Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[NH:25][C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.ClCCl>CN(C)C=O>[Br:1][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[NH:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1)=[O:27])[CH2:10][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3ccccc32)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3cc(Br)ccc32)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
N-Bromosuccinimide (2.6 g, 14.5 mmoles) was added to a solution of N-[2-(indolin-1-yl)-5-bromophenyl]-4-methyl-1-piperazinecarboxamide (5.0 g, 12.0 mmoles) in dimethylformamide (50 ml). The solution was stirred at room temperature for 15 minutes and at 60° C. for 15 minutes. The solution was cooled and poured into dichloromethane (500 ml). The layers were separated and the organic phase was washed with water (3×500 ml), brine (500 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography over silica gel (60 g, eluted with 4% methanol:96% dichloromethane, 1 l). The appropriate fractions were pooled and concentrated to give 4.8 g (84%) of product. Recrystallization from chloroform and hexane gave the analytical sample, mp 118°-119.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:23]=[CH:22][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:24][S:25]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26].[CH2:34]=O>C(O)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:12])=[CH:22][CH:23]=2)=[N:4][C:3]=1[CH2:24][S:25]([CH:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: C=O
Reactant: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Solvent: O=CO
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C)CC1
Reaction time: 0.2 h
Yield: 11 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide (322 mg, 0.69 mmol, 1.00 equiv) and paraformaldehyde (0.21 g, 10.00 equiv) in formic acid (15 mL) was stirred overnight at 110° C. The resulting mixture was concentrated under vacuum and the crude product (320 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN/H2O (5% up to 60% in 12 min, up to 100% in 1 min, down to 5% in 1 min); Detector, UV 254 nm, to give 36.5 mg (11%) of 4-[5-methyl-4-[(1-methylpiperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-[2-(pyridin-3-yl)ethyl]benzamide as a white solid. LC-MS: (ES, m/z): 483 [M+H]+, 242. 1HNMR (400 MHz, CD3OD, ppm): δ 8.47 (s, 1H), 8.42-8.40 (s, 1H), 8.08-8.06 (d, 2H), 7.90-7.88 (d, 2H), 7.81-7.79 (d, 1H), 7.42-7.39 (m, 1H), 4.41 (s, 2H), 3.69-3.66 (t, 2H), 3.21-3.06 (m, 1H), 3.06-2.99 (m, 4H), 2.50 (s, 3H), 2.30 (s, 3H), 2.26-2.23 (m, 2H), 2.12-2.06 (m, 2H), 1.95-1.87 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1ccc2cc(O)ccc2n1
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reaction time: 72 h

Procedure:
To a solution of 2-Methyl-quinolin-6-ol (4.13 g, 0.0259 mol), c is 4-tert-Butyl-cyclohexanol (4.86 g, 0.0311 mol) and triphenylphosphine (9.53 g, 0.0363 mol; Supplier=Aldrich) in tetrahydrofuran (100 mL, 1 mol; Supplier=Acros), cooled in an ice bath, was added diisopropyl azodicarboxylate (7.61 mL, 0.0363 mol; Supplier=Acros) in Tetrahydrofuran (10 mL, 0.1 mol; Supplier=Acros). The reaction mixture was stirred for 72 h allowing to reach room temperature. The solvent was removed under reduced pressure and the residue was taken up in methylene chloride, adsorbed onto silica gel and purified by flash chromatography (0-30% ethyl acetate in hexanes) to give the title compound in 56% yield. ESI-MS (M+H+): 298.3.
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:26]12[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:30][NH:29][CH2:28][CH2:27]2>>[CH2:30]1[N:29]([C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[CH:17]3)=[O:19])[CH2:28][CH2:27][N:26]2[CH2:34][CH2:33][CH2:32][CH:31]12
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Reactant: C1CC2CNCCN2C1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN2CCCC2C1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1,4-diazabicyclo[4.3.0]nonane (purchased at Matrix Ref 8078), to give the desired product as a white solid (65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.[CH2:42]([N:44]([CH2:47]C)[CH2:45]C)[CH3:43].CN(C=[O:53])C>>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:20][CH2:21][N:22]([C:43](=[O:53])[CH2:42][N:44]([CH3:47])[CH3:45])[CH2:23][CH2:24]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)CN(C)C)CC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one (20 mg, 0.03 mmol) in DMF (1.0 mL) was added 2-(dimethylamion)acetyl chloride hydrochloride (0.17 mmol, 26 mg) and triethyl amine (0.18 mmol, 18 mg). The reaction mixture was stirred at room temperature 1 h and the solid byproduct was removed by filtration. The remaining filtrate was purified by preparative RP-HPLC to afford 6-(5-chloro-4-(2-(isopropylsulfonyl)-phenylamino)pyrimidin-2-ylamino)-2-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-5-isopropoxyisoindolin-1-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1.[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>>[CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH:22][C:28]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:29])[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1
Reactant: CC(C)N=C=O
Reactant: CC1(C)Cc2cccc(NC3=Nc4ccc(N)cc4CO3)c2O1
Product: CC(C)NC(=O)Nc1ccc2c(c1)COC(Nc1cccc3c1OC(C)(C)C3)=N2
Yield: 67.8 %

