Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].Cl.[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38])[CH3:33].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:38][CH2:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:39])=[O:27])=[CH:24][CH:23]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)#[N:2]
Reactant: CCOC(=O)CCN
Reactant: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C#N)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C#N)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a mixture of 4-{[(3-cyano-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (240 mg) synthesized above, β-alanine ethyl ester hydrochloride (137 mg), 1-hydroxybenzotriazole monohydrate (136 mg), triethylamine (248 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate/hexane) to give the title object compound (285 mg, 95%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].C(N(CC)CC)C.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>C(OCC)C>[CH3:1][N:2]([CH3:4])[NH:3][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C)N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
A 500-mL round bottomed flask was charged with 1,1-dimethylhydrazine (3.88 mL, 50 mmol), triethylamine (7.52 mL, 53 mmol), and diethyl ether (250 mL). To this stirred solution at 0° C. was slowly added pivaloylchloride (6.28 mL, 50 mmol). The resultant white suspension was stirred at ambient temperature for 18 h. This suspension was then filtered through a sintered glass funnel to afford a colorless solution. The volatile components were then removed and the resultant white solid was sublimed at 65° C./0.05 Torr to afford LtBu,NMe2H as colorless crystals (6.95 g, 96%): mp 120-122° C.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([C:13]([NH:26][CH:27]2[C:37](=[O:38])[N:29]3[CH:30]([C:35]#[N:36])[C:31]([CH3:34])([CH3:33])[S:32][C@H:28]23)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C.Cl>O.C(Cl)(Cl)Cl>[C:7]1([C:13]([NH:26][CH:27]2[C:37](=[O:38])[N:29]3[CH:30]([C:35]4[NH:41][N:40]=[N:39][N:36]=4)[C:31]([CH3:34])([CH3:33])[S:32][C@H:28]23)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam benzene solvate, (258 mg., 0.5 mmole), sodium azide (33 mg. 0.5 mmole), triethylamine hydrochloride (69 mg., 0.5 mmole) and chloroform (10 ml.) isstirred and heated to reflux for three hours. Sodium azide (0.5 mmole) is then added to the mixture and refluxing continued overnight. One equivalent of each of sodium azide and triethylamine hydrochloride are added to the mixture which is refluxed for an additional 2 hours. These additions are repeated twice more after which the mixture is again refluxed overnight. The mixture is cooled to room temperature and chloroform (10 ml.) added followed by water (10 ml.). The pH is adjusted to 2.0 with 6N hydrochloric acid, the mixture thoroughly mixed and the layers separated. The chloroform phase is washed with water (10 ml.) and is then seeded with a crystal from the product of Example 13. Crystallization occurs within five minutes. The slurry is stirred for ten minutes and then slowly added to an equal volume of hxane. The resulting slurry is stirred for 15 minutes and then filtered. The filter cake is washed with hexane and then air dried. Yield = 124 mg., 51.5%.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1.O>[N:1]1([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15](=[S:26])[NH2:16])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: S
Reactant: N#Cc1ccc(Cn2cnc3ccccc32)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ccc(Cn2cnc3ccccc32)cc1
Yield: 87 %

Procedure:
A stirred solution of 4-(1H-benzimidazol-1-ylmethyl)benzonitrile (0.50 g, 2.14 mmol) and triethylamine (Et3N) (0.24 g, 2.37 mmol) in pyridine (2 mL), was bubbled through with H2S (g) at room temperature for 2 h. The reaction mixture was diluted with water and filtered. The filtercake was washed with cold water and dried under vacuum to afford the title compound in 87% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 5.54 (s, 2H), 7.16-7.22 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.45-7.52 (m, 1H), 7.62-7.68 (m, 1H), 7.79 (d, J=8.8 Hz, 2H), 9.30 (bs, 1H), 9.80 (bs, 1H). LCMS (ESI+) 268 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:11]1)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2N)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 2,2-dimethylpropionic acid 2-[(R)-3-(2-amino-5-fluorophenylamino)piperidin-1-yl]ethyl ester (500 mg, 1.48 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (309 mg, 1.63 mmol) and HOAt (202 mg, 1.48 mmol) in DCM (30 mL) was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (341 mg, 1.78 mmol). The reaction mixture was stirred in the ice bath for 1.5 h, then diluted with DCM, washed with 2M Na2CO3 and then water. The organic fraction was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 50-100% EtOAc in cyclohexane) affording the title compound as a purple gum (quantitative). LCMS (Method B): RT 2.50 min [M+H]+ 509.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1)[CH2:19][CH2:20][CH3:21].