Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C(=O)C.O1CCCC1>[CH:44]1([C:42]([NH:41][C:39]2[N:40]=[C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]4[CH:29]=[C:28]([NH:27][C:7]([C:5]5[N:4]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:49]=[CH:48][CH:47]=4)=[N:37][N:36]3[CH:38]=2)=[O:43])[CH2:45][CH2:46]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(-c2ccccc2)n1
Yield: 71.4 %

Procedure:
Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (294 mg, 1.45 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (127 μL, 1.45 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.97 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 255, the title compound (342 mg, 71%) was obtained as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([C:7]([O:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH3:6].C(N(CC)CC)C.[O:29]1[CH2:34][CH2:33][N:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C(Cl)Cl>[CH3:6][N:5]([C:7]([O:9][C@@H:10]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH2:4][CH2:3][N:2]([C:35]([N:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1)=[O:36])[CH3:1]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CNCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)OC(=O)N(C)CCN(C)C(=O)N1CCOCC1
Yield: 88.8 %

Procedure:
Methyl 2(S)-[N-(2-methylaminoethyl)-N-methylaminocarbonyloxy]- 3-phenylpropionate (8.0 g) was dissolved in methylene chloride (40 ml), and triethylamine (4.13 g) was added thereto under cooling. Thereto was dropwise added morpholinocarbonyl chloride (4.07 g) at 0°-10° C. over 30 minutes. After the dropwise addition, the mixture was stirred at said temperature for 60 minutes, washed with 5% hydrochloric acid, water, an aqueous solution of 6% sodium hydrogencarbonate, and water in this order, and the solvent was evaporated under reduced pressure to give 9.83 g of methyl 2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionate (yield 88.8%).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.CC1CCCC(C)(C)C=1/C=C/C(/C)=C\C=C\C(\C)=C\C(O)=O.[CH:48]1([N:54]=[C:55]=[N:56][CH:57]2[CH2:62][CH2:61][CH2:60]CC2)CCCCC1>O1CCCC1>[CH3:1][N:54]([C:55]1[CH:60]=[CH:61][CH:62]=[CH:57][N:56]=1)[CH3:48]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 277 mg of radicicol, 665 mg of trans-vitamin A acid (trans-retinoic acid), 10 ml of dry tetrahydrofuran, 470 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 388 mg of the title compound were obtained.
Reaction SMILES: C[CH2:2][O:3][CH2:4][CH2:5]O.[C:7]([O:12][CH3:13])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:14]([O:19][CH2:20][CH2:21][OH:22])(=[O:18])[C:15]([CH3:17])=[CH2:16].CC(N=NC(C#N)(C)C)(C#N)C>>[C:7]([O:12][CH2:13][CH2:5][CH:4]1[O:3][CH2:2]1)(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:14]([O:19][CH3:20])(=[O:18])[C:15]([CH3:17])=[CH2:16].[C:14]([O:19][CH2:20][CH2:21][OH:22])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: CCOCCO
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=C(C)C(=O)OCCC1CO1
Temperature: 90 °C

Procedure:
To 140 g of ethyl cellosolve were added 42 g of 3,4-epoxybutyl methacrylate⟦,9⟧, 9 g of methyl methacrylate, 9 g of hydroxyethyl methacrylate and 0.3 g of AIBN. The mixture was gently stirred and heated up to 90° C. During this treatment, nitrogen was continuously blown into the reaction system for more than about four hours. Consequently obtained was a light yellow solution measuring approximately 80 CPS in viscosity (molecular weight about 18,000). Thus a copolymer of 3,4-epoxybutyl methacrylate, methyl methacrylate and hydroxyethyl methacrylate was formed.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[S:3]([CH3:6])(=[O:5])=[O:4]>CO.[Pd]>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: CN(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: CN(c1ccccc1N)S(C)(=O)=O
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of N-methyl-N-(2-nitrophenyl)methanesulfonamide (900 mg, 3.91 mmol) in methanol (5 mL) was added palladium on carbon (10% by weight, 416 mg, 0.39 mmol). The solution was purged with hydrogen and then stirred for 4 hours under 1 atm of hydrogen. The crude reaction was filtered, concentrated and purified by chromatography to provide N-(2-aminophenyl)-N-methylmethanesulfonamide (540 mg, 60% yield). Product not characterized.
Reaction SMILES: [C:1]12([N:6]3[CH:19]=[C:18]4[C:8]([C:9](=[O:20])[CH2:10][C:11]5([CH2:17]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]5)=[N:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[N:22]1>>[C:1]12([N:6]3[CH:19]=[C:18]4[C:8]([C:9](=[O:20])[CH2:10][C:11]5([CH2:17]4)[CH2:16][CH2:15][N:14]([C:30]([C:26]4[CH:25]=[C:24]6[C:29](=[CH:28][CH:27]=4)[NH:21][N:22]=[CH:23]6)=[O:31])[CH2:13][CH2:12]5)=[N:7]3)[CH2:4][CH:3]([CH2:2]1)[CH2:5]2
Reactant: O=C1CC2(CCNCC2)Cc2cn(C34CC(C3)C4)nc21
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Product: O=C1CC2(CCN(C(=O)c3ccc4[nH]ncc4c3)CC2)Cc2cn(C34CC(C3)C4)nc21

