Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH2:34](OC(C1(SC2SC(N)=NC=2)CCC1)=O)C.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:33][C@H:30]1[CH2:29][CH2:28][C@H:27]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]3([C:3]([OH:5])=[O:4])[CH2:1][CH2:34][CH2:6]3)=[CH:9][N:10]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)C1(Sc2cnc(N)s2)CCC1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2ccccc2)C(=O)Nc2ncc(SC3(C(=O)O)CCC3)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-amino-thiazol-5-ylsulfanyl) -cyclobutanecarboxylic acid ethyl ester prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:14])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1F)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 15.4 %

Procedure:
To a solution of the above crude Boc-Tyr(2-F)-OH (0.82 g), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.77 g, 2.11 mmol) and CMPI (0.81 g, 3.17 mmol) in THF (5 ml), TEA (1.18 ml, 8.44 mmol) was added under cooling with ice and stirred at room temperature for 23 hours. The reaction mixture was mixed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:concentrated aqueous ammonia=30:1:0.05), giving the titled compound (0.21 g, 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:8]1[CH2:10][C:11](=[O:12])[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]1=2
Reactant: Nc1cnccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2ccncc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
In a 500 ml flask equipped with a reflux apparatus, 3-amino-pyridin-4-ol (7.8 g, 71 mmol) was dissolved in N,N-dimethyl formamide (350 ml). To the reaction solution was added chloroacetyl chloride (6.2 ml, 78 mmol) dropwise at room temperature and then stirred at room temperature for 30 minutes. Potassium carbonate (24 g, 177 mmol) was added thereto and the mixture was heated at 100□ for 40 hours. After completion of the reaction, water was added thereto. The mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by recrystallizing from solvents of ethyl acetate and n-hexane to obtain white solid (5.6 g, 53%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11]
Reactant: O=S1(=O)CCCO1
Reactant: CC1CCCCC1N
Solvent: C1CCOC1
Product: C[C@H]1CCCC[C@H]1NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-methylcyclohexylamine (98% cis and trans isomers, 10.0 g, 88.3 mmol) in tetrahydrofuran (60 mL) was slowly added a solution of 1,3-propane sultone (10.5 g, 84.1 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×50 mL). The solid was dissolved in 50% EtOH/water (200 mL); and solution was treated with Dowex 50WX8 resin (15 g). The suspension stirred at room temperature for 15 min. The resin was removed by filtration. The filtrate was concentrated to half of the original volume on a rotary evaporator. The solid product slowly crystallized. The product was collected by filtration, washed with acetone (2×50 mL) and dried in a vacuum oven (50° C.), to afford compound DJ (10.4 g, 53%): 1H NMR (D2O, 500 MHz) δ ppm 3.15 (m, 1H), 3.03 (m, 1H), 2.88 (t, 2H, J=7.3 Hz), 2.76 (m, 1H), 1.98 (m, 3H), 1.68 (m, 2H), 1.51 (m, 2H), 1.18 (m, 3H), 1.01 (m, 1H), 0.92 (m, 3H). 13C NMR (D2O, 125 MHz) δ ppm 62.97, 48.16, 42.72, 34.77, 33.50, 27.57, 24.51, 24.23, 21.51, 17.80. ES-MS 234 (M-1).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:3](=[O:9])[N:4]([CH3:12])[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1c(=O)[nH]cc(F)c1=O
Reaction time: 24 h

Procedure:
5-Fluorouracil, namely Compound (5) (1.30 g; 10 mmol), methyl iodide (CH3I) (2.13 g; 15 mmol) and potassium carbonate (0.69 g; 5 mmol) were added to acetone (20 ml), and the resulting mixture was stirred at 60°-70° C. for 24 hours. The reaction solution obtained was filtered to remove potassium carbonate, and the filtrate was concentrated under reduced pressure. To the resulting residue was added a small volume of chloroform, and then the residue was fractionated by column chromatography on silica gel (eluent: chloroform) to isolate 5-fluoro-3-methyluracil, namely Compound (6) shown above (355 mg) as white needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:28][C:35](=[O:37])[CH3:36])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A solution of 6-(1-Azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (68.2 mg, 0.143 mmol) and triphenylphosphine (56.3 mg, 0.215 mmol) in tetrahydrofuran (5.0 mL) and water (0.10 mL) was stirred at 60° C. for 20 hr. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine as a white solid (67.2 mg). To a solution of 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (67.9 mg) and pyridine (0.12 mL, 1.48 mmol) in tetrahydrofuran (5.0 mL) was added acetyl chloride (0.051 mL, 0.717 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (33.1 mg, 0.067 mmol, 47%) as white crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(=O)(O)[O-].[Na+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18].[OH-].[Na+]>O.C(O)C>[N+:17]([CH:20]([CH3:21])[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][CH:10]=1)[OH:9])([O-:19])=[O:18]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(C(O)C(C)[N+](=O)[O-])cc1