Procedure:
Prepared from the above described N2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (150 mg, 0.49 mmol) and isopropyl isocyanate (42 mg, 0.49 mmol) according to the procedure described for Example 16. Obtained the title compound as a white solid (131 mg, 68%), MS (ISP) m/e=395.3 [(M+H)+].
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=1.[CH2:22]([O:24][C:25](=[O:31])[C:26](OCC)=[O:27])[CH3:23].Cl>C(#N)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:20]#[N:21])[C:26](=[O:27])[C:25]([O:24][CH2:22][CH3:23])=[O:31])=[CH:15][CH:14]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A 542 μL (3.63 mmol) sample of DBU was added to a solution of 500 mg (3.30 mmol) of 4-chlorophenylacetonitrile and 493 μL (3.63 mmol) of diethyloxalate in 1.6 mL of acetonitrile. After ca. 10 min, the mixture was diluted with ethyl acetate and acidified with dilute HCl. The organic phase was washed with three portions of water, dried and stripped to an oily solid. Trituration with hexane/butyl chloride yielded 414 mg, m.p. 135-136° C. A second crop of 35 mg gave a total yield of 54% of ethyl 3-(4-chlorophenyl)-3-cyano-2-oxopropanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:16][C:17](O)=[O:18])[NH:12][N:13]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]3[CH:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])[CH2:15][CH2:16][C:17](=[O:18])[N:12]3[N:13]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1
Reactant: COc1nc(-c2n[nH]c(C(CCC(=O)O)c3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(-c2nc3n(n2)C(=O)CCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reaction time: 19 h
Yield: 63.9 %

Procedure:
4-[5-[6-Methoxy-5-(4-methyl-imidazol-1-yl)-pyridin-2-yl]-2H-[1,2,4]-triazol-3-yl]-4-(2-trifluoromethylphenyl)-butyric acid (208 mg) was dissolved in tetrahydrofuran (4.3 ml). Diisopropylethylamine (220 ul), 1-hydroxybenzotriazole (86.8 mg) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (334 mg) were added at room temperature and the reaction was initiated. After 19 hours, the reaction was terminated with water, followed by dilution with ethyl acetate. The organic layer was washed with saturated ammonium chloride and brine and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 100%) to obtain the title compound (128 mg) as an orange solid.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][O-:34].[Na+]>CO.C(OCC)(=O)C>[CH3:33][O:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a solution of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 15 mg, 0.03 mmol) in methanol (1 mL) was added sodium methoxide solution (5.4M solution in methanol, 11 uL, 0.06 mmol) and the reaction mixture was then stirred at 90° C. for 16 h. The reaction mixture was concentrated in vacuo to give a crude residue which was diluted with ethyl acetate and washed with water, sat.NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography to yield the desired product as a white solid (14 mg, 94%). MS (ESI): 486.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:15]([O:17]C)=[O:16])=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=2[CH:3]=1.CO.C1COCC1.O.[Li+].[OH-]>O>[Br:1][C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:15]([OH:17])=[O:16])=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Methyl 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 17 mg, 0.050 mmol) was suspended in a 1:1:1 mixture of MeOH/THF/water (0.6 ml). LiOH (39 mg) was added and the mixture stirred at room temperature for one hour. Water and 6NHCl was added and the resulting precipitate was filtered. The material was purified by preparative HPLC. Genevac evaporation provided 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid as a solid (2.1 mg, 13% yield). LCMS (ES): >95% pure, m/z 324 [M]+, 326[M+2]+; 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.75 (dd, J=1.6, J=8.0, 1H), 7.90 (d, J=8.4, 1H), 8.03 (d, J=1.6, 1H), 12.06 (s, 1H) ppm.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Br)[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].O>CN(C=O)C>[F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1NC(C)(C)C
Yield: 40.4 %

Procedure:
A solution of 6.0 g (0.015 mol) of product from Example 106, 1.48 g (0.0147 mol) of triethylamine and 2.15 g (0.0244 mol) of t-butylamine in 30 ml of DMF was stirred at 50° C. for 12 hours. The reaction mixture was poured into H2O, and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 2.8 g of a brown oil. The crude product was kugelrohr distilled at 67 Pa and collected at a pot temperature of 154°-155° C. affording 2.5 g (42%) of product as a beige solid; mp 30°-31° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH2:3][CH2:2]1.O[CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[NH2:21][CH2:20][CH2:19][N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NCCN(CC1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of N-(cyclopropylmethyl)-2-nitrobenzenesulfonamide (1.7 g, 6.4 mmol), t-butyl N-(2-hydroxyethyl)carbamate (1.3 g, 8.3 mmol) and triphenylphosphine (2.2 g, 8.3 mmol) in toluene (20 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (3.6 g, 8.3 mmol) with ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to a half its original volume, and diethyl ether (30 mL) was added thereto. The precipitates were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=49:1 to hexane:ethyl acetate=1:1) to obtain a condensed compound as an oily matter. A 4 M hydrogen chloride/ethyl acetate solution (20 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added water (70 mL) and extracted. The aqueous layer was collected by separation and washed with ethyl acetate. The aqueous layer was basified with a 4 N aqueous sodium hydroxide solution (pH=12), and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=19:1 to ethyl acetate) to obtain the title compound (1.2 g, yield 62%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>CS(C)=O>[N:15]1([C:6]2[N:5]=[C:4]([NH2:8])[CH:3]=[CH:2][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cc(Cl)ccn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(N2CCCC2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 36.8 %

Procedure:
A mixture of 4-chloro-2-aminopyridine (19.3 g, 0.150 mol), K2CO3 (41.7 g, 0.30 mol) and pyrrolidine (32.0 g, 0.45 mol) in DMSO (150 mL) was stirred at 190° C. for 10 hours. After cooling to room temperature, water (300 mL) was added and extracted with ethyl acetate (150 mL×4). The combined organic layers were washed with water (25 mL×3), dried over Na2SO4 and concentrated in vacuo, the residue was purified by silica gel chromatography (10:1 ethyl acetate/petroleum ether) to obtain 6-(pyrrolidin-1-yl)pyridin-2-amine (9.0 g, 37% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[C:23][Si](C)(C)C)=[N:20][C:19]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[CH:32][CH:33]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
tert-Butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-(2-trimethylsilylethynyl)pyrazin-2-yl]carbamate (42.6 g, 74.25 mmol) was dissolved/suspended in methanol (510 mL) and 2M aqueous sodium carbonate (425.8 mL, 851.6 mmol) was added to the rapidly stirred mixture. An oil separated out and more methanol (100 mL) was added to dissolve. The mixture was stirred at ambient temperature for 1 hour. The slurry was poured into a mixture of EtOAc/water (800 mL/1 L). The organic phase was separated and the aqueous extracted with EtOAc (2×250 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was slurried in 5% EtOAc/Petrololeum Ether and stirred for 90 minutes at ambient temperature. The precipitate was isolated by filtration, washed with Petroleum Ether and dried to give the sub-title product as a white solid (33.1 g, 89% Yield). 1.18 (d, 6H), 1.37 (s, 18H), 3.50 (sept, 1H), 4.99 (s, 1H), 8.03 (d, 2H), 8.44 (d, 2H) and 9.35 (s, 1H) ppm; MS (ES+) 502.1.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([NH:7][C:8]2[C:9]([OH:24])([CH3:23])[CH:10](S([O-])(=O)=O)C=C(CCC=O)C=2C)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[I-:31].[Na+].C(OCC)(=[O:35])C>CC(C)=O>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([NH:7][C:8](=[O:35])[C:9]([OH:24])([CH3:23])[CH2:10][I:31])=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2]
Reactant: [I-]
Reactant: CC1=C(Nc2ccc(C#N)c(C(F)(F)F)c2)C(C)(O)C(S(=O)(=O)[O-])C=C1CCC=O
Reactant: CCOC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(O)(CI)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
In a 50 ml flask, equipped with a magnetic stirrer, 0.135 g of the tosylate compound of Example 12 was treated with an excess of sodium iodide (>10 equivalents) in 10 ml of acetone at reflux for 48 hours. After cooling to room temperature, the reaction mixture was transferred to a separation funnel and 20 ml of ethyl acetate was added. The organic layer was washed with 20 ml of water, 20 ml of 0.5M aqueous Na2S2O3, and 20 ml of brine, dried (Na2SO4) and concentrated at reduced pressure. The crude product was purified by column chromatography (Merck 60 SiO2, eluens=ethyl acetate/heptane=3/2) to give two fractions. The first fraction was the product as was determined by 1H-NMR spectroscopy. Isolated yield: 0.048 g (40%).
Reaction SMILES: O=O.O.O.O.O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][O-:14])=[O:12].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22](=[O:25])[O:23][O-].[Mg+2:29].C1(C)C=CC(S(O)(=O)=[O:37])=CC=1.[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([OH:47])=[O:46].[Cl:51][C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][CH:61]=1)[C:55]([O:57][OH:58])=[O:56]>>[OH2:12].[OH2:23].[OH2:37].[OH2:46].[Cl:51][C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][CH:61]=1)[C:55]([O:57][O-:58])=[O:56].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](=[O:12])[O:13][O-:14].[Mg+2:29].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O-:25])=[O:23].[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([O-:47])=[O:46].[Mg+2:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: O=C(O[O-])c1cccc(Cl)c1
Agent: O=O
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])c1cccc(Cl)c1

Procedure:
These data are consistent with our assignment of the product from Example 1 as magnesium bis(3-chloroperoxybenzoate) tetrahydrate. A reanalysis of this product in deuterated methanol again showed signals at 174.49 and 172.65 ppm. Addition of 4-toluenesulfonic acid to protonate this product resulted in a shift of the signals to 168.05 and 165.88 ppm, features consistent with 3-chlorobenzoic acid and 3-chloroperoxybenzoic acid formed from protonation of magnesium bis(3-chloroperoxybenzoate) tetrahydrate [and the corresponding decomposition product, magnesium bis (3-chlorobenzoate)]. The results show that the product from Example 1 is the same after protonation in solution as the corresponding peroxycarboxylic acid.