Procedure:
The title compound was prepared by a method analogous to that described in Example 1, using 2-(bicyclo[1.1.1]pentan-1-yl)-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(2H)-one and 1H-indazole-5-carboxylic acid. +ESI (M+H) 416.2; HPLC retention time 2.32 minutes (Method A).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([Cl:13])[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][CH2:3][OH:2])[CH:6]=[C:7]([Cl:13])[C:8]=1[OH:12]
Reactant: COC(=O)Cc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1cc(Cl)c(O)c(Cl)c1
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
A solution of (3,5-dichloro-4-hydroxy-phenyl)-acetic acid methyl ester (15) (15.7 g, 67.09 mmol) in anhydrous tetrahydrofuran (600 mL) under argon cooled to −10° C. was treated slowly dropwise with a 1 M solution of lithium aluminum hydride in tetrahydrofuran (67.1 mL, 67.1 mmol). The reaction mixture was stirred for 5 min after the addition was complete and was quenched at −10° C. by the dropwise addition of a 10% aqueous Rochelle's Salt solution (80 mL). The reaction suspension was stirred 10 min. Ethyl acetate (100 mL) was then added to the suspension. The mixture was then filtered. The solids were rinsed with ethyl acetate (2×500 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×200 mL). The organic layers were combined and washed with a 0.1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered and concentrated to afford the first crop of solid. The resulting solid was placed under high vacuum overnight. The aqueous layer was acidified to pH=5 by the addition of a 1N aqueous hydrochloric acid solution and was then re-extracted with ethyl acetate (3×200 mL). The organic layers were combined and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered and concentrated. The resulting solid was placed under high vacuum overnight to afford 2,6-dichloro-4-(2-hydroxy-ethyl)-phenol (16) (13.9 g, 100%); LRMS for C8H8Cl2O2 (M+) m/z=207 Molecular Weight=207.0578; Exact Mass=205.9901
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15]>ClC(Cl)C>[N:2]1([C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15])[CH2:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1=CCN(C)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1=CCN(C(=O)OC(C)Cl)CC1
Temperature: 25 °C

Procedure:
Ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate (47 g, 278 mmol) in dichloroethane (800 mL) was treated with α-chloroethyl chloroformate (50 g, 350 mmol) dropwise at 0° C. The mixture was warmed to room temperature, refluxed for 2 hours, and then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and the residue was purified via column chromatography (SiO2, ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 6.88 (m, 1H), 6.61 (q, 1H), 4.22 (q, 2H), 4.16 (m, 2H), 7.35 (d, 2H), 3.58 (m, 2H), 2.44 (m, 2H), 1.82 (d, 3H), 1.30 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[C@H:11]([CH3:34])[C@@H:12]4[C@@H:29]([C@H:30]([OH:32])[CH3:31])[C:28](=[O:33])[N:13]4[C:14]=3[C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])=[CH:8]2)=[C:4]([C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[O:36])[N:3]=1.[N+](C1C=CC(COC([NH:54][S:55]([NH:58][CH2:59][CH2:60][CH2:61]O)(=[O:57])=[O:56])=O)=CC=1)([O-])=O>>[Cl:1][C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[C@H:11]([CH3:34])[C@@H:12]4[C@@H:29]([C@H:30]([OH:32])[CH3:31])[C:28](=[O:33])[N:13]4[C:14]=3[C:15]([O-:17])=[O:16])=[CH:8]2)=[C:4]([C:35]([C:37]2[CH:38]=[N+:39]([CH2:61][CH2:60][CH2:59][NH:58][S:55](=[O:57])(=[O:56])[NH2:54])[CH:40]=[CH:41][CH:42]=2)=[O:36])[N:3]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(Cl)nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Reactant: O=C(NS(=O)(=O)NCCCO)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4c(Cl)nc(C(=O)c5ccc[n+](CCCNS(N)(=O)=O)c5)c4s3)[C@H](C)[C@H]12
Yield: 29.3 %