Procedure:
The procedure of Example 1 was followed for the reaction of 74 g of p-isopropylbenzaldehyde and 57 g of sodium bisulfite with 75 g of 1-nitroethane and 40 g of sodium hydroxide. Water and ethanol served as solvents. The product weighed 41 g and was a light yellow oil which slowly crystallized on standing: ir (film) 2.85 (m), 3.35 (m), 6.5 (s), 7.2 (m), 7.35 (m), 9.5 (m), 11.95 (m) microns; nmr (CDCl3) 7.1 (4H, s), 5.0 to 4.6 (2H, m) 3.05 (1H, broad), 2.9 (1H, quintet), 1.3 (6H, d), 1.5 to 1.2 (3H, m) ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[CH2:26][CH3:27])=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CCc1ccccc1C(=O)O
Agent: Cl
Product: CCc1ccccc1C(=O)N1CCC(N2N=C(c3ccc(OC)c(OC)c3)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-ethylbenzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Br:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Br)C[C@H]1N
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.11 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.082 g), DBU (0.054 g) and anhydrous acetonitrile (5 ml) was refluxed for 1.5 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml) and washed with 10% aqueous citric acid solution and water successively. The organic layer was concentrated under reduced pressure and to the oily residue was added methanol to crystallize. The resulting precipitate was collected by filtration, washed with chilled methanol and this was added to concentrated hydrochloric acid-methanol (1:1, 2 ml) and stirred for an hour at room temperature. The reacting mixture was neutralized with concentrated aqueous ammonia, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:concentrated aqueous ammonia=20:6:1) and then recrystallized from dichloromethanemethanol (1:1) to give the title compound (0.04 g) as pale yellow powder, mp 186°-190° C. (decompd.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]([NH:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][NH2:28])=[O:24])=[CH:17][CH:16]=1>CCOCC.[OH-].[Na+]>[CH2:21]([O:22][C:23]([NH:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][NH:28][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:24])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(N[C@@H](CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
A solution of 21.4 g of 2-naphthylsulfonyl chloride in 200 ml of ether is added dropwise while stirring to a solution of 15 g of N-α-Z-L-2,3-diaminopropionic acid in 189 ml of 1N sodium hydroxide solution. The mixture is left to stir for a further 6 hours. Subsequently, the reaction mixture is poured into ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The organic is washed with water, dried and evaporated. After chromatography of the residue on silica gel with methylene chloride/methanol/acetic acid (94:5:1) there are isolated 17.9 g of N-[(benzyloxy)carbonyl]-3-(2-naphthylsulfonamido)-L-alanine.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1>C(N)CN.C(O)(C)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:3][CH2:4][CH2:5][NH2:6]
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CC(C)O
Solvent: NCCN
Product: NCCNc1nc2ccccc2[nH]1
Temperature: 10 °C
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-1H-benzoimidazole (1 g) in 4 mL of ethane-1,2-diamine was heated to 10° C. for several hours until complete by HPLC. The reaction was allowed to cool and diluted with a mixture of chlororform and isopropanol (3:1). The organic phase was washed with water then dried and concentrated to give 216 mg of product as a solid which was used in the next step without further purification. MS(ES): m/e (EI*) 177.1 [M+H]
Reaction SMILES: [Li]CCCC.[CH2:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[I:17]I.O>O1CCCC1>[CH2:6]([C:12]1[O:13][C:14]([I:17])=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: II
Reactant: CCCCCCc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1ccc(I)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of n-BuLi (24.7 mL, 1.6 M in hexanes, 39.5 mmol, 1.4 equivalents) was added dropwise to a solution of 2-hexylfuran (4.3 g, 28.3 mmol) in dry tetrahydrofuran (THF, 50 mL) at −78° C. under N2. The reaction mixture was warmed to 0° C., stirred for 10 min and cooled again to −78° C. To this solution was added slowly iodine (9.3 g, 36.7 mmol) in 25 mL of THF, and the solution was warmed slowly to 0° C. and stirred for 2 h at 0° C. After addition of 100 mL of water, the solution was extracted with hexane. The organic layer was washed with aqueous Na2S2O3 solution (30 mL) and water, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane) to afford 6 g of 2-hexyl-5-iodofuran (76%) as a pale brownish oil. 1H NMR (300 MHz, CDCl3): δ6.37 (d, J=3.14 Hz, 1H), 5.88 (d, J=3.16 Hz, 1H), 2.60 (t, J=7.56, 7.56 Hz, 2H), 1.58 (td, J=15.11, 7.66, 7.66 Hz, 2H), 1.24-1.39 (m, 6H), 0.86 (t, J=6.77, 6.77 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 162.3, 120.6, 108.0, 84.3, 31.6, 28.8, 28.3, 27.8, 22.6, 14.1 ppm. HRMS (FD): m/z calcd for C10H15IO: 278.0168. Found 278.0172.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)=[CH:15][C:14]=1[N+:29]([O-:31])=[O:30]>CS(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)=[CH:15][C:14]=1[N+:29]([O-:31])=[O:30])[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cccc(Nc2ccc(F)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(Nc2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a suspension of 60% of NaH in mineral oil (300 mg, 7.41 mmol) in DMSO (2.5 mL) is added dimethyl malonate (851 μL, 7.41 mmol). The mixture is heated to 60° C. for 10 minutes and then cooled to ambient temperature before (4-fluoro-3-nitro-phenyl)-(3-nitro-phenyl)-amine (686 mg, 2.47 mmol) is added. The resulting mixture is heated to 60° C. for 3 hours and quenched with saturated aqueous NH4Cl solution. The mixture is extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The crude product is purified by column chromatography (EtOAc/Hexane, gradient) to give the desired product: 1H NMR (400 MHz, CDCl3) δ. 7.94 (s, 1 H), 7.88 (d, 1 H), 7.70 (d, 1 H), 7.51-7.47 (m, 1 H), 7.44-7.40 (m, 2 H); 7.32-7.28 (m, 1H), 5.27 (s, 1H), 3.83 (s, 6H); LC-MS: 390.3 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[CH:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Nc2ccccc2)nc1
Reactant: NCCCc1ccccc1
Product: O=C(NCCCc1ccccc1)c1ccc(Nc2ccccc2)nc1

