Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[CH:3]=1.ClC1C(C(OCC)=S)=C(C)[N:18]=C(C)C=1.C1COCC1.O1CCOCC1>C(N(CC)CC)C>[NH2:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: CCOC(=S)c1c(Cl)cc(C)nc1C
Reactant: CCOC(=S)c1cnc(C)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=S)c1cnc(C)cc1N

Procedure:
In accordance with Scheme 1 below, ethyl 4-chloro-2-methylthiopyridine-5-carboxylate (II with A=CH) (prepared according to Todd et al., J. Amer. Chem. Soc. (1943), 65, 350-354; Pesson, M., Eur. J. Med. Chem. (1974), 9(6), 585-590; Shadbolt, R., J. Chem. Soc. (1967), 13, 1172-1178) or ethyl 4-chloro-6-methyl-2-methylthiopyridine-5-carboxylate (II with A=C-Me) (prepared according to the method described in WO 2005/105 801) is reacted with an amine of formula R5—NH2 (in which R5 is as defined previously in relation to formula (I) according to the invention) in an organic solvent such as THF or dioxane, and in the presence of an organic base, for example triethylamine, at room temperature, according to the method described by D. Boschelli et al. in J. Med. Chem. (1998), 41, 4365-4377, to give an ethyl 4-amino-2-methylthiopyridine-5-carboxylate derivative of formula (III).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([B-](F)(F)F)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[K+].[F:19][C:20]1[C:25]([CH2:26][CH2:27][OH:28])=[C:24](I)[CH:23]=[CH:22][N:21]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:7]([C:24]1[CH:23]=[CH:22][N:21]=[C:20]([F:19])[C:25]=1[CH2:26][CH2:27][OH:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: F[B-](F)(F)Cc1ccccc1
Reactant: OCCc1c(I)ccnc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: OCCc1c(Cc2ccccc2)ccnc1F