Procedure:
The title compound (64 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 218 mg of 4-nitrobenzyl (1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate and 160 mg of 3-(4-nitrobenzyloxycarbonylaminosulfonyl)aminopropanol were used as the starting compounds.
Reaction SMILES: [N+](C1C=CC(S(OC[C@H]2O[C@@H](N3C4N=CN=C(NC(=O)C5C=CC=CC=5)C=4N=C3)[C@H](OC)[C@@H]2O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1)([O-])=O.Cl[CH2:59][C@H:60]1[O:64][C@@H:63]([N:65]2[C:82]3[N:81]=[CH:80][N:79]=[C:69]([NH:70][C:71](=[O:78])[C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:68]=3[N:67]=[CH:66]2)[C@H:62]([O:83][CH3:84])[C@@H:61]1[O:85][Si:86]([C:99]([CH3:102])([CH3:101])[CH3:100])([C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.[Li][N:104]=[N+:105]=[N-:106]>CS(C)=O>[N:104]([CH2:59][C@H:60]1[O:64][C@@H:63]([N:65]2[C:82]3[N:81]=[CH:80][N:79]=[C:69]([NH:70][C:71](=[O:78])[C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:68]=3[N:67]=[CH:66]2)[C@H:62]([O:83][CH3:84])[C@@H:61]1[O:85][Si:86]([C:99]([CH3:102])([CH3:101])[CH3:100])([C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[N+:105]=[N-:106]
Reactant: [Li]N=[N+]=[N-]
Reactant: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CCl)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Agent: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Solvent: CS(C)=O
Product: CO[C@@H]1[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CN=[N+]=[N-])O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
(FIG. 8C) The above mixture of 14 and 15 (3.9 g) was dissolved in dry DMSO (30 mL) and LiN3 (1.18 g, 24 mmol) was added. The reaction mixture was stirred at 80° C. overnight, then concentrated in vacuo (oil pump). After standard work up and column chromatography using 1-2% gradient MeOH in CH2Cl2 16 was obtained as a colorless foam (2.55 g), 1H NMR δ 8.92 (br s, 1H, NH), 8.72 (s, 1H, H2), 8.15 (s, 1H, H8), 8.02-7.36 (m, 15H, 3×Ph), 6.14 (d, J1',2' =3.4, 1H, H1'), 4.44 (app t, J3',4' =5.1, 1H, H3'), 4.27 (m, 1H, H4'), 4.01 (app t, J2',1' =3.4, J2',3' =4.9, 1H, H2'), 3.53 (dd, J5',4' =3.2, J5',5" =13.3, 1H, H5'), 3.37 (dd, J5",4' =4.5, J5",5' =13.3, 1H, H5"), 3.29 (s, 3H, OMe), 1.13 (s, 9H, t-Bu).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15].Cl[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19]>>[CH2:21]([O:20][C:18](=[O:19])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)Cl
Reactant: CC(=O)NCCc1c[nH]c2ccc(N)cc12
Product: C=CCOC(=O)Nc1ccc2[nH]cc(CCNC(C)=O)c2c1

Procedure:
The product from example 3 (5 mmol) is then treated with allyl chloroformate in the same manner as above, and purified on silica gel with 5% methanol in chloroform as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>C(O)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19][CH2:20][NH:21]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)c(C)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(c2ccc(C(F)(F)F)c(C)c2)C1
Reaction time: 2 h
Yield: 109.8 %