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:25]2[N:24]=[N:23][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:27]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:33]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.58 mmol, 0.126 g) in DMF (1.0 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (1.74 mmol, 0.07 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.29 mmol, 0.10 g) in DMF (0.5 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 12 hour. The reaction was poured into a mixture of water (10 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 cartridge using ethyl acetate/hexanes gradient to give 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-Fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=3)[C:8]2=[O:12])[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred suspension of ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate (3.00 g, 11.8 mmol) in anhydrous N,N-dimethylformamide (20 mL) under nitrogen atmosphere was added in one portion sodium hydride (60% in mineral oil, 0.57 g, 14.15 mmol). The mixture was stirred for 1 hour, then 4-(trifluoromethyl)benzyl bromide (3.39 g, 14.16 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added. The resulting reaction mixture was stirred for 16 hours, then was partitioned between ethyl acetate (200 mL), water (100 mL) and brine (50 mL). The aqueous layer was extracted with ethyl acetate (200 mL) and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with 10% ethyl acetate in hexanes to afford the title compound as a cream solid in 89% yield (4.32 g): 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 6.17 (s, 1H), 4.53 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.86-3.79 (m, 2H), 3.50-3.43 (m, 2H), 2.50 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 413.3 (M+1).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=1)[CH2:9][N:10]1[C:14](=[O:15])[C:13]2([CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)[N:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11]1)(=[O:4])=[O:3]>CO.[Pd]>[O:15]=[C:14]1[C:13]2([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[N:12]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:11][N:10]1[CH2:9][C:8]1[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:39]=[CH:38][CH:37]=1
Reactant: CS(=O)(=O)Nc1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a solution of benzyl 3-(3-(methylsulfonamido)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.82 g, 1.49 mmol) in methanol (15 mL), was added 10 wt % palladium on carbon (0.15 g). After stirring under hydrogen at room temperature and atmospheric pressure for 18 hours, the reaction mixture was filtered, washed with methanol, concentrated in vacuo to obtain N-(3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide (0.62 g, 99%).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[CH3:7].[CH2:13]1[O:15][CH2:14]1.[NH4+].[Cl-]>C1COCC1>[CH2:6]([C:8]1[O:9][C:10]([CH2:13][CH2:14][OH:15])=[CH:11][CH:12]=1)[CH3:7]
Reactant: CCc1ccco1
Reactant: C1CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
n-BuLi (2.5 M in hexane, 4.4 mL, 11 mmol) was added to a solution of 2-ethylfuran (1.05 mL, 10 mmol) in THF (10 mL) at −25° C. The solution was warmed to rt and stirred for 3 h. Ethylene oxide (0.75 mL) was added at −78° C. The reaction was stirred for 0.5 h at −15° C. and overnight at rt. Aqueous sat. NH4Cl was added and the mixture was extracted with ether (3×). The combined extracts were washed with water (1×) and brine (1×) and dried over Na2SO4. Purification by flash chromatography on silica gel eluting with 30% EtOAc/70% hexane gave 1.12 g (8.02 mmol, 80.2%) of compound 245A as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:18][CH2:17]1.C(OCC)(=O)C.ClCCl>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:1]3[C:9]4[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=4[CH:3]=[CH:2]3)[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: ClCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: O=C1CCCc2[nH]ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2c1ccn2CCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 1,5,6,7-tetrahyro-indol-4-one (51.5 mmol) in DMSO (60 mL) was added powdered sodium hydroxide (53.9 mmol) and the mixture was stirred at ambient temperature for 0.5 h. 1-(2-Chloroethyl)-4-(3-chlorophenyl) piperazine (49.0 mmol) was then added as a solution in DMSO (20 mL) and the resulting mixture stirred at ambient temperature for 24 h then heated to approximately 60° C. for 2 h, after which time TLC (ethyl acetate:dichloromethane 1:1) showed complete reaction. The reaction was poured into ice cold water (300 mL) and stirred for 0.5 h. A solid mass formed and was separated by decanting the water. The aqueous layer was extracted with dichloromethane (100 mL). The solid mass was dissolved with dichloromethane (100 mL) and the combined organics were dried with sodium sulfate and the solvent removed under vacuum. The resulting sludge was triturated with hexanes (100 mL) for 2 h and the suspension vacuum filtered and washed with hexanes. The obtained solid was under vacuum resulting in a tan powder (14.57 g) as the titled compound, NEO-376).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)=[O:13])[CH2:6]2)#[N:2].S(=O)(=O)(O)[OH:28]>FC(F)(F)C(O)=O>[CH2:23]([NH:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]([NH2:2])=[O:28])[CH:4]=3)[CH2:8]2)=[O:13])=[CH:16][CH:17]=1)=[O:26])[CH2:24][CH3:25]
Reactant: O=S(=O)(O)O