Procedure:
As generally described in Molander, G. A.; Ito, T., Cross-Coupling Reactions of Potassium Alkyltrifluoroborates with Aryl and 1-Alkenyl Trifluoromethanesulfonates. Organic Letters 2001, 3, (3), 393-396, a 10 mL, Biotage microwave vessel was charged with cesium carbonate (0.460 g, 1.41 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.0517 g, 0.0706 mmol), potassium benzyltrifluoroborate (0.140 g, 0.706 mmol), 2-(2-fluoro-4-iodopyridin-3-yl)ethanol (0.1257 g, 0.471 mmol) and a stir bar. The vessel was sealed, and purged with Argon by piercing the septa with an Ar line and an 18-gauge needle. To the vessel was added 5 mL THF and 1 mL water. The needles were removed, and the vessel placed in a 90° C. heater block for 24 h. The solution was cooled. The THF was removed under a stream of nitrogen, and 5 mL CH2Cl2 was added. The biphasic solution was loaded onto a 10 mL Varian Chem elute CE 1005 and extracted with CH2Cl2 (5×10 mL). The solvent was removed in vacuo. The residue was passed through a 15 mL plug of SiO2 conditioned with CH2Cl2, and eluted with 50 mL 10% EtOH in CH2Cl2. The solvent was removed in vacuo. The sample was purified using a Waters Spherisorb S5 column (20×250 mm, 60 Å pore, 5 μm particle size); flow=20 mL/min; A=DCE, B=EtOH; isocratic at 1% B. A band that eluted from 7.7-9.3 minutes was isolated. The solvent was removed in vacuo to afford 2-(4-benzyl-2-fluoropyridin-3-yl)ethanol. 1H NMR (400 MHz, CDCl3) δ ppm 1.66 (br. s., 1 H) 2.95 (td, J=6.77, 0.44 Hz, 2H) 3.77 (dd, J=6.85, 6.46 Hz, 2 H) 4.12 (s, 2 H) 6.91 (d, J=5.18 Hz, 1 H) 7.07-7.16 (m, 2 H) 7.21-7.27 (m, 1 H) 7.31 (tt, J=7.29, 1.71 Hz, 2 H) 7.97 (d, J=5.09 Hz, 1 H). 13C NMR (101 MHz, CDCl3) δ ppm 28.81 (s, 1 C) 38.30 (d, J=3.47 Hz, 1 C) 61.64 (s, 1 C) 119.13 (d, J=30.34 Hz, 1 C) 123.24 (d, J=3.47 Hz, 1 C) 126.79 (s, 1 C) 128.80 (s, 4 C) 138.29 (s, 1 C) 144.92 (d, J=16.04 Hz, 1 C) 154.04 (d, J=5.63 Hz, 1 C) 162.88 (d, J=237.55 Hz, 1 C). MS (ESI pos. ion) m/z (MH+): 232.1, calcd for C14H14FNO+H+=232.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>C(O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A mixture of ethyl 7-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indole-2-carboxylate (1.03 g), 8N aqueous sodium hydroxide solution (1.3 mL), tetrahydrofuran (5 mL) and ethanol (15 mL) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.92 g, yield 90%) as colorless crystals. melting point>277° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].C([Cl:30])(=O)CCCCCCC/C=C\CCCCCCCC>ClCCl>[ClH:30].[ClH:30].[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: NCCNCCNCCN
Solvent: ClCCl
Product: Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
1.12 g (7.5 mmol) of triethylenetetramine was added to 25 mL of dichloromethane and dissolved with stirring in an ice water bath at 5° C. for 30 minutes. To the solution, a solution of 2.00 g (6.0 mmol) of oleoyl chloride in 20 mL of dichloromethane in a separate reactor was added slowly dropwise while it was allowed to react at 5° C. for 3 hours. Due to hydrogen chloride produced during the reaction, unreacted triethylenetetramine HCl was precipitated. Before the end of the reaction, the upper layer solution was taken and analyzed by thin layer chromatography (TLC) with a mobile phase of ethanol:chloroform (2:1) to determine whether the reaction was completed. After it was determined that the reaction had completed, the precipitate was removed using filter paper.
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>C1COCC1>[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:2])=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C=O)cc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A suspension of 34.1 g of methylriphenylphosphonium bromide in 400 mL of dry THF was treated with 10.7 g of potassium t-butoxide under a nitrogen atmosphere. After stirring for 10 min at room temperature, the yellow solution was treated with a solution of 21.2 g of p-t-butoxycarbonyloxybenzaldehyde in 100 mL of dry THF. After stirring for one hour, the mixture was poured into cold water and extracted with ethyl acetate. The organic phase was washed, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC to yield 16.6 g (79%) of pure p-t-butoxycarbonyloxystyrene. Alternately, IIIc was purified by distillation under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])=[O:25])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[C:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH:27]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)c1cccc(N)c1
Product: CCOC(=O)c1cccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 88.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (400 mg, 1.18 mmol) and m-ethoxycarbonylaniline (250 μL, 1.5 mmol) to give 510 mg of the title compound (89%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (bs, 1H), 10.25 (s, 1H), 8.20 (bs, 1H), 7.85 (d, 1H, J=8.1 Hz), 7.65 (d, 1H, J=8.1 Hz), 7.30 (t, 1H, J=8.1 Hz), 7.24 (d, 1H, J=2Hz), 7.17 (d, 1H, J=2 Hz), 5.16~5.27 (m, 1H), 4.32 (q, 2H, J=7.2 Hz), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.55~2.68 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H), 1.33 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[C:15]([CH3:16])=[N:14][CH:13]=[C:12]([CH3:17])[N:11]=1>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[C:15]([CH3:16])=[N:14][CH:13]=[C:12]([CH3:17])[N:11]=2)[N:8]=[CH:7]1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: NCCc1c[nH]cn1
Solvent: CC(C)O
Product: Cc1cnc(C)c(NCCc2c[nH]cn2)n1

Procedure:
1 g (8.9 mmol) of histamine and 1.28 g (8.9 mmol) of 2-chloro-3,6-dimethylpyrazine in 10 ml of 2-propanol are brought to reflux for 3 days, evaporated and the residue is chromatographed on a column of silica gel, using mixtures of chloroform and methanol (1, 10 and 20% respectively) to give the title compound in the form of an oil. The latter is converted to a monohydrated dioxalate salt which is crystallized from an isopropanol/ether (1/1) mixture. M.p.: 164°-165° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][C@@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][OH:11])=[O:6].[H-].[Na+]>CN(C=O)C>[OH:11][CH2:10][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][N:7]1[CH2:2][CH2:3][CH2:4][C:5]1=[O:6]
Reactant: O=C(CCCCl)NC[C@H](CO)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CO)CN1CCCC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.6 %

