Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:24]([CH:25]=[O:26])[CH2:23][O:22][C@@H:21]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[C@@H:24]([C@@H:25]([OH:26])[C@@H:8]([N+:9]([O-:11])=[O:10])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:23][O:22][C@@H:21]([CH2:27][CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Yield: 63.8 %

Procedure:
Add 1-phenyl-2-nitroethane (91 mg, 0.61 mmol) to a solution of 2-(S)-(2-cyclohexylethyl)-5-(R)-formylmorpholine-4-carboxylic acid tert-butyl ester (164 mg, 0.50 mmol) in dry tetrahydrofuran (6 mL). Cool to 0° C. and add tetrabutylammonium fluoride (0.25 mL of a 1 M solution in tetrahydrofuran, 0.25 mmol) and refrigerate the solution overnight. Dilute with ethyl acetate, wash with cold saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 2.5:97.5 ethyl acetate:dichloromethane) to give the desired compound as a white foam (152 mg, 63%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCON=C(C(C)=O)C(=O)OCC
Yield: 99.5 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformamide (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[Br-:11].[Br-].O1CCOCC1>CCOCC>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)c1ccccc1O
Reactant: [Br-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-isopropylphenol (12) (2.0 g, 14.6 mmol) in 15 ml of Et2O at 0° C. was added dioxane dibromide (3.62 g, 14.6 mmol, 1 eqv). The, solution was allowed to stir for 30 min at rt. The reaction mixture was washed with sat. NaCl and 10% NaHCO3. The Et2O phase was concentrated in vacuo and then vacuum distilled (142-145° C., 20 mm Hg) to yield 2.07 g of a clear oil (66%) which solidified upon standing: 1H NMR (500 MHz, CDCl3) δ 1.23 (d, J=3.7 Hz, 6H), 3.16 (m, 1H), 4.84 (s, 1H), 6.61 (d, J=8.6 Hz, 1H), 7.15 (d, J=11.0 Hz, 1H), 7.28 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.33, 27.17, 113.24, 116.99, 129.34, 129.50, 136.91, 151.81; LRMS (EI) (M+, 214/216).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:30]2[CH2:32][CH2:31]2)=[C:11]([F:29])[CH:12](O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:30]2[CH2:32][CH2:31]2)=[C:11]([F:29])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1
Reactant: OC(Cc1ccc(F)c(Oc2ccccc2)c1)C(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
A suspension of sodium hydride (6.3 mg, 0.26 mmol) in tetrahydrofuran (1 mL) is treated with a solution of 1-(p-chlorophenyl)-1-cyclopropyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-1-buten-3-ol (106.7 mg, 0.25 mmol) in tetrahydrofuran (1.5 mL), stirred at 50° C. for 10 minutes, cooled to room temperature, treated with a solution of p-toluenesulfonyl chloride (49.6 mg, 0.26 mmol) in tetrahydrofuran (1 mL), stirred at 60° C. for 1 hour, quenched with water, and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product (62 mg, 61% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([CH3:17])[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:18][OH:19])[CH3:2].[Mn]([O-])(=O)(=O)=[O:21].[K+]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([CH3:17])[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:11][C:6]=2[N:5]=[C:4]1[C:18]([OH:21])=[O:19])[CH3:2]
Reactant: CCCC(=O)c1cc2nc(CO)n(CC)c2cc1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCCC(=O)c1cc2nc(C(=O)O)n(CC)c2cc1C

Procedure:
In a manner analogous to that described in Example 12, 5.2 g of 1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol can be oxidised with 4.5 g of potassium permanganate to give 1-ethyl-5-butyryl-6-methyl-benzimidazole-2-carboxylic acid with a melting point >80° (decomposition).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[N:9][CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[CH2:5]1.C(Cl)Cl.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(OC)(C)(C)C.O>[CH3:3][N:4]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:14][CH:13]=2)=[N:9][CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[CH2:5]1
Reactant: CN1Cc2ccccc2C(c2ccccc2)N=C1Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Solvent: O
Product: CN1Cc2ccccc2C(c2ccccc2)N=C1Cc1ccc(NS(C)(=O)=O)cc1
Yield: 7.2 %

Procedure:
To a cooled mixture of the diamine dihydrochloride of Example 378 (b) (1.16 g, 28 mmol), CH2Cl2 (25 mL) and pyridine (6 mL) under nitrogen was added methanesulfonyl chloride (0.64 g, 56 mmol). The reaction mixture was stirred, with cooling in ice-bath, for 13/4 hours and then was poured into a solution of water/saturated Na2CO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the organic layers were combined and washed with water/saturated Na2CO3. The organic layer was dried over Na2SO4, the solvent was removed in vacuo, and the residue was diluted with hexane. A precipitate formed which was slurried with t-BuOMe and collected by filtration. The solid was recrystallized from hot CH2Cl2 /hexane to afford 0.85 g (73%) of 4,5-dihydro-4-methyl-1-phenyl-3-[1-(4-methylsulfonylaminophenyl)methyl]-1H-2,4-benzodiazepine as an off-white solid, m.p. 182°-185° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:41].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:1][C:2]1[C:3]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[N:4][CH:5]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:7]=1)=[C:24]([CH3:41])[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[N:26]2
Reactant: N#Cc1ccc(-c2ncc(N3CCOCC3)cc2N)cc1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1-c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(3-amino-5-morpholinopyridin-2-yl)benzonitrile (54.9 mg, 0.2 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (85.7 mg, 0.3 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (15.2 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (0) (8.2 mg, 9 μmol), and sodium tert-butoxide (58.8 mg, 0.6 mmol) in dry toluene (2.0 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a film that was triturated with MeOH to afford a white solid as 4-(3-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinopyridin-2-yl)benzonitrile. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, m), 8.06 (1H, d, J=2.4 Hz), 7.98 (2H, m), 7.95 (2H, m), 7.78 (2H, m), 7.65 (1H, d, J=7.8 Hz), 7.40 (1H, td, J=5.3, 2.8 Hz), 6.98 (1H, dd, J=13.6, 8.4 Hz), 6.98 (1H, dd, J=13.6, 8.4 Hz), 6.55 (1H, d, J=2.0 Hz), 3.90 (4H, m), 3.30 (4H, m), 2.25 (3H, s). Mass Spectrum (pos.) m/e: 535.2 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[NH:6][C:4]1=[O:5].[N+:12]([C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19])([O-:14])=[O:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[N+:12]([C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([N:2]([C:3]3([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[NH:6][C:4]3=[O:5])[C:21](=[O:20])[C:16]=12)=[O:19])([O-:14])=[O:13]
Reactant: CC1(N)CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CCC(=O)NC1=O
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A stirred mixture of α-amino-α-methylglutarimide hydrochloride (1.2 g, 6.7 mmol), 3-nitrophthalic anhydride (1.3 g, 6.7 mmol), and sodium acetate (0.6 g, 7.4 mmol) in acetic acid (30 mL) was heated to reflux under nitrogen for 6 hours. The mixture then was cooled and concentrated in vacuo. The resulting solid was slurried in water (30 mL) and methylene chloride (30 mL) for 30 min. The suspension was filtered, the solid was washed with methylene chloride, and dried in vacuo (60° C., <1 mm) to afford 1.44 g (68%) of 3-(3-nitrophthalimido)-3-methylpiperidine-2,6-dione as a off-white solid: mp 265–266.53° C.; 1H NMR (DMSO-d6) δ 11.05(s, 1H), 8.31(dd, J=1.1 and 7.9 Hz, 1H), 8.16–8.03 (m, 2H), 2.67–2.49 (m, 3H), 2.08–2.02 (m, 1H), 1.88 (s, 3H); 13C NMR (DMSO-d6) δ 172.20, 171.71, 165.89, 163.30, 144.19, 136.43, 133.04, 128.49, 126.77, 122.25, 59.22, 28.87, 28.49, 21.04; HPLC, Water Nova-Pak/C18 column, 4 micron. 1 mL/min, 240 nm, 20/80 CH3 CN/0.1% H3 PO4(aq), 7.38 min(98%). Anal. Calcd For C14H11N3O6: C, 53.00; H, 3.49; N, 13.24. Found: C, 52.77; H, 3.29; N, 13.00.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C1(C)C=CC=CC=1>[CH3:8][N:9]([C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:10][CH2:11][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and piperidine (62 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-(4-nitro-phenyl)-(2-piperidin-1-yl-ethyl)-amine as a di-TFA salt (74 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH3:25][O:26][C:27]([C:29]1[N:30]=[N:31][N:32]([C:42]2[CH:47]=[C:46]([CH:48]([CH3:50])[CH3:49])[C:45]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:44][C:43]=2[O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:33]=1[C:34]1[CH:39]=[CH:38][C:37](CO)=[CH:36][CH:35]=1)=[O:28]>C(Cl)Cl>[CH3:25][O:26][C:27]([C:29]1[N:30]=[N:31][N:32]([C:42]2[CH:47]=[C:46]([CH:48]([CH3:50])[CH3:49])[C:45]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:44][C:43]=2[O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([CH2:20][Br:24])=[CH:38][CH:39]=1)=[O:28]
Reactant: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CBr)cc1
Reaction time: 1 h
Yield: 87 %

Procedure:
Triphenylphosphine (1.45 g, 5.54 mmol) and carbon tetrabromide (1.84 g, 5.54 mmol) were added to a solution of 1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-(4-hydroxymethyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.4 g, 4.26 mmol) in dry DCM (48 ml) at 0° C. The mixture was stirred at this temperature for one hour, then the solvent was removed under reduced pressure and the residue was purified by column chromatography (PE/AcOEt: 70:30). The title compound was obtained as an oil (2.32 g, 87%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C1(C)C=CC=CC=1>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])=[CH:5][C:6]=1[OH:10])=[O:23])([OH:18])=[O:17]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(O)c1

Procedure:
2-(2′-Carboxybenzoyl)-5-diethylaminophenol was prepared as follows. A mixture of m-diethylaminophenol (1 mole) and phthalic anhydride (1.2 moles) was refluxed in toluene (2.0 L) for about 16 hours, cooled, and the resulting solid filtered, washed with toluene and dried to give 2-(2′-carboxybenzoyl)-5-diethylaminophenol in 70% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.C([CH2:11][S:12]([CH2:15][S:16]([CH2:19][C:20](O)=O)(=[O:18])=[O:17])(=[O:14])=[O:13])(O)=O>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:11]/[S:12]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:18])=[O:17])(=[O:14])=[O:13])=[CH:2]1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: O=Cc1ccsc1
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccsc1)CS(=O)(=O)/C=C/c1ccsc1
Yield: 55 %

Procedure:
A solution of thiophene-3-carbaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 55% yield. m.p. 150-152° C.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=3)[N:10]([C:19]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].CC(=CC)C.P([O-])(O)(O)=[O:34].[Na+].Cl([O-])=O.[Na+].[Cl-].[NH4+]>C(O)(C)(C)C.O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:34])=[O:18])[CH:15]=3)[N:10]([C:19](=[O:20])[NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C=O)cc12
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 3.3 h
Yield: 87.2 %

Procedure:
1′-Acetyl-N-(5-chlorothiazol-2-yl)-5-formylspiro[indoline-3,3′-pyrrolidine]-1-carboxamide (7.6 mg, 0.0188 mmol) was dissolved in t-butanol (1.5 mL) and water (0.5 mL). Thereafter, 2-methyl-2-butene (52 μL, 0.50 mmol), sodium dihydrogen phosphate (14 mg, 0.113 mmol) and sodium chlorite (15 mg, 0.169 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 3.3 hours. Thereafter, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with chloroform:methanol=5:1. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to obtain the captioned compound (6.9 mg, 87%) in the form of a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:9]=[C:8]([CH3:10])[O:7][N:6]=1.O.[NH2:13][NH2:14]>C(O)CCC>[CH3:10][C:8]1[O:7][N:6]=[C:5]([CH2:4][C:3]([NH:13][NH2:14])=[O:2])[CH:9]=1
Reactant: NN
Reactant: COC(=O)Cc1cc(C)on1
Solvent: O
Solvent: CCCCO
Product: Cc1cc(CC(=O)NN)no1
Yield: 90 %

