Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:22]=[C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:30])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.S(Cl)(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:22]=[C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:30])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19][CH2:13][CH2:14][CH2:2][CH2:3][CH3:4])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=C(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Reaction time: 0.33 h
Yield: 115.8 %

Procedure:
10-bromo-2-carboxymethyloxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 6 was suspended in anhydrous benzene (10 ml), and to the suspension was added thionyl chloride (0.95 ml) at room temperature. The mixture was heated under reflux in an argon atmosphere for 3 hours and allowed to cool. The solvent was evaporated under reduced pressure, and after adding anhydrous benzene (5 ml), the solvent was evaporated again. The resulting residue was dissolved in anhydrous methylene chloride (3 ml), and the solution was added dropwise to a solution of 1-pentanol (0.065 ml) and triethylamine (0.18 ml) dissolved in methylene chloride (30 ml) in an ice bath, and the solution was stirred for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was repeatedly washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residual crude crystals were washed with ether, and recovered by filtration to obtain the title compound (200 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10](C=C)[N:9]2[C:16](=[O:22])[C:17]([O:19][CH2:20]C)=[O:18])=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[N:9]3[C@H:10]([CH2:20][O:19][CH:17]([OH:18])[C:16]3=[O:22])[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1C(=O)C(=O)OCC
Solvent: CO
Product: O=C1C(O)OC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Temperature: -78 °C
Yield: 13.6 %

Procedure:
A solution of ethyl [(2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidin-1-yl]oxoacetate (220 mg) in methanol (5 mL) was cooled to −78° C., and ozone gas was bubbled through the reaction solution for 20 minutes. Sodium borohydride (164 mg) was added to the reaction solution while stirring at −78° C., and the reaction solution was stirred at that temperature for 30 minutes. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 26 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([O:13][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])[CH2:10][CH:11]=[CH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC(O)CNC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: C=CCC(CNC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
Rac-(2-hydroxy-pent-4-enyl)-carbamic acid tert-butyl ester (5 g, 24.8 mmol; prepared according to Tetrahedron Lett. (2006), 47, 3295) was added dropwise to a mixture of TBDMSCl (3.7 g, 1 eq.) and imidazole (1.7 g, 1 eq.) in THF (55 mL). The mixture was stirred at rt overnight, filtered and the filtrate washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by FC (Hept/EA:1, EA) to give the title intermediate as a colourless oil (2.8 g, 36% yield).
Reaction SMILES: [C:1]([O:7][CH2:8][Cl:9])(=[O:6])[C:2](C)([CH3:4])[CH3:3].C(Cl)(=O)C1C=[CH:15][C:14]([O:17][CH3:18])=[CH:13]C=1.C=O>[Cl-].[Zn+2].[Cl-]>[CH3:18][O:17][C:14]1[CH:15]=[CH:4][C:2]([C:1]([O:7][CH2:8][Cl:9])=[O:6])=[CH:3][CH:13]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1ccc(C(=O)OCCl)cc1
Reaction time: 16 h
Yield: 12 %

Procedure:
A similar procedure (Iyer, R. P. et al. Synth. Commun. 1995, 25, 2739-2749) to that described for the preparation of 41 was followed using p-anisoyl chloride (5.0 g, 29.4 mmol), paraformaldehyde (883 mg, 29.4 mmol) and zinc chloride (31 mg, 0.22 mmol), at 80° C. for 16 h. Purification by flash chromatography (hexane/ethyl acetate 4:1) afforded chloromethyl p-methoxybenzoate (48) as a yellow oil (0.74 g, 3.69 mmol, 12%). 1H NMR (300 MHz, CDCl3) δ 3.87 (3H, s, OMe), 5.94 (2H, s, CH2), 6.92-6.96 (2H, m, Ar), 8.01-8.06 (2H, m, Ar).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38].[OH-].[K+].CN1CCCC1=O.Cl>>[CH2:35]([S:39][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCS
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Reaction time: 5 h
Yield: 83 %

