Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[CH:7]([CH3:9])[CH3:8]>O.C(O)(=O)C>[N:1](=[C:11]([C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[OH:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)C(C)C
Reaction time: 0.5 h
Yield: 116.1 %

Procedure:
A solution of sodium nitrate (43.8 g.) in water (92 ml.) was added dropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3 g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutes then at room temperature for 3 hours, water (100 ml.) was added and the mixture extracted with ether. The extracts were washed with water, saturated sodium bicarbonate solution and water. After drying (CaSO4), the solution was evaporated to give ethyl 2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][S:11]([C:14]1[N:19]=[C:18]([CH3:20])[C:17](N)=[CH:16][CH:15]=1)(=[O:13])=[O:12].N(OC(C)(C)C)=O.[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>CN(C)C=O.COCCOC.CCCCCC>[CH3:10][S:11]([C:14]1[N:19]=[C:18]([CH3:20])[C:17]([O:32][C:29](=[O:31])[CH3:30])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(=O)Oc1ccc(S(C)(=O)=O)nc1C
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
A solution of boron trifluoride etherate (670 μL, 5.3 mmol) in dimethylformamide (2 mL) was cooled to −15° C. using an ice-acetonitrile bath, and then stirred for 15 min at this temperature. A solution of 6-methanesulfonyl-2-methyl-pyridin-3-ylamine (Intermediate 4; 653 mg, 3.5 mmol) in 1,2-dimethoxyethane (16 mL) was added dropwise to the solution at −15° C. and the stirring was continued for a further 15 min. tert-Butyl nitrite (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 90%; 483 mg, 4.2 mmol) was added dropwise, and the reaction mixture was stirred at −15° C. for 15 min and then at 0° C. for 1 h. Hexane (20 mL) was added and the solid was filtered off and washed with hexane. The solid was added to acetic anhydride (5 g, 49 mmol) and the mixture was heated at 100° C. for 1 h. The acetic anhydride was evaporated under high vacuum and then 1 M aqueous sodium carbonate solution was added. The mixture was extracted three times with dichloromethane. The dichloromethane was evaporated and the residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate/hexane to give acetic acid 6-methanesulfonyl-2-methyl-pyridin-3-yl ester (331 mg, 41%) as a solid. 1H NMR (CDCl3) δ 2.39 (s, 3H), 2.52 (s, 3H), 3.22 (s, 3H), 7.62 (d, 1H, J=8.2 Hz), 7.98 (d, 1H, J=8.4 Hz).
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([O:14][C:15]([NH:17][CH3:18])=[O:16])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:19])[C@H:6]1[N:5]([CH3:20])[CH2:4][CH2:3]2.CC([O-])(C)C.[K+].CC(O)=O.[CH3:31][C@:32]12[C:39]3[CH:40]=[C:41](O)[CH:42]=[CH:43][C:38]=3N(C)[C@H]1N(C)CC2.C(N1C=CN=C1)(N1C=CN=C1)=O.C1C2C(=CC=CC=2)CCN1>C1COCC1>[CH2:18]1[C:40]2[C:39](=[CH:38][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:17]1[C:15]([O:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[N:7]([CH3:19])[C@H:6]1[N:5]([CH3:20])[CH2:4][CH2:3][C@@:2]21[CH3:1])=[O:16]
Reactant: CNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Reactant: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Agent: CC(C)(C)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CC[C@@]2(C)c3cc(OC(=O)N4CCc5ccccc5C4)ccc3N(C)[C@@H]12
Reaction time: 0.5 h

Procedure:
To a solution of physostigmine (2.75g) in dry THF (28 mL) at 25° C. under a nitrogen atmosphere was added KOtBu (1.28 g) over 0.25 hour. The mixture was kept at 25° C. for 0.5 hour and then treated with glacial HOAc (0.6 mL, 1 equiv., pH=10) to give a mixture containing physostigmine (II) and eseroline (HI) in a 1/99 HPLC ratio. Addition of 1,1'-carbonyldiimidazole (1.92 g, 1.2 equiv) in 1.0, 0.05, 0.05 and 0.1 equiv. portions at 0.25 hour intervals at 20° C. gave after 10 min following each addition the following HPLC ratio of imidazolecarbonyl intermediate (V) and eseroline: 95/5, 96/4, 97/3 and 98/2. Addition of glacial HOAc (3.4 mL, 6 equiv., pH=5) followed by 1,2,3,4-tetrahydroisoquinoline (1.6 g, 1.2 equiv., added over 0.5 hour at 15° C.) gave after 15 hour at 25° C. a mixture containing (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo-[2,3-b]indol-5-y13,4-dihydro-2(1H)-isoquinolinecarboxylate and eseroline in a 97/3 HPLC ratio.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][O:20][CH3:21])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][C:28]2[NH:29][C:30](=[O:32])[S:31][C:27]=2[CH:26]=1>>[CH2:22]([N:17]([CH2:18][CH2:19][O:20][CH3:21])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([NH:24][C:25]4[C:34]([O:35][CH3:36])=[CH:33][C:28]5[NH:29][C:30](=[O:32])[S:31][C:27]=5[CH:26]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:16])[CH3:23]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
100 mg (283 μmol) (RS)-4-chloro-N-ethyl-N-(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 90a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 11.0 mg (7%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(#N)C>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:13][C:3]1[C:2]([Cl:1])=[C:7]([CH3:8])[N:6]=[C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])[N:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OC(=O)N(C)C)c1Cl
Yield: 20 %

Procedure:
A mixture of 3.9 g (0.015 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.6 g (0.015 mole) triethylamine, 1.7 g (0.015 mole) dimethylcarbamoyl chloride, and 80 ml acetonitrile was refluxed 3 days. Rotary evaporation to concentrate the solution yielded a precipitate that was removed by filtration. Rotary evaportation of the filtrate gave a residue which was triturated with petroleum ether to give 1.0 g (20% yield; mp 87°-88° C.) of product. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]12(O)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH:17][C:18]1[CH:23]=[C:22]([CH3:24])[O:21][C:20](=[O:25])[C:19]=1[SH:26]>>[C:6]12([S:26][C:19]3[C:20](=[O:25])[O:21][C:22]([CH3:24])=[CH:23][C:18]=3[OH:17])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Product: Cc1cc(O)c(SC23CC4CC(CC(C4)C2)C3)c(=O)o1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Ice (22 g.) was slowly added to 90 g. of concd. sulfuric acid with stirring, keeping the temperature below 35°C. by means of an ice-salt bath. 1-Adamantanol (18.2 g., 0.120 mole) was added followed by the slow addition of 15.8 g. (0.100 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone, keeping the temperature of the reaction mixture between 0° and 5°C. The ice bath was then removed from the reaction vessel, and the reaction mixture was warmed to 30°-40°C. with vigorous stirring for 1.5 hours. The mixture was then poured into ice water and allowed to stand for about 15 hours. The crude, solid product was collected on a filter, dried in vacuo over calcium chloride and recrystallized from ethanol (Darco) to give 8.3 g. (28 percent) of colorless needles, m.p. 175.5°-176.5°C. A second recrystallization from ethanol gave the pure product as colorless needles, m.p. 176°-177°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:28]([O-])=O)[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:28][C:4]1[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1N
Yield: 92.8 %

Procedure:
To a solution of 2-(5-chloro-3-nitro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (1.25 g, 2.86 mmol) in ethanol (50 mL) was added platinum dioxide (0.92 g). The mixture was hydrogenated on a Parr shaker at 35 psi of hydrogen for 5 minutes at ambient temperature. The reaction was then purged with nitrogen and filtered through celite. The filtrate was concentrated in vacuo to give the title compound (1.08 g).
Reaction SMILES: C[O:2][C:3](=[O:47])[CH:4]([C:24]1[S:25][C:26]([C:29]2[C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[N:31](S(C3C=CC=CC=3)(=O)=O)[CH:30]=2)=[CH:27][CH:28]=1)[NH:5][C:6]([C:8]1[C:9](=[O:23])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7].C(Cl)Cl.C[O-].[Na+]>CO>[F:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[F:21])[CH2:14][N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([NH:5][CH:4]([C:24]2[S:25][C:26]([C:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)=[CH:27][CH:28]=2)[C:3]([OH:47])=[O:2])=[O:7])[C:9]1=[O:23]
Reactant: COC(=O)C(NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)s1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC(C(=O)O)c1ccc(-c2c[nH]c3ncccc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-{[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-acetic acid methyl ester (0.085 g, 0.00012 mol;) was dissolved in Methylene chloride (3 mL, 0.05 mol;) then 0.5 M of Sodium methoxide in methanol (3 mL) was added and the reaction was heated at 75 C for 1 hour. LC-MS showed the disappearance of starting material and the appearance of product at 1.34 520.75. The reaction was concentrated and dissolved in DMSO and methanol 1:1 for purification by Gilson Preparative HPLC. ES (+) MS m/e=520.75
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1F)[N:8]([CH2:15][CH2:16][F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[ClH:29]>CS(C)=O.C(O)C>[ClH:29].[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[N:8]([CH2:15][CH2:16][F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(CCF)c12
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCO
Product: COc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)O)cn(CCF)c12
Temperature: 70 °C
Reaction time: 6 h