Procedure:
A solution of (R)-benzyl 1-(4-chlorobutanamido)-3-hydroxypropan-2-ylcarbamate (3.9 g, 11.9 mmol) in DMF was cooled to 0° C., followed by the addition of NaH (0.72 g, 17.9 mmol). The mixture was stirred at rt for 4 h. DMF was removed under high vacuum, and the residue was taken up in EtOAc, washed with 1 N HCl, saturated NaHCO3, NaCl, dried over Na2SO4, and concentrated to give the crude product, which was purified by column chromatography to give (R)-benzyl 1-hydroxy-3-(2-oxopyrrolidin-1-yl)propan-2-ylcarbamate (1.1 g, yield 33%). 1H NMR (CDCl3, 400 MHz) δ 7.39-7.27 (m, 5H), 5.45 (d, 1H), 5.10 (d, 1H), 4.70 (s, 2H), 3.72 (m, 1H), 3.54-3.40 (m, 4H), 3.20-3.17 (m, 1H), 2.40 (t, 2H), 2.07 (t, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:10]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:11]2[CH:10]=[C:9]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:22]=1
Reactant: OB(O)c1cccs1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2cccs2)cc1Nc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
To a mixed solution of toluene 2.0 mL, ethanol 0.6 mL and water 0.4 mL of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added thiophene-2-boronic acid 42 mg, sodium carbonate 64 mg and tetrakis(triphenylphosphine)palladium(0) 13 mg at room temperature, and it was stirred under application of pressure at 160° C. for 5 minutes. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 0.5 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane] to give methyl 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoate. 2.0 mol/L Sodium hydroxide aqueous solution 1.0 mL was added to ethanol 7.0 mL solution of the obtained methyl 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoate, and it was stirred at room temperature for 1 hour and 30 minutes. 0.5 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture, the organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoic acid 3.5 mg of pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ccsc2)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ccsc2)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1.38 g of 5-(4-chloro-phenyl)-6-methyl-4-(3-thienyl)-2H-pyridazin-3-on e and 6 ml of phosphorus oxychloride were mixed. The mixture was stirred for 1 hour on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue was added ethyl acetate and ice water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-partitioned. The organic layer was washed with brine three times, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 1.34 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(3-thienyl)pyridazine (hereinafter, described as compound (9) of the present invention.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>ClCCl>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CO)c3o2)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(OC)cc(CBr)c3o2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 233.5 %

Procedure:
Benzyl Alcohol 3 (1.02 g, 3.59 mmole) was dissolved in dichloromethane (70 mL) and cooled to −78° C. in an dry ice/acetone bath. Boron tribromide (1.0 M in dichloromethane), (3.95 mL, 3.95 mmole) was added drop wise over 15 minutes. After 30 minutes, the light orange solution was allowed to come to room temperature and reacted for an additional four hours. The solution was concentrated and added to saturated sodium bicarbonate, and extracted with ethyl acetate. Organic layers were combined and washed with water and brine, dried over magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 2.91 g (81%) of benzyl bromide 17 as a white solid: Mp=158-160° C.; 1H NMR (DMSO-d6) δ 7.88 (d, 2 H, J=8.8 Hz), 7.23 (s, 1 H), 7.11 (d, 2 H, J=2.5 Hz), 7.09 (d, 2 H, J=8.9 Hz), 6.99 (d, 1H, J=2.5 Hz), 4.96 (s, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)=[O:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-nitropyridin-2-amine (0.5 g, 3.59 mmol) was slurried in DCM (12 ml). TEA (2.5 ml, 18 mmol) and DMAP (88 mg, 0.72 mmol) were added. 2,2-dimethylpropanoyl chloride was added prop wise and the mixture stirred at RT overnight. The mixture was diluted into water (30 ml):saturated sodium bicarbonate (aq, 10 ml), extracted with DCM (3×30 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered, and the volatiles removed in vacuum. The material was purified by chromatography on SiO2 eluting with 10% acetone: hexanes to give the titled compound.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4].[Na+].[I-:25]>CC(C)=O>[I:25][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4]
Reactant: [I-]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CI)ccc1OCc1ccccc1
Yield: 95.3 %