Procedure:
5-Chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole (38.1 g, 0.08 mol), n-butyl mercaptan (9 g, 0.10 mol), potassium hydroxide (10.1 g, 0.18 mol) and N-methylpyrrolidone (99 g, 1.0 mol) are charged to a reactor and heated to 170°0C. The reaction mass is held at 170° C. with vigorous stirring for five hours. The reaction is judged as complete using thin layer chromatography. The temperature is reduced to 5° C. and 100 mL of aqueous 2N hydrochloric acid are then added to the reactor. The liquid is decanted and the solids are dissolved in ethyl acetate. The organic layer is washed with aqueous 2N hydrochloric acid followed by water. The ethyl acetate is stripped off and the product is crystallized from ethanol and toluene. The title compound is obtained as a yellow crystalline product in 83% yield. The structure is verified by 1Hnmr.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.Cl>C(Cl)(Cl)Cl>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:18]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCCNc2ccc(Cl)cc2[N+](=O)[O-])CC1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of 2,5-dichloronitrobenzene (95.5 g., 0.497 mole) and 1-(3-aminopropyl)-4-methylpiperazine (82.2 g., 0.522 mole) was heated in a nitrogen atmosphere at 130° C. for five hours and cooled to room temperature. The mixture was poured into a separatory funnel containing 1500 ml. of 3N HCl and 500 ml. chloroform. After shaking and separation of layers, the chloroform was withdrawn and the aqueous layer extracted with fresh CHCl3. The aqueous layer was made alkaline with 20% NaOH and the resulting oil extracted with 3 × 600 ml. CHCl3. The combined extracts were dried over Na2SO4 and the solvent evaporated at reduced pressure to give 131.5 g. (85% yield) of 2-[3-(4-methyl-1-piperazinyl)propylamino]-5-chloronitrobenzene as a dark orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].OO.C(O)(=[O:20])C>C1(C)C=CC=CC=1.C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:20]
Reactant: Cc1cc(O)c(SCCC(C)C)c(=O)o1
Reactant: CC(=O)O
Agent: OO
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(S(=O)CCC(C)C)c(=O)o1
Temperature: 25 °C

Procedure:
4-Hydroxy-3-isopentylthio-6-methyl-2-pyrone (4.5 g., 0.020 mol), 30% hydrogen peroxide (2.44 g., 0.0220 mol), and 35 ml. glacial acetic acid were combined and stirred over night at room temperature. The clear solution was diluted with a mixture of toluene and ethanol and the acetic acid was removed by codistillation in vacuo. A yellow liquid was recovered which solidified upon cooling. The compound was recrystallized from n-hexane to recover 2.5 g. (51 percent) of shiny yellow platelets. One additional recrystallization from n-hexane gave the pure compound as tiny white crystalline needles: m.p. 80°-81°C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:21])[CH2:4][CH2:3]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(c1)N(CCN1CCC(NCc3cc4c(cn3)OCCO4)CC1)C(=O)CO2

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methyl-2H-1,4-benzoxazin-3(4H)-one (Intermediate 91), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carb aldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as an oil, 4.7 mg (2%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[CH:19][C:20]4[N:21]([CH:23]=[C:24]([NH:26]C(=O)C(F)(F)F)[N:25]=4)[CH:22]=3)[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[OH-].[Na+].C(O)C>O>[NH2:26][C:24]1[N:25]=[C:20]2[CH:19]=[CH:18][C:17]([O:16][C:12]3[CH:11]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:15]=[CH:14][CH:13]=3)=[CH:22][N:21]2[CH:23]=1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(F)(F)F)cn4c3)c2)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A mixture of 1,3-dimethyl-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]-1H-pyrazole-5-carboxamide (328 mg, 0.715 mmol), 1N aqueous sodium hydroxide solution (3 mL) and ethanol (3 mL) was stirred at 40° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, methanol/ethyl acetate=0/100→20/80) to give the title compound (205 mg, 79%) as a white solid.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:24][CH2:25][C:26](OC)=[O:27]>CO.C[O-].[Na+]>[Cl:24][CH2:25][C:26]([NH:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:27]
Reactant: CCCCCCCCCCCCCCCCCCOCCCN
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOCCCNC(=O)CCl
Yield: 92 %