Procedure:
0.11 g (0.0004 mole) of 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Preparation 15) and 0.20 g (0.002 mole) of N-methylpiperazine were dissolved in 3 ml of dimethyl sulfoxide, and the mixture was stirred at 70° C. for 6 hours. At the end of this time, the solvent and excess N-methylpiperazine were distilled off at the same temperature and under reduced pressure, and the residue was washed with ethyl acetate to give a pale-yellow powder. This powder was suspended in a mixture of 20 ml of ethanol and 1 ml of concentrated hydrochloric acid, and the suspension was concentrated by evaporation under reduced pressure. 20 ml of water were added to the residue, and the mixture was filtered to remove insoluble materials. The filtrate was concentrated by evaporation under reduced pressure to give 30 mg of 6-fluoro-1-(2-fluoroethyl)-8-methoxy-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride as a colorless powder melting at 270°-272° C. (with decomposition).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[CH3:8][N:9]1[C:18]2[NH:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:27]([CH3:41])[CH:26]=3)=[O:24])[CH2:13][C:12]=2[CH:11]=[N:10]1>ClCCl.C(N(CC)CC)C>[CH3:1][S:2]([N:38]1[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:23]([N:14]3[CH2:13][C:12]4[CH:11]=[N:10][N:9]([CH3:8])[C:18]=4[NH:17][C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]3=4)=[O:24])=[CH:26][C:27]=2[CH3:41])[CH2:40][CH2:39]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride (Compound number 408) (2.67 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=539.2
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:25][C@H:26]1[CH2:32][CH2:31][C@H:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][N:28]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:27]1=[O:47].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C.CN(C)C=O>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH:2]([NH:25][C@H:26]2[CH2:32][CH2:31][C@H:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][N:28]([CH2:39][C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[C:27]2=[O:47])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2ccccc2)CC[C@H](N)C1=O
Reactant: CCOC(=O)C(Br)CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OC(C)(C)C)CC1)N[C@H]1CC[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.08 g of ethyl 2-bromo-6-(1-t-butoxycarbonyl4-piperidyl)hexanoate, 0.85 g of t-butyl rel-α-[3(S)amino-2-oxo-6(R)-phenylperhydroazepin-1-yl]acetate, 0.4 g of sodium iodide and 1.4 g of sodium carbonate were added to 15 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 days. Ethyl acetate and water were then added to the reaction mixture, and, after stirring, the ethyl acetate layer was separated, washed with an aquous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as the eluent.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][C@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:37]([OH:39])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:33]6[CH2:34][CH2:35][C@H:36]([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:37]6=[O:39])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
To a suspension of 47 (230 mg, 0.51 mmol, scheme 15) in DCM (5.1 mL) were added (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (224 mg, 1.03 mmol) and acetic acid (59 μl, 1.03 mmol). After stirring for 20 min at room temperature, NaBH(OAc)3 (326 mg, 1.54 mmol) was added. The reaction mixture was stirred for 16 h, quenched by addition of 1N NaOH, and concentrated. The solid was collected by filtration and purified by Biotage (SNAP 50 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 107 (120 mg, 0.19 mmol, 37% yield). MS (m/z): 633.7 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH2:5][O:6][C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)=[O:8].Cl>O1CCOCC1>[NH:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[O:6][CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:25]=[C:24]([Cl:26])[CH:23]=2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)OCc1cc(Cl)cc(Cl)c1

Procedure:
A reaction mixture comprising tert-butyl 4-((((3,5-dichlorobenzyl)oxy)carbonyl)amino)piperidine-1-carboxylate (2.01 g, 4.98 mmol) and 4M HCl in dioxane (1.246 ml, 4.98 mmol) in dioxane (16.61 ml) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. No further purification under taken and the material was dried and taken on to the next step.
Reaction SMILES: Cl.C([O:9][CH:10]([NH:27][C:28](=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:38])=[NH:37])[C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])C1C=CC=CC=1.CN(C)C=O>C(O)(=O)C.[Pd]>[NH:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28](=[O:39])[NH:27][CH:10]([OH:9])[C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:36]([NH2:38])=[NH:37]
Reactant: N=C(N)NCCCCCCC(=O)NC(OCc1ccccc1)C(=O)NCCCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCC(=O)O
Yield: 57.5 %

