Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C)C=O>[O:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCc2c(O)cccc21
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of 2,3-dihydro-4-hydroxy-1H-inden-1-one (1.0 g) in N,N-dimethylformamide (10 mL), imidazole (1.01 g) and tert-butyldimethylsilyl chloride (1.32 g) were sequentially added and the resultant reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ethyl acetate-saturated aqueous sodium bicarbonate and the resultant reaction mixture was subjected to a phase separation. The organic phase was washed sequentially with water and a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate=95:5 to 90:10) to obtain the subject compound (1.63 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.C([C:39]([NH2:41])=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:39]=[NH:41])[CH:7]=[N:6]2)=[O:30])[N:17]=1
Reactant: CCC(N)=O
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CNC=N)n1)c1csc(N)n1)C(=O)O
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (100 mg, 0.159 mmol) and ethylformamidate hydrochloride (17.4 mg, 0.159 mmol) in DMF (1 mL) was added DIPEA (41 mg, 0.32 mmol). After 2 h of stirring, more ethylformamidate hydrochloride (9.0 mg, 0.082 mmol) and DIPEA (20 mg, 0.16 mmol) was added. After an additional 4 h the solution was concentrated and washed with ether. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (15.5 mg, 18%) as mixture of amidine tautomers. LCMS: m/z=556.8 (M−1); 1H NMR (400 MHz, D2O): δ 7.73 (s, 0.4H), 7.65 (s, 0.6H), 7.57 (m, 1H), 6.83 (s, 1H), 5.37 (d, J=5.6 Hz, 1H), 4.80-4.61 (m, 3H assumed; obscured by solvent residual peak) 4.48 (s, 0.4H), 4.45 (s, 0.6H), 1.17 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine gives 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)#[N:13].[N:23]1C=CC=CC=1>>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:23][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:2]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:19])=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anydrous pyridine (10 mL) was added dropwise 4-cyanobenzoyl chloride (660 mg, 4.0 mmol) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 3 hrs aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After rinsing the resin and filtration, water (25 mL) was added to the filtrate and a beige solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. for 5 hrs. The title compound (774 mg) was obtained as a beige solid (83%) in 97.7% purity by HPLC (MaxPlot detection between 230 and 400 nm) 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.45 (m, 1H), 8.12 (d, J=8.3 Hz, 2H), 8.05 (m, 3H), 7.71 (d, J=7.8 Hz, 1H), 7.52 (dd, J=7.9, 7.8 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)cc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (400 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-[{[4-({1-[5-(4-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. Ethyl 3-[{[4-({1-[5-(4-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (210 mg, 34%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=C(F)[C:16]=1[F:25]>O1CCCC1>[F:25][C:16]1[C:15]([F:14])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[C:5]=1[CH2:4][C:3]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a suspension of NaH (11.3 g, 60% oil dispersion, 282 mmol) in tetrahydrofuran (THF) (35 mL) in an ice-bath was added a solution of diethyl malonate (45.2 g, 42.9 mL, 282 mmol) in THF (70 mL) over a period of an hour so that the reaction temperature was kept below 20° C. Some white solid precipitated during the addition. To the above reaction mixture was added a solution of 1,2,3-trifluoro-4-nitrobenzene (25.0 g, 141 mmol) in THF (35 mL) over a period of 1 hour so that the reaction temperature was kept below 10° C. The ice-bath was removed and the mixture was stirred at ambient temperature for 2 hours. Acetic acid (18 mL) was added to the reaction solution, and THF was evaporated under reduced pressure. Chloroform (200 mL), H2O (250 mL), and concentrated HCl (18 mL) were added. The organic layer was separated, concentrated, mixed with 4N HCl (45 mL) and acetic acid (35 mL), and refluxed for 14 hours. The reaction mixture was allowed to cool to room temperature. The solid precipitated upon cooling was filtered off, washed with diisopropyl ether, and dissolved in MeOH (70 mL). After treating with active carbon, the solvent was evaporated, and the crystalline residue washed with isopropyl ether, and filtered off to give the title compound (17.6 g, 58% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.05-8.01 (m, 1H), 7.47 (dd, J=17.4, 8.9 Hz, 1H), 4.10 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[C:25]([CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[O:26])=[CH:11][CH:10]=1>CCOCC>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1

Procedure:
With stirring, trifluoroacetic acid (10 ml) was added to 4-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2yl]carbonyl-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (1.65 g, 3.77×10-3 mole). After 30 minutes the reaction was cooled in an ice bath and ether (150 ml) was added. The flask was stoppered and placed in the refrigerator. After several hours, the solid was collected by filtration, washed with EtzO, and dried by suction. Crystallization from ethanol/ether afforded [1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidinylmethanone, mono (trifluoroacetate) as colorless needles: 1.45 g (84%), m.p. 213°-215° C. (decomp).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.CN(C)CCN>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CCN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2)C(=O)C1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (prepared according to procedure reported in JP2005504737, 2.0 g, 9.99 mmol), 1-bromo-4-fluorobenzene (1.748 g, 9.99 mmol), N,N-dimethylethylenediamine (0.070 g, 0.799 mmol) and potassium hydrophosphate (KHPO4) (3.13 g, 17.98 mmol) in toluene (10 ml) was added copper (I)iodide (0.101 g, 0.529 mmol) at 25° C. The reaction mixture was heated to 80° C. for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C., diluted with ethyl acetate (25 ml) and filtered through a plug of celite and concentrated to give crude product. The crude product was purified over silica gel (100-200 mesh) by column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (0.8 g, 27.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[C:5]([C:13]([O:15]CC)=[O:14])[CH:6]=[N:7]2.S(=O)(=O)(O)O>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[C:5]([C:13]([OH:15])=[O:14])[CH:6]=[N:7]2.[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[CH:5][CH:6]=[N:7]2
Reactant: CCOC(=O)c1cnc2cc(Cl)cc(Cl)c2c1O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C(O)c1cnc2cc(Cl)cc(Cl)c2c1O
Product: Oc1ccnc2cc(Cl)cc(Cl)c12
Temperature: 150 °C

Procedure:
5,7-Dichloro-3-ethoxycarbonyl-4-hydroxyquinoline (114.4 g; 0.4 mole) and 343.2 g of 70% sulfuric acid were charged in a 1,000 ml four-necked flask equipped with stirrer, thermometer and distilling tube and the mixture was heated at 150° C. with stirring. Reaction was continued by heating up to 165° C. during three hours together with evaporation of the by-produced ethanol outside the reaction system. The reaction product was analyzed by liquid chromatography whereupon and it was found that the starting 5,7-dichloro-3-ethoxycarbonyl-4-hydroxy-quinoline disappeared and that 5,7-dichloro-3-carboxy-4-hydroxyquinoline in 22% yield and 5,7-dichloro-4-hydroxyquinoline in 78% yield were produced.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[C:25]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:30]=[CH:29][C:28]([CH2:31][C@@H:32]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:33][C@@H:34]([CH3:38])[C:35]([OH:37])=[O:36])=[CH:27][CH:26]=1.[C:53](Cl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OC(C)C)(=O)C.O.C(N(CC)CC)C>[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH:22][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH3:3].[C:25]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:26]=[CH:27][C:28]([CH2:31][C@@H:32]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:33][C@@H:34]([CH3:38])[C:35]([OH:37])=[O:36])=[CH:29][CH:30]=1
Reactant: CCOC(=O)[C@@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
10 g (2S,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1=R2=H, R3=Et) in isopropyl acetate (50 ml) is added to a mixture of pivaloyl chloride (4.1 ml) in isopropyl acetate (50 ml). The mixture is then stirred for 40 min at room temperature. Triethylamine (10.3 ml) in isopropyl acetate (30 ml) is then added over a period of 1 h. The resulting mixture is stirred for 16 h. Citric acid (7.5 g) dissolved in water (30 ml) is added and the phases are separated. The organic phase is washed twice with water (30 ml) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(2,2-dimethylpropionylamino)-2-methylpentanoic acid ethyl ester (3-a, R1=Piv, R2=H, R3=Et). 1H NMR (DMSO): 1.05 (9H), 1.09 (3H), 1.15 (3H), 1.54 (1H), 1.78 (1H), 2.48 (1H), 2.72 (2H), 3.97 (1H), 4.00 (2H), 7.15 (1H), 7.25 (2H), 7.34 (1H), 7.45 (2H), 7.55 (2H), 7.62 (2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:16]C(=O)OC(C)(C)C)[C:9](=[O:15])[N:10]2[CH2:14][CH2:13][S:12][CH2:11]2)[CH2:4][CH2:3]1.