Procedure:
The title compound was prepared in analogy to example 1, but starting from 6-phenylamino-nicotinic acid and using 3-phenyl-propylamine in the third step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][N+:21]=1[O-].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(N)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol), 2-chloro-4-nitro-pyridine oxide (2.2 g, 12 mmol) and Cs2CO3 (5.7 g, 18 mmol) were mixed in DMF (50 mL) and stirred at room temperature for 1 h. Water was added and the reaction mixture was adjusted to pH 3. The reaction mixture was extracted with ethyl acetate. The organic layers were concentrated to give a residue. The residue was purified by flash column chromatography (dichloromethane:methanol=15:1) to give the title compound (0.77 g, 29%) as a brown solid. MS found (electrospray): (M+H)+=389.1.
Reaction SMILES: [O:1]=[C:2]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH:28]1([S:33][CH2:34][CH2:35]Cl)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[O:1]=[C:2]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:35][CH2:34][S:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:7][C@@H:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 65 °C
Reaction time: 17 h
Yield: 39.4 %

Procedure:
A mixture of 4.9 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate, 2.9 g of 2-chloroethyl cyclopentyl sulfide, 9 g of potassium carbonate, and 2.7 g of potassium iodide in 130 cm3 of acetonitrile was stirred for 17 hours at a temperature in the region of 65° C. After cooling to a temperature in the region of 20° C., the reaction mixture has 150 cm3 of water added and was extracted with 3 times 60 cm3 of ethyl acetate. The organic extracts were combined, washed with 2 times 50 cm3, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil was obtained, which product was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 4 cm; silica volume 300 cm3), elution was carried out with pure ethyl acetate, and approximately 70-cm3 fractions were collected. The fractions comprising the expected product were combined and then concentrated under the above conditions. 2.6 g of methyl (3R,4R)-4-(3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate were obtained in the form of an oil with a yellow color.
Reaction SMILES: O.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][S:10][N:11]=[C:7]2[CH:6]=1)([O-])=O>C1COCC1.[Zn]>[N:9]1[S:10][N:11]=[C:7]2[CH:6]=[C:5]([NH2:2])[CH:13]=[CH:12][C:8]=12
Reactant: O=[N+]([O-])c1ccc2nsnc2c1
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2nsnc2c1
Yield: 47.9 %

Procedure:
To a suspension of MoCl5 (8 g) in 50 ml of THF was added 10 ml of H2O and followed by the addition of Zn dust (3 g) 5 minutes later. 5-Nitrobenzo-2,1,3-thiadiazole (1.0 g) was then added to this mixture and the resulting reaction mixture was kept under reflux for 20 minutes. Benzo[1,2,5]thiadiazol-5-ylamine (0.4 g) was isolated by filtration and purified by column chromatography to be used in the next step.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([Si](C)(C)C)[N:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[CH:14][N:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)c1cn(C2CCC3(CC2)OCCO3)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cn(C2CCC3(CC2)OCCO3)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.1 %

Procedure:
A solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-trimethylsilanyl-1H-[1,2,3]-triazole (1.60 g, 5.68) in 41 mL of dry THF was treated by a 1M solution of tetrabutylammonium fluoride in THF (9.0 mL, 9.0 mmol). The resulting mixture was stirred for 48 h at room temperature under nitrogen. It was diluted with EtOAc, washed with saturated aqueous ammonium chloride, water and brine, dried over Na2SO4 and concentrated to give 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,3]triazole (1.06 g, 89%).