Procedure:
A mixture of (R)-2-bromo-1-[4-(phenylmethoxy)-3-[(methyl-sulfonyl)amino]phenyl]ethanol (880 mg, 2.2 mmol) and NaI (3.66 g, 24.4 mmol) is refluxed in acetone (35 mL) for one hour. After the mixture is filtered, the filtrate is concentrated, and the residue is separated into ethyl acetate and water. The organic phase is washed with a 25% (w/w) aqueous sodium bisulfite solution, and dried over magnesium sulfate to give the desired (R)-2-iodo-1-[4-(phenylmethoxy)-3-[(methyl-sulfonyl)amino]phenyl]ethanol (938 mg, yield: 95%).
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]=[CH:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11]NC(=O)C2C=CC(N3CCN(CC4C=NC=CC=4)CC3)=CC=2)=[CH:9][CH:8]=1)=[O:4].C(OC(=O)C=CC1C=CC(C[S:49](=[O:58])(=[O:57])[NH:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=CC=1)C>>[OH:1][NH:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][S:49](=[O:58])(=[O:57])[NH:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[CH:34][CH:35]=1
Reactant: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Reactant: CCOC(=O)C=Cc1ccc(CS(=O)(=O)Nc2cccnc2)cc1
Product: O=C(C=Cc1ccc(CS(=O)(=O)Nc2cccnc2)cc1)NO
Yield: 64 %

Procedure:
The titled compound was prepared as described in the process (1-3) using the compound from the process (9-3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:29][S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])(=[O:32])=[O:31])[CH:19]=[CH:20][C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:29][S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])(=[O:31])=[O:32])[CH:19]=[CH:20][C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)ccc2Cc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(Oc1ccc(Cc2ccccc2)c(OCC2CCNCC2)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.2 %

Procedure:
A solution of 380 mg (0.666 mmol) of 2-chlorobenzenesulfonic acid 3-[[1-N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]-4-benzylphenyl ester, as prepared in the preceding step, in 5 mL of methylene chloride was added 3 mL of 4N HCl in dioxane. The reaction mixture was stirred at ambient temperature for 1 h, carefully quenched with with saturated NaHCO3, dried (K2CO3), and concentrated to give 381 mg of crude title compound as an oil which was used as is in the next step. 1H-NMR (300 MHz, CDCl3) δ 7.96 (d, 1H), 7.54-7.63 (m, 2H), 7.34-7.40 (m, 1H), 7.08-7.24 (m, 4H), 6.91 (d, 1H, J=8 Hz), 6.66 (d, 1H, J=2 Hz), 6.54 (dd, 1H, J=2, 8 Hz), 3.88 (s, 2H), 3.66 (d, 2H, J=5 Hz), 3.10 (d, 2H, J=12 Hz), 2.62 (t, 2H, J=10 Hz), 1.1-1.2 (m, 4H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C25H26ClNO4 S: 472.1 (M+H). Found: 472.6.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:21][NH2:22])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(Br)cc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(Br)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{9} (6.23 g, 18.3 mmol, 1 equiv.), anhydrous hydrazine (2.3 mL, 73.1 mmol, 4 equiv.), ethanol (25.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{9} (4.64 g, 78%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.39 (d, 2H, J=8.5 Hz) 7.15 (d, 2H, J=8.5 Hz), 3.83 (br s, 2H), 3.41 (s, 2H) 3.04 (s, 2H), 2.49 (br s, 4H), 2.41 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 136.9, 131.2, 130.5, 120.8, 61.9, 60.4, 53.5, 52.9.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.N[C@@H:38]([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)[C@@H:39]([OH:49])[CH:40]([OH:48])[CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C.C(N(CC)CC)C>[NH2:1][CH:41]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH:40]([OH:48])[CH:39]([OH:49])[CH2:38][CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
50 mg of L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine was dissolved in 0.2 ml of dry DMF, and 28.2 mg of 1-hydroxybenzotriazole and 33.2 mg of DCC were added thereto at 0° C. under stirring. Then, 55.2 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was dissolved in 0.2 ml of dry DMF, and 31.1 mg of triethylamine was added thereto for neutralization. This mixture was added to the previous reaction solution, and the mixture was stirred at 0° C. for two hours and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform/methanol= 20/1) to obtain 20.1 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless