Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[S:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=O>[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=2[N:10]=[C:14]2[CH2:15][CH2:16][S:11][CH2:12][C:13]=12
Reactant: O=c1ccccs1
Reactant: N#Cc1ccc(F)cc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c2c(nc3cc(F)ccc13)CCSC2
Temperature: 50 °C
Yield: 62.4 %

Procedure:
A mixture of 4-fluoroanthranilonitrile (4.47 g) and freshly fused, pulverized ZnCl2 (6.7 g) in 20 ml of nitrobenzene was heated at 50° C. for 45 minutes. To the resulting suspension was added thiopyran-2-one (5.1 g). This was heated at 130° C. for 3 hours. The resulting precipitate was filtered, rinsed with ether and partioned between 2-butanone and NH4OH solution. The aqueous layer was extracted with 2-butanone and the combined organics were washed with water and dried (MgSO4). The resulted in 4.8 g of a tan solid, m.p. 234°-237° C. d., which was recrystallized from ethyl acetate to give 3.0 g of a white powder, m.p. 235°-237° C. d.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([NH:34][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Reactant: NCCc1ccccc1
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)NCCc3ccccc3)cc2)=C(C)C1=O
Yield: 65.5 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and phenethylamine (91 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (170 mg, 0.38 mmol, yield 65%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[C:10]1([C:16](Cl)(Cl)Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[S:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: Nc1ccccc1S
Agent: Cl
Product: c1ccc(-c2nc3ccccc3s2)cc1
Yield: 33.1 %

Procedure:
As in Example 1b, 16.2 g (0.1 mol) of 2-aminothiophenol hydrochloride is reacted at 180° C bath temperature with 19.5 g (0.1 mol) of benzotrichloride (B). By extracting the reaction products with benzene and chromatographing the benzene extract on an Al2O3 column, 7.0 grams of Compound II were obtained, M.P. 105°-110° C (33% of the theory). A small specimen was recrystallized from ethanol: M.P. 113°-114° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3](O)=[O:4].S(Cl)([Cl:12])=O>>[CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([Cl:12])=[O:4]
Reactant: CCCC(C)(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCC(C)(C)C(=O)Cl
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
2,2-dimethyl valeric acid (49.0 g, 377 mmol) was added dropwise over 1 hour with stirring to freshly distilled thionyl chloride (102 g, 860 mmol) that was cooled in a water bath. After stirring for an additional 1/2 hour in a warm water bath, excess thionyl chloride was removed by distillation and the crude acid was then fractionally distilled to give 49.7 g of product that assayed >95% by gas chromatography, bp 45°/10.5 mm (lit. bp 45°/10 mm).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18]CC)=[O:17])=[CH:4]1)[CH3:2].Cl.[OH-:22].[Na+]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([OH:22])[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: [OH-]
Reactant: CCOC(=O)c1cn(CC)c2cc(F)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(O)cc21
Temperature: 25 °C
Yield: 91 %

Procedure:
A suspension of 1.2 g of ethyl 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate (European Offenlegungsschrift No. 230053, C.A. 108:112498) in 25 ml of 2N aqueous sodium hydroxide solution is heated at reflux for 4 hrs. After cooling to room temperature the reaction mixture is adjusted to pH 3 to 4 with 37% aqueous hydrochloric acid and the precipitate is filtered off under suction, washed with 200 ml of water and 200 ml of diethyl ether and dried. 980 mg (91%) of 1-ethyl-6-fluoro-7-hydroxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are isolated as a colourless solid. M.p.>250°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.Br[C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32]([C:45]3[N:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ncccn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-phenyl)-methane sulfonamide (prepared as described in example 35, 0.45 g, 0.73 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 2-bromopyrimidine (0.173 g, 1.09 mmol), cesium carbonate (0.475 g, 1.46 mmol), Pd(dppf)2Cl2 (0.026 g, 0.036 mmol) are added and the resulting solution is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrimidin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-phenyl}-methane sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.13 (br, 1H), 8.91 (d, 2H), 8.57 (s, 1H), 8.25 (d, 2H), 8.05 (m, 1H), 7.83 (m, 1H), 7.58 (d, 2H), 7.45 (m, 6H), 7.17 (dd, 1H), 3.01 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 569.9 (M+H+).
Reaction SMILES: CS[C:3]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(OCC)C>C(O)(=O)C.S([O-])([O-])(=O)=O.[Cu+2].[Zn]>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(SC)c1cccs1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C(C)c1cccs1
Yield: 0.1 %

Procedure:
Methyl α-methylthio-α-(2-thienyl)propionate (432 g) was dissolved in 4 ml of acetic acid, and 32 mg of anhydrous copper sulfate and 400 mg of zinc powder were added. With stirring, the mixture was heated under reflux for 3.5 hours. After cooling, 30 ml of diethyl ether was added, and the insoluble matter was separated by filtration, followed by washing with 10 ml of diethyl ether. The filtrate and the washing were combined, and washed with 10 ml of water. After 20 ml of water was further added, sodium carbonate was gradually added to neutralize the acetic acid present. The organic layer was then separated, washed with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to short-path distillation (bath temperature 100°-110° C./8 mmHg) to afford 297 mg of methyl α-(2-thienyl)propionate as a colorless oil in a yield of 87%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1N
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1NC(=O)c1ccccc1
Yield: 45.4 %

Procedure:
3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (30 mg, 0.072 mmol) was reacted with benzoyl chloride (9 IIl, 0.079 mmol) via procedure V to afford 17 mg of 3-benzamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide as a white solid. MS (Q1) 520 (M)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[CH:7]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:6]12>CO>[SH:4][CH2:3][CH2:2][NH:1][C:5](=[O:15])[CH:6]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:7]1[C:8]([OH:10])=[O:9]
Reactant: NCCS
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CO
Product: O=C(O)C1CCCCC1C(=O)NCCS
Reaction time: 7 h
Yield: 99.4 %

Procedure:
To a solution of 7.72 g (0.1 mole) of cysteamine in 40 cm3 of methanol, maintained under an inert atmosphere and cooled to a temperature between 0° and 5° C., there are added, by portions, 15.43 g (0.1 mole) of hexahydrophthalic anhydride. After 7 hours of stirring at this temperature, there remains only traces of the starting cysteamine. The solution is evaporated to dryness under reduced pressure at ambient temperature. 23 g of N-(2-mercapto ethyl) hexahydrophthalamic acid are obtained in the form of a colorless oil.
Reaction SMILES: C(OC(N(C(OC(C)(C)C)=O)C1C2C(=CC(NC(C3C=CC(CC(O)CC)=CC=3)C([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=3)=O)=CC=2)C=CN=1)=O)(C)(C)C.[C:52]([O:56][C:57]([N:59]([C:92]([O:94][C:95]([CH3:98])([CH3:97])[CH3:96])=[O:93])[C:60]1[C:69]2[C:64](=[CH:65][C:66]([NH:70][CH:71]([C:75]3[CH:80]=[CH:79][C:78]([CH2:81][CH:82]([O:84][Si:85]([C:88]([CH3:91])([CH3:90])[CH3:89])([CH3:87])[CH3:86])[CH3:83])=[CH:77][CH:76]=3)[C:72]([OH:74])=O)=[CH:67][CH:68]=2)[CH:63]=[CH:62][N:61]=1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>>[C:52]([O:56][C:57]([N:59]([C:92]([O:94][C:95]([CH3:97])([CH3:96])[CH3:98])=[O:93])[C:60]1[C:69]2[C:68](=[CH:67][C:66]([NH:70][CH:71]([C:75]3[CH:76]=[CH:77][C:78]([CH2:81][CH:82]([O:84][Si:85]([C:88]([CH3:89])([CH3:91])[CH3:90])([CH3:87])[CH3:86])[CH3:83])=[CH:79][CH:80]=3)[C:72]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=3)=[O:74])=[CH:65][CH:64]=2)[CH:63]=[CH:62][N:61]=1)=[O:58])([CH3:53])([CH3:55])[CH3:54]
Reactant: CCC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc1)O[Si](C)(C)C(C)(C)C
Product: CC(Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc([N+](=O)[O-])c2)cc1)O[Si](C)(C)C(C)(C)C
Yield: 96 %

Procedure:
According to the procedure for the preparation of 70F, 77D (150 mg, 0.225 mmol) afforded 172 mg (96%) of 77E as a brown glass. MS (ESI) m/z 800.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([OH:16])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH2:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:25])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2cc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2cc1O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 3,7-dihydroxynaphthalene-2-carboxylic acid methyl ester (3.32 g, 15.5 mmol), bromoacetic acid tert-butyl ester (2.29 mL, 15.5 mmol) and potassium carbonate (4.28 g, 31.0 mmol) in DMF (20 mL) is stirred at 60° C. for 18 h. The reaction mixture is poured to EtOAc, wash with water and brine. It is then dried with MgSO4 and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].C1C(=O)N([Br:24])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][Br:24])[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21

Procedure:
The mixture of 6-bromo-7-methyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.20 g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2′-azobisisobutyronitrile (0.3 g, 1.8 mmol) and CCl4 (120 mL) was heated at reflux for 16 hours. The mixture was concentrated under reduced pressure to about 50 mL. The reaction was then filtered, and the solid was washed with Et2O (20 mL). The combined organic solution was then concentrated under vacuum to generate crude product. Crude 62.2 was generated as a brown oil and used directly in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-methoxy-benzoyl chloride (0.51 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the product was isolated by filtration, washed with MeCN (10 mL) and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methoxy-benzamide as a white solid (0.99 g, 79% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.58 min (97.92%); mp: 215-217° C.; 1H NMR (DMSO-d6) δ 1.94-2.20 (m, 1H, CHH), 2.39-2.70 (m, 2H, CHH, CHH), 2.78-3.04 (m, 1H, CHH), 3.82 (s, 3H, CH3), 4.63 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.02 (d, J=8.9 Hz, 2H, Ar), 7.76-7.97 (m, 5H, Ar), 9.08 (t. J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.55, 48.99, 55.37, 113.60, 121.91, 123.53, 126.11, 129.11, 129.74, 131.59, 133.40, 147.87, 161.75, 165.91, 167.00, 167.15, 169.82, 172.73; LCMS: MH=422; Anal Calcd for C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.40; H, 4.46; N, 10.12.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[S:13][C:14]([CH2:17][OH:18])=[CH:15][N:16]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[C:32](=[O:36])[NH:31][CH2:30]3)O1>>[OH:18][CH2:17][C:14]1[S:13][C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:36])[NH:31][CH2:30]4)=[CH:3][N:4]=2)=[N:16][CH:15]=1
Reactant: OCc1cnc(Nc2ncc(Br)n3ccnc23)s1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Product: O=C1NCc2cc(-c3cnc(Nc4ncc(CO)s4)c4nccn34)ccc21

Procedure:
Prepared from the product of Step 2 and Intermediate 4 (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one) according to the procedure described in Example 1, Step 2. 1H-NMR (400 MHz, d6-DMSO) =4.52 (s, 2H, CH2), 4.67 (d, 2H, CH2), 5.40 (t, 1H, OH), 7.36 (s, 1H, Har), 7.71 (s, 1H, Har), 7.81 (s, 1H, Har), 7.89 (m, 2H, Har), 7.99 (s, 1H, Har), 8.09 (s, 1H, Har), 8.79 (s, 1H, H), 11.61 (s br, 1H, NH). LCMS: Rt 2.04 min (90.0%). MS (MH+, m/z) 379.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)c(N)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
The starting material, 5-benzyloxy-2-fluoro-4-methylaniline, was obtained by adding iron powder (2.88 g, 51 mmol), in portions, to a solution of 5-benzyloxy-2-fluoro-4-methylnitrobenzene (4.8 g, 18 mmol) in acetic acid (33 ml) and water (5.7 ml), at ambient temperature. The mixture was heated and after stirring at 100° C. for 10 minutes, it was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water, aqueous saturated sodium carbonate solution and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using petroleum ether/ethyl acetate (8/2) as eluent to give 5-benzyloxy-2-fluoro-4-methylaniline (3.65 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Br[CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.C1COCC1.C(OCC)C.O.C(=O)(O)[O-]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]
Reactant: Oc1cccc(Br)c1
Reactant: COC(=O)C(Br)CC(C)C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)C)Oc1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
3-Bromophenol (2.99 g, 17 mmoles) in a mixture of DMF (3 mL) and THF (15 mL) was treated with potassium tert-butoxide (1.85 g, 16.5 mmoles) and stirred for 30 minutes. Methyl 2-bromo-4-methylpentanoate (2.5 mL, 15.75 mmoles) was added in one portion and the reaction was stirred overnight. The reaction was diluted with diethyl ether, water and sat. aq. bicarbonate. The phases were separated and the organic phase was washed with 2 portions of 1.2 N hydrochloric acid and then brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue which was purified by flash chromatography to give methyl 2-(3-bromophenoxy)-4-methylpentanoate.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:8][C:9]=1[C:10]([OH:12])=[O:11])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:25]O>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2[S:8][C:9]([C:10]([OH:12])=[O:11])=[C:5]([CH2:4][C:1]([O:3][CH3:25])=[O:2])[N:6]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O