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C#N)cc3C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(N)=O)cc3C2)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5-cyano-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (30 mg, 0.9 mmol) in sulfuric acid (0.1 mL) and trifluoroacetic acid (0.3 mL) was stirred at room temperature for 16 hours. The reaction was treated with ice and the suspension was stirred for 10 minutes and filtered. The solid collected was washed with water and dried under vacuum; the solid was purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.26 (t, J=5.7 Hz, 1H), 7.97-8.00 (bs, 1H), 7.81-7.86 (m, 2H), 7.75-7.79 (m, 2H), 7.63-7.68 (m, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.34-7.39 (bs, 1H), 4.81-4.82 (bs, 4H), 3.16-3.24 (m, 2H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 367 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][CH:20]=[CH:19][CH2:18]2)[N:12]=1.BrC1C=CC=C(N2CCCC2)N=1.[Cl-].[NH4+]>CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].O1CCCC1>[CH2:1]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][CH:20]=[CH:19][CH2:18]2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Brc1cccc(N2CC=CC2)n1
Agent: [Ni]
Agent: Brc1cccc(N2CCCC2)n1
Agent: CC(C)P(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C1=CCN(c2cccc(Cc3ccccc3)n2)C1
Temperature: 25 °C

Procedure:
72.3 ml of a tetrahydrofuran solution containing 1.07 mol of benzylmagnesium chloride was added dropwise into a mixture of 11.6 g of a mixture of 2-bromo-6-(3-pyrroline-1-yl)pyridine and 2-bromo-6-(pyrrolidine-1-yl)pyridine and 20 ml of tetrahydrofuran containing 1.4 g of 1,3-bis(diphenylphosphino)propanenickel(II) chloride over 10 minutes in an ice bath. After cooling at room temperature overnight, the reaction solution was poured into aqueous saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with aqueous saturated sodium chloride and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane and then with hexane/ethyl acetate (20:1), to give 11.8 g of the title compound as a mixture with 2-benzyl-6-(pyrrolidine-1-yl)pyridine.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6]C1C=C(B(O)O)C=CC=1.[NH2:16][C:17]1[CH:18]=[C:19]([B:23]([OH:25])[OH:24])[CH:20]=[CH:21][CH:22]=1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.Cl>N1C=CC=CC=1.O>[C:26]([OH:31])(=[O:32])[CH2:27][CH2:28][C:29]([NH2:6])=[O:30].[NH2:16][C:17]1[CH:18]=[C:19]([B:23]([OH:25])[OH:24])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: Nc1cccc(B(O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Synthesis of this material was accomplished using a modification of the procedure in Weith, et al. Biochemistry 9:4396-4401 (1970). 3-Amino-phenylboronic acid hemisulfate (100 g, 0.535 moles) was suspended in anhydrous pyridine (240 mL). The mixture was stirred magnetically and chilled in an ice/water bath under an atmosphere of dry nitrogen. Succinic anhydride (56.5 g, 0.565 moles) was added to the flask, and the reaction mixture was allowed to warm to room temperature. After stirring overnight (at least 12 hours), all solids had dissolved. The majority of the pyridine was removed on a rotary evaporator (bath temperature ≤55° C.) to give a viscous, amber-colored syrup. The syrup was co-evaporated with water (100 mL), and the residue was then dissolved in water (700 mL). The amber solution was chilled in an ice-water bath, and concentrated hydrochloric acid (30-50 mL) was added slowly to yield a final pH of 1 (pH paper). During this addition, a white solid precipitated. The suspension was chilled for 1 hour at 4° C. The solid was filtered and washed with cold water (100 mL). The solid was then crystallized from hot water, and dried in vacuo over KOH pellets. Yield: 100 g (80%); m.p. 171°-172° C. (open capillary, uncorrected). 1H NMR (300 MHz, DMSO-d6): δ 12.07 (broad singlet, 1H, CO2H), 9.83 (singlet, 1H, ArNHCOR), 7.95 (singlet, 2H, BOH), 7.67 (singlet, 1H, ArH), 7.65 (doublet, J=7.9 Hz, 1H, ArH), 7.41 (doublet, J=7.0 Hz, 1H, ArH), 7.20 (apparent triplet, J=7.8 Hz, 1H, ArH), 2.60-2.40 (multiplet, 4H, COCH2). 13C NMR (75.5 MHz, DMSO-d6) δ 174.2, 170.2, 138.7, 129.0, 127.8, 125.2, 121.2, 31.0, 28.9. HPLC: Retention time of product, 8.6±0.1 minutes using an Applied Biosystems/Brownlee Aquapore Butyl 2.1×220 mm cartridge, and a mixed gradient elution as follows: A, 0.1M triethylammonium acetate, pH 6.5; B, methanol at a flow rate of 0.5 mL/minute beginning with 100% A/0% B, for 5 minutes, then to 0% A/100% B over 30 minutes at ambient temperature. Detection was carried out using a diode array detector: 260 nm, 280 nm, 300 nm. The sample amount was 5 mg/mL in methanol.
Reaction SMILES: F[C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C(C)=CC=CC=2N=1.[Cl:21][C:22]1[S:23]C2C=CC(Cl)=CC=2N=1>>[Cl:21][C:22]1[S:23][C:2]2[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Cc1cccc(N)c1F
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: Cc1cccc2nc(S)sc12
Product: Cc1cccc2nc(Cl)sc12
Temperature: 180 °C

Procedure:
The title compound was prepared from 2-fluoro-3-methylaniline via 2-mercapto-7-methyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 180° C. for 24 h in a sealed tube.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].CO.CC(C)=[O:40]>>[C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N+:28]([CH2:31][CH2:32][O:33][CH3:34])([O-:40])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: COCCN1CCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)CC1
Reactant: CC(C)=O
Solvent: CO
Product: COCC[N+]1([O-])CCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)CC1

Procedure:
Using the same procedure as described for example 40, (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide (75 mg, 0.157 mmol) was oxidized to give the title compound after chromatography with 50% methanol/acetone.