at reflux for 6 days. The mixture was allowed to cool to room temperature and purified by flash chromatography on silica gel with 5% NH3 (2N in MeOH) 5% MeOH in CH2Cl2 to afford the product. The product was dissolved in CH2Cl2/EtOAc (1:1) and the solution was treated with a 2 M ethereal HCl (2 mL). The resulting slurry was filtered, and the solid was washed with hot EtOAc (3×) to give a yellow solid (29 mg, 23%). 1H NMR (DMSO-d6; 400 MHz): d 1.53 (m, 2), 1.64 (m, 2), 1.84 (m, 2), 2.68 (s, 3), 3.86 (m, 2), 4.32 (br t, 2), 4.80 (t, 1), 7.34 (s, 1), 7.48-7.58 (m, 3), 8.11 (d, 2), 8.89 (s, 1), 9.17 (s, 1), 13.90 (s, 1). MS m/z: 353 (M+1). Anal. Calcd for C20H24N4O2.2HCl: C, 56.47; H, 6.16; N, 13.18. Found: C, 56.36; H, 6.08; N, 13.21.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[C:18]2[C:28]([O:30][CH3:31])=[O:29])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[C:18]2[C:28]([O:30][CH3:31])=[O:29])[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(N)CC1
Reaction time: 72 h
Yield: 102.3 %

Procedure:
A solution of methyl 1-(2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl)-6-methoxy-1H-indole-2-carboxylate (Intermediate 13, 520 mg, 1.2 mmol) in dioxane (4 mL) was treated at room temperature under vigorous stirring with a solution of HCl in dioxane (4M, 2 mL). After 3 days, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (60 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL), the aqueous phase was extracted three times with dichloromethane (3×50 mL) and the combined organic phases were dried over sodium sulfate to give 407 mg (100% yield) of the crude product as colorless solid, mp 101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].C(=O)(O)[O-].[Na+].Cl[S:24]([C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:26])=[O:25]>O1CCOCC1>[CH3:32][O:31][C:29]([C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[S:24]([NH:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)(=[O:26])=[O:25])=[O:30]
Reactant: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 9 h
Yield: 71.6 %

Procedure:
2.3 g of p-nitro-D-phenylalanine are suspended in 25 ml of dioxan and treated with 10 ml of 1N sodium hydroxide solution and 1.7 g of sodium bicarbonate. A solution of 2.6 g of methyl 2-chlorosulfonylbenzoate in 22 ml of dioxanl is added dropwise thereto and the mixture is stirred at room temperature for 9 hours. The reaction mixture is poured into ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. There are obtained 3.2 g of N-[[-(methoxycarbonyl)phenyl]sulfonyl]-3-(p-nitrophenyl)-D-alanine.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:22]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:23]([C:39]([NH:41][C@H:42]([C:44](O)=[O:45])[CH3:43])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:22]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[C@H:23]([C:39]([NH:41][C@H:42]([C:44]([NH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:45])[CH3:43])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
compound SP303r2. To a solution of Trp-NHPh (202 mg, 0.723 mmol) in CH2C12/DMF (3 mL, 1/1) at 0° C. were successively added N-Boc-Tyr(Bn)-Ala-OH (320 mg, 0.723 mmol), EDC (153.6 mg, 0.8 mmol) and HOBt (108 mg, 0.8 mmol). The resulting mixture was allowed to warm up to room temperature overnight. The solvent was evaporated and the crude was triturated with water. After filtration, the solid was collected and purified by precipitation in CH2Cl2/MeOH to give a white amorphous solid (160.3 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=7 Hz, 3H, CH3), 1.28 (s, 9H, (CH3)3), 2.63 (m, 1H, CH2), 2.89 (m, 1H, CH2), 3.06 (dd, J=14.5 Hz, 7.5 Hz, 1H, CH2), 3.2 (dd, J=14.5 Hz, 6.1 Hz, 1H, CH2), 4.1 (m, 1H, CHα), 4.34 (m, 1H, CHα), 4.69 (m, 1H, CHα), 5.02 (s, 2H, CH2 (Bn)), 6.88 (d, J=8.5 Hz, 2 aromatic H Tyr), 6.94 (m, 2 aromatic H Trp), 7.03 (t, J=7.4 Hz, 2 aromatic H Trp), 7.16 (m, 3 aromatic H), 7.25-7.42 (m, 8H), 7.58 (m, 3H), 8.02 (d, J=7.2 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 10 (s, 1H, NH), 10.8 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6) δ 18.2 (CH3), 27.7 (CH2 Trp), 28.1 ((CH3)3), 36.3 (CH2 Tyr), 48.1, 54.2, 55.7 (CHα Ala, Tyr, Trp), 69 (CH2 (Bn)), 78 (C(CH3)3), 109.5, 111.2, 114.2, 118.2, 118.4, 119.4, 120.8, 123.3, 123.5, 127.3, 127.5, 127.7, 128.3, 128.6, 130.1, 130.3, 135.9, 137.2, 138.8 (25 aromatic C), 155.2, 156.8 (Car-O, CO carbamate), 170, 171.5, 172.1 (3 CO amide). Anal. Calcd. for C41H45N5O6, 0.5H2O: C, 69.08; H, 6.5; N, 9.82. Found: C, 68.82; H, 6.34; N, 9.79.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[CH3:16][O:17][C:18]([C:20]1[CH:21]=[CH:22][C:23](O)=[CH:24][CH:25]=1)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:23]2[CH:22]=[CH:21][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:25][CH:24]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(=O)CCC2CCN(C(=N)N)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
A mixture of 5 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 3.23 g of methyl p-hydroxybenzoate, 4.38 g of dicyclohexylcarbodiimide, 100 ml of dry dimethylformamide and 20 ml of dry pyridine was stirred at room temperature for 24 hours, and the mixture was treated in the same procedure as in Example 11. The crystals obtained were recrystallized from isopropanolether to obtain 5.7 g (yield: 72.7%) of p-methoxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 163° to 164.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([CH:25]([C:42]([O-])=[O:43])[CH2:26][C:27](=[O:41])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:27]2([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:29])[CH2:26][CH:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:42](=[O:43])[O:41]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(Cc1ccccc1)C(=O)[O-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(Cc3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 6 ml of dichloromethane were dissolved 286 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 540 mg of the Compound (73) obtained in Example 73. To the solution was added 325 mg of DCC dissolved in 2 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the crystals which separated out were filtered off. The filtrate was washed with water and dried (Na2SO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1) to give 553 mg of the subject Compound (75) as a pale yellow oily product.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][CH:3]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:24]>>[C:5]1([NH2:24])[C:6]2[C:11](=[CH:10][CH:9]=[N:8][CH:7]=2)[CH:2]=[CH:3][N:4]=1
Reactant: Clc1ncc(Br)c2ccncc12
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nccc2ccncc12

Procedure:
Bromination gives 4-bromo-2,7-naphthyridin-1(2H)-one CAS 959558-27-1, which is converted into 4-bromo-1-chloro-2,7-naphthyridine by chlorinating compounds, such as POCl3 and/or PCl5. Reaction with ammonia or ammonia equivalents gives 2,7-naphthyridin-1-ylamine.