Procedure:
As described for example 112a, (5-methyl-isoxazol-3-yl)-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 90 min. Evaporation of all volatiles afforded the title compound as a white solid (yield: 90%). 1H-NMR (300 MHz, DMSO): δ=2.36 (d, J=0.7 Hz, 3H), 3.39 (s, 2H), 4.25 (s, 2H), 6.13 (d, J=0.7 Hz, 1H), 9.27 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24]>CO.O1CCCC1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]([OH:30])=[O:29])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: O=C(O)c1ccccc1S
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)O)cc1
Yield: 95.5 %

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzene sulfonamide in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran, and 0.23 g (1.5 mmol) of thiosalicylic acid. The product was washed with ether and dried in vacuo to give 0.66 g of the title compound, mp 276°-278° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:46][CH2:47][C:48]3[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=3[CH3:54])=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(C2CCCC2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3CCCC3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To a solution of 4-cyclopentylbenzoic acid (95 mg, 0.5 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) and triethylamine (202 mg, 2 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (120 mg, 0.8 mmol) was added. After stirring at room temperature for 4 hours, the mixture was washed with water (50 mL). Organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) and to afford 4-cyclopentyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (35 mg, 22%) as white solid. LRMS (M+H+) m/z: calcd 324.18. found 324. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, CD3OD): δ 7.71 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 6.10 (s, 1H), 4.48 (s, 2H), 3.08-3.02 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 2.10-2.05 (m, 2H), 1.84-1.62 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])/[CH:55]=[C:50]2\[S:51][C:52]([CH3:54])=[N:53][N:49]\2[CH2:45][CH2:46][CH2:47][CH3:48])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.86-0.96 (m, 3 H) 1.27-1.41 (m, 2 H) 1.69-1.78 (m, 2 H) 2.47-2.49 (m, 3 H) 4.29 (t, 2 H) 6.77 (s, 1 H) 7.36-7.48 (m, 1 H) 7.64-7.70 (m, 1 H) 7.98-8.04 (m, 1 H) 8.12-8.19 (m, 1 H); MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:20]1[CH2:22][CH2:21]1)[CH2:10][C:11](=[O:19])[C:12](=[N+]=[N-])[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N>C(Cl)Cl>[CH:20]1([C@H:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:11](=[O:19])[CH2:10]2)[CH2:22][CH2:21]1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)C[C@H](NC(=O)OC(C)(C)C)C1CC1
Agent: N#N
Solvent: ClCCl
Product: COC(=O)C1C(=O)C[C@@H](C2CC2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
(S)-Methyl 5-(tert-butoxycarbonylamino)-5-cyclopropyl-2-diazo-3-oxopentanoate (30) (2.75 g, 8.84 mmol) was dissolved in CH2Cl2 (45 mL). The solution was evacuated and purged with N2 three times after which Rh2(OAc)4 (195 mg, 0.44 mmol) was added. The resulting green solution was stirred at rt for 1 h and was subsequently concentrated under vacuum. The residue was purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1 to give 1.75 g (70%) of (5S)-1-tert-butyl 2-methyl 5-cyclopropyl-3-oxopyrrolidine-1,2-dicarboxylate (31). Retention time (min)=1.981 method [1], MS (m/z) 306.2 (M+Na)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C:8]([OH:10])=O)=[N:2]1.[N+]([O-])(O)=O.[O:15]([CH2:19][CH2:20][NH2:21])[N+:16]([O-:18])=[O:17].C(OC(C)C)(C)C>>[O:15]([CH2:19][CH2:20][NH:21][C:8](=[O:10])[CH2:7][O:6][C:3]1[CH:4]=[CH:5][O:1][N:2]=1)[N+:16]([O-:18])=[O:17]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1ccon1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(COc1ccon1)NCCO[N+](=O)[O-]
Yield: 54.1 %

Procedure:
Following a similar treatment to that in Example 2 and using 286 mg of 3-isoxazolyloxyacetic acid and 338 mg of nitroxyethylamine nitrate, 250 mg of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).