[CH:24]1[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[C:26]([I:34])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[NH2:16][C@@H:8]([CH:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:30]([C:29]2[CH:24]=[CH:25][C:26]([I:34])=[CH:27][CH:28]=2)(=[O:32])=[O:31])[CH2:7][CH2:6]1)[C:9](=[O:15])[N:10]1[CH2:14][CH2:13][S:12][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCSC1)[C@H]1CC[C@H](N)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCSC1)C1CCC(NS(=O)(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 50 mg (0.139 mmol) of tert-butyl trans-(1S)-1-(4-aminocyclohexyl)-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl-carbamate in 1 mL of methylene chloride was added 53 mg (0.175 mmol) of pipsyl chloride, and 0.022 mL (0.27 mmol) of pyridine, and the reaction was stirred at ambient temperature for 16 h. The solvent was removed in vacuo and the product purified by preparative thin layer chromatography (TLC) (silica gel, 5:95 methanol:methylene chloride) afforded 51 mg of the title compound as is Boc carbamate. Deprotection was effected by treatment with 2 mL of a 1:1 mixture of trifluoroacetic acid:methylene chloride at ambient temperature for 2 h, followed by concentration in vacuo and removal of the excess trifluoroacetic acid by azeotropic distillation with methylene chloride. Purification by preparative TLC (silica gel, 9:1:90 methanol:concentrated ammonium hydroxide:methylene chloride) afforded 37 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 7.94 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz), 4.64–4.62 (m, 0.45H), 4.58–4.52 (m, 1H), 4.47–4.43 (m, 0.55H), 3.91–3.64 (m, 2H), 3.41 (d, 0.45H, J=7 Hz), 3.37 (d, 0.55H, J=7 Hz), 3.07 (t, 1.1H, J=6 Hz), 3.02 (t, 0.9H, J=6 Hz), 3.00–2.92 (m, 1H), 1.84–1.72 (m, 3H), 1.59–1.52 (m, 1H), 1.48–1.38 (m, 1H), 1.23–1.10 (m, 3H), 1.09–0.97 (m, 1H).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH3:15])[CH:2]=[CH2:3].[CH2:16]([O:19]N[C@H]1CN[C@@H](C(N)=O)C=C1C)C=C.C(N(CC)C(C)C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:16](=[O:19])[N:10]2[CH2:11][C@H:6]1[C:7]([CH3:15])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@@H](C(N)=O)C=C1C
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a solution of (2S,5R)-5-(allyloxyamino)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide and (2R,5R)-5-(allyloxyamino)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 22, 0.429 g, 2.03 mmol) and N,N-diisopropylethylamine (1.415 mL, 8.12 mmol) in acetonitrile (170 mL) at 0° C. was added triphosgene (0.241 g, 0.81 mmol) as a solution in acetonitrile (1.5 mL). The triphosgene solution was added at a rate of 0.1 mL/min. Once addition was complete the reaction was warmed to room temperature and stirred over weekend. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded (2S,5R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (0.312 g, 64.8%) as a light yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36].O>CN(C=O)C>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: O=C1CC(C(F)(F)F)=NN1c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
To a solution of 2,4-dihydro-2-phenyl-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =CF3 ; R3 =H) (1.12 g; 4.91 mmol) in DMF (25 ml) was added 280 mg (4.83 mmol) of KF followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g, 3.3 mmol) and the resulting mixture was stirred at room temperature for 24 hours and then was poured into water. The above mixture was extracted with ethyl acetate and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.29 g (18%) of 4-isopropyl-6-methoxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a solid
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:8](Cl)=[O:9].[S-:24][C:25]#[N:26].[K+].[CH2:28]([SH:30])[CH3:29]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:8]([NH:26][C:25](=[S:24])[S:30][CH2:28][CH3:29])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1Oc1ccc(F)cc1F
Reactant: CCS
Reactant: N#C[S-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCSC(=S)NC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-methanesulfonamidobenzoyl chloride (0.7 g) and potassium thiocyanate (0.73 g) in toluene (6 ml) was refluxed overnight. Ethyl mercaptan (0.68 ml) was added to the resulting mixture. The mixture was stirred for 5 hours at 60° C. and concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried and concentrated to give a yellow powder of ethyl N-[3-(2,4-difluorophenoxy)-4-methanesulfonamidobenzoyl]dithiocarbamate (0.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:8]([CH2:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:10]=1)=[O:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[C:8]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(CCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 0.03 h
Yield: 73.2 %

Procedure:
The compound of step 2 (150 mg, 0.428 mmol) was dissolved in THF. N-methylmorpholine (56 mg, 0.556 mmol) and isobutylchloroformate (70 mg, 0.514 mmol) were added at room temperature. After stirring for 2 minutes, the mixture was filtered and rinsed with THF. Sodium borohydride (65 mg, 1.71 mmol) was added to the filtrate and thereafter slowly methanol until intensive foaming indicated the start of the reaction. After 5 minutes the reaction was complete as indicated by LC-MS analytics. Volatiles were evaporated in vacuo, the remainder was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the combined organic extracts were dried over sodium chloride and evaporated to dryness. This raw material was purified by silica gel chromatography with a hetpane/ethyl acetate gradient to yield the title compound (106 mg)