Procedure:
A four-necks-flask equipped with a stirrer, a temperature gage, a dehydrating pipe and a dropping funnel was charged with 327.6 g of 3-octadecyloxypropylamine obtained in the same manner as in Example 21, 900 g of methanol and 3.9 g of a methanol solution of 28% sodium methylate as a catalyst. 113.9 g of methyl chloroacetate was added to the mixture in one hour while the mixture was kept at 15 to 25° C. and the resulting mixture was reacted for 30 hours. After the reaction was completed, the precipitated crystal was filtered. The crystal was washed with 300 g of methanol and then dried to obtain 371.8 g of 2-chloro-N-(3-octadecyloxypropyl)-acetamide as a white powder.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:27]O)[CH:23]=2)[N:18]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:17]1=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:27][F:7])[CH:23]=2)[N:18]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:17]1=[O:35]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(Cn2c(=O)c3cc(CO)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(CF)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
0.11 ml of DAST is added dropwise to a solution of 0.1 g of the compound obtained in Step 14.3 in 2 ml of DCM cooled to −78° C. The reaction medium is stirred for 2 hours at −78° C. and then allowed to warm to room temperature. It is neutralized with saturated NaHCO3 solution. The resulting mixture is extracted with DCM. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (95/5, v/v) to (30/70, v/v) to give 0.032 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:18](=O)=[O:19].CN(C=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[CH:18]=[O:19]
Reactant: Fc1ccc(OC(F)(F)F)cc1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1cc(OC(F)(F)F)ccc1F
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A solution of 1-fluoro-4-trifluoromethoxy-benzene (21.0 g, 117 mmol) in THF (233 mL) was cooled to <−70° C. and tert.-butyllithium (86 mL, 1.5 M in pentane, 129 mmol) was added at such a rate that temperature was kept <−70° C. Stirring in the dry ice bath was continued for 15 min, then DMF (11.6 mL, 150 mmol) was added dropwise keeping temperature <−70° C. After 30 min the reaction mixture was allowed to reach rt, quenched with saturated NH4Cl solution and extracted with diethylether. The organic phase was washed with brine, concentrated and chromatographed (SiO2, heptanes:ethyl acetate=100:0 to 80:2) to afford the title compound (11.0 g, 53%) as a light yellow oil. 1H-NMR (300 MHz, DMSO): δ=7.60 (t, J=9.2 Hz, 1H), 7.75-7.85 (m, 2H), 10.20 (s, 1H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[CH:23][C:22]=1[F:36])(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[C:22]([F:36])=[CH:23][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[C:25]([N+:1]([O-:4])=[O:2])[CH:26]=1)(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)N1CCCC1c1ccc(NC(=O)c2ccccn2)cc1F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
94 mg of potassium nitrate was added to a trifluoroacetic acid (3 ml) solution of pyridine-2-carboxylic acid-(4-(1-acetyl-pyrrolidin-2-yl)-3-fluoro-phenyl)-amide, and the reaction liquid was stirred at room temperature for 2 days. The reaction liquid was distilled under reduced pressure, diluted with chloroform, and made basic with aqueous saturated sodium bicarbonate solution, and then extracted with chloroform. The organic layers were combined, washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:59]([CH3:61])[CH3:60])[C:7]([N:9]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([C:35]2[NH:39][C:38]([CH:40]4[CH2:44][CH2:43][CH2:42][N:41]4[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]([CH3:49])[CH3:48])=[N:37][CH:36]=2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[CH2:56][CH2:57][CH2:58][C@H:10]12)=[O:8])=[O:4].[CH3:62][O:63][C:64](N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:59]([CH3:61])[CH3:60])[C:7]([N:9]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([C:35]2[NH:39][C:38]([CH:40]4[CH2:44][CH2:43][CH2:42][N:41]4[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]4[CH2:49][CH2:64][O:63][CH2:62][CH2:48]4)=[N:37][CH:36]=2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[CH2:56][CH2:57][CH2:58][C@H:10]12)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@@H]7CCC[C@@H]7N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc(C4CCCN4C(=O)[C@@H](NC(=O)OC)C4CCOCC4)[nH]3)ccc2-5)C[C@@H]2CCC[C@@H]21)C(C)C
Yield: 56 %