Procedure:
Methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)isonicotinate (2.32 g, 7.86 mmol) was dissolved in acetic acid (150 mL) and platinum(IV) oxide (36 mg, 0.16 mmol) was added. Hydrogenation in a Büchi hydrogenator at room temperature and 6 bar for 2 h. The catalyst was filtered off. More platinum(IV) oxide was added and hydrogenation continued until starting material was consumed. Catalyst was filtered off and the solvent was evaporated to yield crude methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate (2.60 g, 110%).
Reaction SMILES: O.[C:2]([OH:8])([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:9]([O:16][CH:17]1[C:22](OC)([O:23]C)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:8][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:9]([O:16][CH:17]1[C:22](=[O:23])[CH2:21][CH2:20][NH:19][CH2:18]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCNCC1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A water/TFA mixed solution (1/1, 35 mL) was added to tert-butyl 3-(benzyloxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (90a) (4.99 g, 14.2 mmol), and the mixture was stirred at 60° C. for one hour. The reaction solution was concentrated to obtain crude 3-(benzyloxy)piperidin-4-one TFA salt as a brown oily substance. A 2 N aqueous sodium hydroxide solution (20 mL) was added to the crude 3-(benzyloxy)piperidin-4-one TFA salt, and a solution of di-tert-butyl dicarbonate (4.36 g, 20 mmol) in THF (10 mL) was added at room temperature. Following stirring for one hour, the reaction solution was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1) to obtain 3.81 g of the title compound as a light brown oily substance (88%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C(O)C>[ClH:2].[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Solvent: CCO
Product: CC(=O)c1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-nitropyridine hydrochloride (9.75 g, 50 mmol) in ethanol (40 ml) was added to a slurry of p-aminoacetophenone (6.76 g, 50 ml) in ethanol (25 ml), and the mixture was stirred at room temperature overnight. The mixture was chilled in ice, and the yellow solid filtered off and dried in vacuo. Yield 10.1 g (69%), m.p. 197°-200° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:29][C@@H:30]2[C:36](=[O:37])[N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:34]3[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=3[S:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C.Br.C(OCC)C>C(O)(=O)C>[C:24]([C@@H:23]([NH:29][C@@H:30]1[C:36](=[O:37])[N:35]([CH2:38][C:39]([OH:41])=[O:40])[C:34]2[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=2[S:32][CH2:31]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:26])=[O:25]
Reactant: CCOC(=O)[C@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
In 1.5 ml of acetic acid is dissolved 0.3 g of tert-butyl 3(R)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 1 ml of 30% hydrogen-bromide acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 0.5 hour. Ethyl ether (80 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 10 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized with 2 ml of acetic acid, and purified by XAD-2 column chromatography (water:methanol=1:1). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.1 g of 3(R)-[1(S)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[S:23][C:22]([NH2:24])=[N:21][CH:20]=2)[N:9]=1.C(=O)([O-])O.[Na+].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[S:23][C:22]([NH:24][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:21][CH:20]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(N)s2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(NC(=O)Oc3ccccc3)s2)n1

Procedure:
A solution of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1,3-thiazol-2-amine (1 g, 2.71 mmol), sodium hydrogen carbonate (342 mg), and phenyl chloroformate (0.511 mL) in dioxane was stirred at RT for 2 hours then concentrated in vacuo. The residue was partitioned between DCM and water and the organic layer dried over sodium sulphate and evaporated to give a foam. The foam was triturated with a mixture of hexane and diethyl ether to give the desired material as a white solid (1.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-piperidinecarboxylic acid ethyl ester (5.0 g) and 2-methoxyphenylboronic acid (5.0 g) in dichloromethane (100 ml) are added pyridine (12.9 ml), anhydrous copper (II) acetate (5.78 g) and Molecular sieves 4 Å (100 g), and the mixture is stirred at 25° C. for 2 days. The reaction solution is filtered, and the filtrate is poured into 10% aqueous citric acid solution, and the organic layer is washed successively with aqueous sodium hydrogen carbonate solution, and saturated brine. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient, 0% to 100% hexane/ethyl acetate) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].O.S(O)(O)(=O)=O.CS[C:26](=[NH:28])[NH2:27].[OH-].[Na+]>CO>[NH:1]([CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6])[C:26]([NH2:28])=[NH:27]
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(N)NCCNS(=O)(=O)c1cccc2cnccc12
Yield: 84.1 %

Procedure:
In 30 ml of methanol was dissolved 3.3 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide obtained in Referential example 1, and to the solution was added 25 ml of water solution containing 5.0 g of S-methylisothiourea sulfate. And to the mixed solution was added 1N aqueous sodium hydroxide solution, the mixed solution thus obtained was heated at reflux for two hours. After the reflux, the methanol was distilled therefrom under reduced pressure, and the white crystals precipitated were separated by filtration under reduced pressure. The crystalline residue thus obtained was recrystallized from methanol to give 3.24 g of N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, i.e., Compound (2) in a yield of 84%.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:24])([F:23])[F:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].C1(C=CC(O)=CC=1)O.C([O-])(O)=O.[Na+]>Cl>[O:2]=[CH:3][CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:22])([F:23])[F:24])[C:6]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:7]
Reactant: COC(CN(C(=O)C1CCCCC1)c1ccccc1OC(F)(F)F)OC
Agent: Cl
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Product: O=CCN(C(=O)C1CCCCC1)c1ccccc1OC(F)(F)F
Temperature: 80 °C
Yield: 87.1 %

Procedure:
A suspension of compound 85B (0.106 g), hydroquinone (0.003 g) in 2 N HCl (1.14 mL) was heated at 80° C. for 30-40 minutes. After cooling to room temperature, NaHCO3 was added (pH=7) and the resulting mixture was extracted with CH2Cl2 (3×10 mL).The combined organic layers were dried (Na2SO4), filtered and evaporated to dryness at reduced pressure to give 0.081 g (88%) of the title compound as an oil.