Procedure:
Mix 4-carboxymethyl-2-(4-chloro-phenyl)-thiazole-5-carboxylic acid (145 g, 482 mmol) in MeOH (900 mL) and treat with sulfuric acid (1.20 mL, 21.68 mmol). Stir the mixture at reflux overnight and then begin distilling the MeOH to concentrate the solution. Collect about 300 mL of MeOH and then reflux for an additional 5 h. Filter the reaction mixture and cool the filtrate in an ice bath for one hour. Collect the yellow precipitate by filtration and rinse with cool MeOH. Dry the solid in a vacuum oven at 45° C. overnight to give 105 g of the title compound. Concentrate the above filtrate to about 200 mL volume and collect 20 g of additional material. 1H NMR (DMSO-d6, 500 MHz): δ 13.72 (br s, 1H), 8.00 (d, 2H, J=8.4), 7.59 (d, 2H, J=8.8), 4.21 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [C:1](#N)[CH3:2].[OH:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:6]1([CH3:23])[CH3:22].OO.S([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C.C1CCCCC1>[CH:2]1([O:4][N:5]2[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([O:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][C:6]2([CH3:23])[CH3:22])[CH2:1][CH2:8][CH2:7][CH2:6][CH2:22]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC#N
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 62 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
2,2′-Dipyridyl (0.056 g, 0.36 mmol) is stirred with 28 ml of acetonitrile. To the acetonitrile solution is added a solution of 0.098 g (0.36 mmol) of ferric chloride hexahydrate in 2 ml of water. This purple mixture is stirred for 10 minutes prior to adding 19 ml of cyclohexane and 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine. A solution of 3.84 g (69.5 mmol) of 50% aqueous hydrogen peroxide is added to the reaction mixture dropwise over 2.25 hours while the temperature is brought to and maintained at 62° C. After the peroxide is added, the reaction mixture is heated at reflux for 1 hour. The reaction mixture is cooled, and peroxide is decomposed by the addition of aqueous sodium sulfite solution. Ethyl acetate is added, and the organic layer is washed with water. The organic layer is concentrated, and the concentrate is purified by flash chromatography with 20:1 heptane-ethyl acetate to afford 4.82 g (74% yield) of the title compound. GC assay is 100%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].BrCN1C(=O)C(C)(C)N(C)C1=O.[C:23]([O:27][C:28]([C@H:30]([C@@H:42]([CH2:51][CH:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)[C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:44])[CH2:31][N:32]1[C:36](=[O:37])[C:35]([CH3:39])([CH3:38])[N:34]([CH3:40])[C:33]1=[O:41])=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([O:27][C:28]([C@@H:30]([C@@H:42]([CH2:51][CH:52]1[CH2:53][CH2:54][CH2:55][CH2:56]1)[C:43]([N:45]1[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1)=[O:44])[CH2:31][N:32]1[C:36](=[O:37])[C:35]([CH3:38])([CH3:39])[N:34]([CH3:40])[C:33]1=[O:41])=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CN1C(=O)N(C[C@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: CN1C(=O)N(CBr)C(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN1C(=O)N(C[C@@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 10.7 g of the ester from Example 3 in 50 ml of tetrahydrofuran was added dropwise at −60° to a solution of 8.76 g of potassium bis-trimethylsilylamide in 80 ml of tetrahydrofluran and the mixture was stirred at −60° for 30 min. Subsequently, a solution of 7.76 g of 3-bromomethyl-1,5,5-trimethylhydantoin in 40 ml of tetrahydrofliran was added at −60° and the mixture was stirred at −60° for 30 min. The reaction mixture was washed with semi-saturated sodium chloride solution and with dilute hydrochloric acid, dried, filtered and concentrated, there being obtained 15.11 g of a 9:1 mixture of 1-[2(R)-[1(R)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3cyclopentylpropionyl]piperidine and 1-[2(R)-[1(S)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (78% yield of pure anti-compound), which was used in the next step without further purification. The mixture can be separated by chromatography on silica gel with hexane/ethyl acetate (1:1).