Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[OH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(CCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1
Yield: 45 %

Procedure:
A mixture of 2-chloro-5-acetylnitrobenzene (Oelschlaeger, H.; Schreiber, O. Liebigs Ann. Chem., 1961, 641, 81., 2 g, 10 mmol), 4-aminophenylethyl alcohol (1.64 g, 12 mmol) and NaHCO3 (1 g, 12 mmol) in DMF (60 mL) was heated at 150° C. for 3 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.36 g (45%) of the title compound as an orange oil; 1H-NMR (CDCl3) δ 9.83 (1H, br.s), 8.20 (1H, d, J=2.1 Hz), 7.94 (1H, dd, J=2.1 Hz, 9.3 Hz), 7.34 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.2 Hz), 7.16 (1H, d, J=9.3 Hz), 3.91 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz), 2.57 (3H, s).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17](SC)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1.O>C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17]([NH:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: C[C@@H](N)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@@H](Nc1ncnc2cc(N)ncc12)c1ccccc1
Temperature: 180 °C
Yield: 10.9 %

Procedure:
A mixture of [R]-1-phenylethylamine (0.072 mL, 0.55 mmol) and 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (97 mg, 0.5 mmol) (described in a previous experimental) is heated at 180° C. under N2 for 1.5 hr. The reaction is then cooled to room temperature producing a precipitate. The mixture is added to water and CHCl3, sonicated and filtered. The phases are separated and the aqueous phase is extracted with CHCl3. The combined extracts are washed with water, saturated brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue purified by using preparative tlc (5% MeOH/CHCl3) and recrystallization from CHCl3 to give 7-amino-4-([R]-1-phenylethylamino)pyrido[4,3-d]pyrimidine (14.5 mg, 11%), mp 231.8-232.1° C. 1H NMR (DMSO) δ 9.23(1H, s), 8.50 (1H, d, J=8.0 Hz), 8.19 (1H, s), 7.41 (2H, d, J=7.0 Hz), 7.31 (2H, t, J=8.0 Hz, 7.21 (1H, tt, J=7.4, 1.2 Hz), 6.45 (2H, s), 6.33 (1H, s), 5.56 (1H, p, J=7.2 Hz), 1.55 (3H, d, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([CH3:43])[C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[NH2:31][S:28]([C:24]1[CH:23]=[C:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([N:39]([CH3:43])[C:40](=[O:42])[CH3:41])=[CH:37][CH:38]=3)[N:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29]
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(S(N)(=O)=O)c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Temperature: 110 °C
Reaction time: 72 h
Yield: 15.7 %

Procedure:
A mixture of 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.21 mmol), N-(4-aminophenyl)-N-methylacetamide (100 mg, 0.61 mmol) and trimethylsilyl chloride (0.050 mL, 0.40 mmol) in nBuOH (2 mL) and dioxane (2 mL) was heated at 110° C. for 4 h. More trimethylsilyl chloride (0.100 mL, 0.79 mmol) was added. The mixture was stirred at 110° C. for another 72 h. It was then purified by HPLC to give N-(4-(4-(3-aminosulfonyl-phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide as a solid (20 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[CH:12]=[N:13][N:14]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=4)[C:15]=3[CH2:16][CH2:17][C:9]=2[CH:8]=1)(=O)=O.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:15]3[CH2:16][CH2:17][C:9]4[CH:8]=[C:7]([CH:31]=[CH2:32])[CH:28]=[CH:27][C:10]=4[C:11]=3[CH:12]=[N:13]2)=[CH:19][CH:20]=1)[CH2:25][CH3:26]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCc1ccc(-n2ncc3c2CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2-3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1c-2cnn1-c1ccc(CCC)cc1
Temperature: 100 °C

Procedure:
To 3-(4-propylphenyl)-4,5-dihydro-3H-benzo[e]indazol-7-yl trifluoromethanesulfonate (Preparation 136D, 240 mg, 0.550 mmol) in dioxane was sequentially added tributyl(vinyl)stannane (0.178 mL, 0.605 mmol), lithium chloride (69.9 mg, 1.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (38.1 mg, 0.033 mmol). Contents were purged with nitrogen gas for 5 min. and heated at 100° C. for 16 h.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O.CCCCCC.C(O)(C)C>CC(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:21])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: CC(C)=O
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 10 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A stirred solution of (9RS,10RS)-2-chloro-9,10-dihydro-9,10-methanoanthracene-9-carboxaldehyde prepared as in Example 1i (290.5 g, 1.14 moles) dissolved in acetone (5.0 L) was cooled to 10° C. and treated with Jones Reagent (950 ml, ~ 1.19 moles) over a period of 1 h. The reaction mixture was stirred overnight at room temperature, then analyzed by TLC [silica gel/methylene chloride:hexane (1:1)]. Conversion of the aldehyde (Rf =0.50) to the desired carboxylic acid (Rf =0.0-0.15) was shown to be complete. Isopropanol (150 ml) was added, and the mixture stirred for another 3 h to quench any excess Jones Reagent. The acetone supernatant was decanted away from the green-black sludge that had formed, and the sludge was washed with acetone (2×1 L). The combined acetone solutions were concentrated on the rotary evaporator to a volume of 1.5 L, then poured into ice/water (6 L) with vigorous stirring. A yellow-white gum precipitated and gradually solidified with continued stirring. The solid was collected by filtration, pulverized to a fine off-white powder in a mortar & pestle, then rewashed with cold water (2×1 L). Vacuum drying afforded the title compound as an off-white powder (304.8 g, 98.7%), mp 175°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])=[CH:41][CH:42]=1
Reactant: NCc1ccc(C(=O)NCC(F)(F)F)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.59 mmol) with 4-aminomethyl-N-(2,2,2-trifluoroethyl)-benzamide (273 mg, 1.17 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethyl-aminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])=O.OC1C=CC=CN=1>C1COCC1.CCOCC>[CH2:13]([N:12]1[CH2:11][CH2:10][C@@H:9]2[CH2:8][CH2:7][N:6]([C@H:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:22])[C@@H:5]2[C:3]1=[O:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H]1[C@H](CCNCCc2ccccc2)CCN1[C@@H](C)c1ccccc1
Agent: Oc1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](c1ccccc1)N1CC[C@H]2CCN(CCc3ccccc3)C(=O)[C@H]21

Procedure:
A solution of (2S,3R)-3-(2-Phenethylamino-ethyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2 carboxylic acid methyl ester (400 mg, 1.05 mmol) and 2-hydroxyl pyridine (100 mg, 1.05 mmol) in THF (10 mL) is stirred at 40° C. for 24 hrs. The reaction is diluted with 50 mL of ether and washed with 2×120 mL of water. After dried and concentrated to give a pale liquid (350 mg, LC/MS shown a clean product only) without further purification for next step reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-3-chlorophenol (1 g, 4.82 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.332 g, 9.64 mmol) and benzyl bromide (0.630 ml, 5.30 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 297 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:27])([F:26])[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)=[N:14]2)=[CH:9][CH:8]=1>CCO.O>[N:2](=[CH:22]/[C:21]1[CH:24]=[CH:25][C:18]([C:15]2[N:16]=[CH:17][N:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]([F:27])([F:26])[F:4])=[CH:8][CH:9]=3)[N:14]=2)=[CH:19][CH:20]=1)\[NH2:3]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C

Procedure:
To a 250 milliliter (mL) round-bottomed flask containing hydrazine hydrate (64% aqueous (aq) solution; 7.27 mL, 15.0 millimoles (mmol)) in EtOH (100 mL) at 80° C. was added 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (5.00 grams (g), 1.50 mmol) portionwise over 5 minutes (min). The solution was stirred at reflux for an additional 3 hours (h) before being diluted with water (H2O; 300 mL) and cooled to 0° C. The precipitated product was collected by vacuum filtration as a white solid (4.89 g, 93%): mp 222-226° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.22 (d, J=8.2 Hz, 2H), 7.84-7.79 (m, 3H), 7.66 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.29 (s, 1H), 5.63 (br s, 2H); ESIMS m/z 348 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>ClCCl>[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 96.1 %

Procedure:
Triethylamine (7.64 g) was added to a suspension of L-proline methyl ester hydrochloride (5 g) and 2-nitrobenzenesulfonyl chloride (7.4 g) in dichloromethane (150 ml), under ice cooling with stirring and the resulting mixture was stirred at room temperature for 17 hours. After water-washing the reaction liquid, it was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with ethyl acetate/hexane (1/3) to give 9.12 g (yield 96.1%) of the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:11][C:8]2([CH2:10][CH2:9]2)[CH2:7][N:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[CH2:15]([O:14][C:12]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:11][C:8]2([CH2:9][CH2:10]2)[CH2:7]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester (244 mg, 0.840 mmol) was dissolved in THF (2.0 mL)/MeOH (1.5 mL) An aqueous solution of LiOH (35.5 mg, 0.84 mmol) was added and stirring at room temperature was continued. After 3 hours, the reaction was neutralized with aqueous HCl (1M) and the organic solvents were removed in vacuo. The crude mixture was diluted with water and EtOAc and the organic layer was collected. All volatiles were removed in vacuo and the crude acid was used without further purification. LCMS-ESI+: calc'd for C15H17NO4: 275.3 (M+). Found: 276.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring mixture of 5-methyl-pyridin-2-ylamine (1.0 g, 9.25 mmol) and pyridine (20 ml) in dry CH2Cl2 add phenylchloroformate (2.2 g, 13.9 mmol) and stir for 24 hours at room temperature. Add water and a solution of 1:1 EtOAc/hexanes and separate the organic layer. Wash the organic layer with 1N HCl three times and with brine once. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (5-methyl-pyridin-2-yl)-carbamic acid phenyl ester. Mass spec.: M+1=229 (AP+). B. 1′-(5-methyl-pyridin-2-yl-carbamoyl)-spiroisobenzofuran-1,4′-piperidine
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]=[N+]=[N-])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[CH:46]1([NH:52][C:53]([C@@H:55]2[CH2:59][CH2:58][CH2:57]N2)=[O:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:57][CH2:58][CH2:59][C@H:55]1[C:53]([NH:52][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:54])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC1)[C@@H]1CCCN1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1)OCc1ccccc1

Procedure:
To 30 ml of an ethyl acetate solution of compound (4) prepared from 1.52 g of compound (3) by the method shown in Reference example 2 was added 785 mg of (S)-N-cyclohexyl-2-pyrrolidinecarboxamide (36) prepared by a known method and then the reaction was maintained overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (90:10:1), 1.30 g of Nα -benzyloxycarbonyl-L-histidyl-N-cyclohexyl-L-prolinamide (37) was obtained.
Reaction SMILES: [OH-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[S:13][C:12]([N:14]=CN(C)C)=[N:11][C:10]=1[CH3:19])=O.[CH2:21]([N:23]([CH2:27][CH3:28])[C:24]([NH2:26])=[NH:25])[CH3:22]>COCCO>[NH2:14][C:12]1[S:13][C:9]([C:7]2[CH:6]=[CH:5][N:26]=[C:24]([N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])[N:25]=2)=[C:10]([CH3:19])[N:11]=1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Reactant: CCN(CC)C(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCN(CC)c1nccc(-c2sc(N)nc2C)n1
Temperature: 125 °C

Procedure:
Powdered sodium hydroxide (150 mg) is added to a solution of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (0.5 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and 1,1-diethylguanidine (259 mg) in 2-methoxyethanol (1.9 ml) and the mixture heated at 125° C. for 1 hour with stirring. The reaction mixture is concentrated under vacuum and purified by normal phase chromatography, eluent; DCM/EtOAc, to give the title compound. ESI-MS: M+H 264 and M−H 262.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].[N:37]#[C:38]Br>C(O)C.CCOC(C)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:10]3[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:8][C:7]4[CH:6]=[CH:5][N:4]5[C:38]([NH2:37])=[N:2][N:1]=[C:3]5[C:12]=4[N:11]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Reactant: N#CBr
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nnc2c3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)cc3ccn12
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30 mg, 0.0620 mmol), cyanogen bromide (19.8 mg, 0187 mmol) in ethanol (2 mL) was stirred at 60° C. for 72 hours. The mixture was diluted with AcOEt, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel. The residue was treated with HCl in MeOH and the mixture was heated in a microwave reactor at 80° C. for 5 min. The solvent was evaporated and the residue was purified by reverse phase HPLC (H2O/0.1% TFA aq.-MeCN/0.1% TFA aq.) to give 9-[4-(1-aminocyclobutyl)phenyl]-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-3-amine (8-1) as a pale yellow solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].N([O-])=O.[Na+].[ClH:22]>>[Cl:22][C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: Cl
Reactant: N#Cc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1cc(Cl)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 2-amino-5-(2,4-dichloro-phenyl)-isonicotinonitrile (880 mg, 3.3 mmol) in HCl conc. (15 mL) was vigorously stirred and cooled to −15° C. (ice/MeOH bath). NaNO2 (4.6 g, 66.7 mmol) was carefully added, then the reaction mixture was slowly warmed to RT and stirred for 24 h. The formed precipitate was filtered, washed with water, and purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→5:95) to yield the title compound (453 mg, 1.6 mmol, 48%). MS: 284 [M+1]+; HPLC: AtRet=2.70.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:16])[N:12]([O:14][CH3:15])[CH3:13])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([N:12]([O:14][CH3:15])[CH3:13])=[O:16]
Reactant: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)N
Reaction time: 0.33 h
Yield: 176 %

Procedure:
The Boc-protected Weinreb amide, [1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester, (1.1 g, 4.47 mmol), was taken up in TFA/CH2Cl2 (1:1, 50 mL) and stirred for 20 min. Removal of the solvent left 2-amino-N-methoxy-2,N-dimethyl-propionamide (1.15 g, 99%, quantitative yield) as its TFA salt. 1H NMR (200 MHz, CD3OD) δ (ppm): 1.63 (s, 6H), 3.25 (s, 3H), 3.78 (s, 3H). MS (ESI, positive ion): m/z 147.3 (M+1)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1CCNCC1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.CN(C=O)C>[CH:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCCc1ccc(N2CCNCC2)cc1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
The product of (1) (the piperazine compound) (5.996 g, 29.1 mmol) was put in a 100 ml-three-necked flask, which was equipped with a Dimroth condenser on the central mouth and septum rubbers on the side mouths. In the flask, DMF (33 ml) was added to dissolve the content, and potassium carbonate (8.034 g, 58.1 mmol) and bromodiphenylmethane (7.543 g, 30.5 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (80 ml) in a 200 ml-conical flask, and the mixture was extracted with diethyl ether (four times, 100 ml each time). The ether layer was washed with brine (twice, 40 ml each time), dried and distilled off under reduced pressure. The residue (10.616 g) was subjected to column chromatography [silica gel, ethyl acetate-n-hexane (1:1)] for separation and purification to give 6.188 g of the above-captioned benzhydrylpiperazine compound (Yield: 57%).