Procedure:
0.79 g (1.41 mmol) of benzyl 7-benzyloxy-15-guanidino-6,9-dioxo-5,8-diazapentadecanoate hydrochloride was dissolved in 10 ml of 1N acetic acid and 10 ml of dimethylformamide and catalytically reduced in the presence of palladium black at room temperature under a hydrogen pressure of 10 kg/cm2 for 34 hours. After filtering off the catalyst, the filtrate was adsorbed on 100 ml of CM-Sephadex® C-25 (Na) and subjected to gradient elution between 500 ml of distilled water and 500 ml of 0.3M sodium chloride. Fractions containing the aimed compound were combined and concentrated to dryness under reduced pressure. 90% ethanol was added to the residue and the insoluble sodium chloride was filtered off. Next, the filtrate was subjected to gradient elution between 500 ml of distilled water and 500 ml of a 30% aqueous solution of acetone by using a column packed with 100 ml of Diaion® HP-20. Fractions containing the aimed compound were combined and concentrated under reduced pressure. The residue was dissolved in a small amount of distilled water and the insoluble matters were filtered off. By lyophilizing the product, 0.280 g of the aimed compound was obtained (yield: 57.8%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1([NH2:20])[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:20][C:17]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH2:19][CH2:18]1)=[O:7]
Reactant: O=C(O)c1cccc(I)c1
Reactant: NC1(c2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NC1(c2ccccn2)CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Iodobenzoic acid (2.7 g, 11.1 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (1.5 g, 11.1 mmol, 1 eq), EDCI.HCl (3.2 g, 16.7 mmol, 1.5 eq), HOBT (2.2 g, 16.7 mmol, 1.5 eq) and DIPEA (6 ml, 33.5 mmol, 3 eq) were dissolved in DCM and the resulting mixture was stirred at room temperature for 18 hours. Water was added to the mixture and the product was extracted with DCM. The organic layer was concentrated and the product crystallized using dichloromethane and hexane. Yield: 2.3 g (57%). 1HNMR (400 MHz, DMSO-d6): δ 1.26 (m, 2H), 1.54 (m, 2H), 7.13 (t, J=4.04 Hz, 1H), 7.29 (m, 2H), 7.69 (t, J=8.06 Hz, 1H), 7.92 (d, J=3.05 Hz, 2H), 8.29 (s, 1H), 8.45 (d, J=4.56 Hz, 1H), 9.33 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:48][N:49]([CH2:51][CH2:52]O)[CH3:50].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:16]([CH2:52][CH2:51][N:49]([CH3:50])[CH3:48])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1
Reactant: CN(C)CCO
Reactant: O=S(=O)(Nc1ccccc1NCCOc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCN(c1ccccc1NCCOc1ccc(Cl)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 59.6 %

Procedure:
The product of Example 1 (10.71 g), triphenylphosphine (9.63 g), and dimethylaminoethanol (3.27 g) were dissolved in tetrahydrofuran (60 ml). To the resultant solution diisopropyl azodicarboxylate (7.43 g) was added dropwise over 30 min with stirring on ice. After completion of dropwise addition of the solution, the mixture was further stirred for one hour at room temperature and the solvent was removed under reduced pressure. The residue was purified through two steps: NH silica gel column chromatography (solvent=hexane:ethyl acetate=3:1,) and silica gel column chromatography (solvent=hexane:ethyl acetate=1:1 and chloroform:methanol=10:1). The resultant product was re-crystallized from ether-hexane, to thereby obtain the target product (7.42 g) in the form of crystals. Mp.: 99° C.; 1H-NMR(270 MHz, CDCl3) δ: 7.65 (2H, d, J=8.58 Hz), 7.41 (2H, d, J=8.58 Hz), 7.25 (2H, d, J=8.91 Hz), 7.18 (1H, m), 6.87 (2H, d, J=8.91 Hz), 6.72 (1H, d, J=8.25 Hz), 6.47 (2H, m), 5.78 (1H, brs), 4.08 (3H, m), 3.51 (2H, m), 3.12 (1H, m), 2.42 (1H, m), 2.22 (1H, m), 2.20 (6H, s).