Procedure:
This compound was made in an analogous manner to methyl {(2S)-1-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid to give methyl [(1S)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate (0.039, 56%). MS (ESI) m/z 874.34 [M+H]+. 1H NMR (400 MHz, cd3od) δ 8.58 (s, 2H), 8.26-8.08 (m, 2H), 7.96-7.75 (m, 4H), 7.65-7.54 (m, 5H), 5.36-5.11 (m, 4H), 4.34-4.04 (m, 4H), 3.97-3.79 (m, 4H), 3.65 (s, 4H), 3.53-3.44 (m, 2H), 2.68-2.47 (m, 4H), 2.32-2.02 (m, 7H), 1.95-1.82 (m, 3H), 1.77-1.54 (m, 4H), 1.49-1.24 (m, 5H), 1.10-0.99 (m, 3H), 0.92-0.85 (m, 4H).
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]3[C@H:26]([NH:27][C:28](=[O:64])/[C:29](=[N:43]\[O:44][C:45]4([C:48]([O:50][CH:51]([C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)=[O:49])[CH2:47][CH2:46]4)/[C:30]4[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[S:33][CH:34]=4)[C:25](=[O:65])[NH:24]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]1[C@H:26]([NH:27][C:28](=[O:64])/[C:29](=[N:43]\[O:44][C:45]2([C:48]([O:50][CH:51]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:49])[CH2:46][CH2:47]2)/[C:30]2[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[S:33][CH:34]=2)[C:25](=[O:65])[NH:24]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Reaction time: 2 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.167 mmol) in DCM (1.7 mL) was added piperidine (16.50 μl, 0.167 mmol). After 2 h, the reaction mixture was concentrated in vacuo and lyophilized in CH3CN/water mixture to afford the title compound (assumed quantitative). LCMS: Rt=0.93 min, m/z=678.5 (M+1), Method 2m_acidic.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:28]=[CH:27][C:15]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.Cl.[CH3:30][NH:31][CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[CH3:30][N:31]([CH3:32])[C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:16](=[O:17])[C:15]2[CH:27]=[CH:28][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)=[O:25]
Reactant: O=C(O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1

Procedure:
In a similar manner to Example 5, Compound 9-2 (27 mg, 5%) was obtained using Compound 50 (500 mg, 1.33 mmol), dimethylamine hydrochloride (230 mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (306 mg, 2.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 2.00 mmol) and N-methylmorpholine (0.439 mL, 4.00 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH2:21][F:22])[C:15]([O:17]CC)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH2:21][F:22])[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(CCF)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc(C(CCF)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from step B (100 mg, 0.3 mmol) in a mixture of THF (1 mL) and methanol (0.3 mL) was added a solution of lithium hydroxide (0.3 mL of a 1 M soln, 0.3 mmol) and the resulting mixture stirred at room temperature for 90 min. 1N HCl (0.3 mL, 0.3 mmol) was added and the mixture evaporated to dryness. The resulting crude product was used immediately without purification.
Reaction SMILES: CO[C:3]1C(OC)=NS(=O)(=O)[N:4]=1.[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2(OC)[NH:30][S:29](=[O:32])(=[O:31])[N:28]=[CH:27]2)[N:20]=1)[C:13]([NH2:15])=[NH:14].CN>>[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2([NH:4][CH3:3])[NH:30][S:29](=[O:32])(=[O:31])[N:28]=[CH:27]2)[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: COC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1
Agent: CN
Product: CNC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1

Procedure:
When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 4-[(2-quanidino-4-oxazolyl]butylamine [prepared according to the procedure described in Belgian Pat. No. 866,155] and the resultant 3-{4-[(2-guanidino-4-oxazolyl]butylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with excess methylamine, the title compound is thereby produced.