Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.FC(F)(F)S(O[C:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C@@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34]([CH3:43])([CH3:42])[O:33][C:32]2=[O:44])[CH2:27][CH:26]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C@@H:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:34]([CH3:42])([CH3:43])[O:33][C:32]4=[O:44])[CH2:27][CH:26]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CC1(C)OC(=O)N(C2CC=C(OS(=O)(=O)C(F)(F)F)CC2)[C@H]1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)OC(=O)N(C2CC=C(c3cnc4[nH]ccc4c3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 h-pyrrolo[2,3-b]pyridine (0.477 g, 1.955 mmol), 4-((S)-5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate (0.82 g, 1.955 mmol) and 2.0 M sodium carbonate (4.89 mL) in dioxane (6.52 mL) was flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.226 g, 0.196 mmol) was added and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with CH2Cl2 and extracted with CH2Cl2. The combined organic layers were concentrated. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% 1M NH3.MeOH in CH2Cl2, to provide (4S)-3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.76 g, 1.961 mmol, 100% yield) as light-yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[Br-].[CH:17]1([Zn+])[CH2:19][CH2:18]1.CN1CCN(C)C1=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH:17]1([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=2)[C:5]([OH:7])=[O:6])[CH2:19][CH2:18]1
Reactant: [Zn+]C1CC1
Reactant: COC(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(C2CC2)c1
Reaction time: 22 h

Procedure:
To a solution of methyl 3-chloro-5-(methylsulfonyl)benzoate (1.32 g, 5.31 mmol) in THF (15 mL) were added PEPPSI-IPr (72.1 mg, 106 μmol, CAS RN 905459-27-0), cyclopropylzinc(II) bromide (0.5 M solution in THF, 25.5 mL, 12.7 mmol) and 1,3-dimethyl-2-imidazolidinone (3 mL) and the reaction mixture was heated to reflux for 22 hours before another batch of cyclopropylzinc(II) bromide (0.5 M solution in THF, 12.7 mL, 6.37 mmol) was added. Stirring at reflux was continued for 22 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with saturated aqueous NaHCO3 solution. The pH of the aqueous phase was adjusted to 1, saturated with solid sodium chloride and extracted three times with EtOAc. The organic layers were dried over MgSO4, filtered and evaporated. The product was purified by preparative SFC (Waters Viridis SFC 2-Ethylpyridine column) using an isocratic mixture of MeOH:carbondioxide (40:60). Light brown solid (0.119 g; 9%). MS (ESI): m/z=239.0 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O>[N:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:20][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1O)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc2nc(-c3ccncc3)oc2c1
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A mixture of 0.8 g of N-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide, 15 ml of carbon tetrachloride, 2.23 g of triphenylphosphine and 0.86 g of triethylamine was heated to reflux for five hours. The mixture was cooled to room temperature. Then, water was poured into the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-(pyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 15”).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)[CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(C2CCCCC2)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixed solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 mL) was added cyclohexanecarbonyl chloride (0.18 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was poured into the reaction system, the mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide. To 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (0.90 mL) and ethanol (2.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. Water (2 mL) was added, and the precipitate was collected by filtration to give the title compound (252 mg) as a white solid.
Reaction SMILES: [CH2:1]([C@H:3]1[C:7](=[O:8])[O:6][C:5](=[O:9])[NH:4]1)[CH3:2].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].CN1CCOCC1.C(OCC)(=O)C.Cl>O1CCCC1>[CH2:1]([C@H:3]1[C:7](=[O:8])[O:6][C:5](=[O:9])[N:4]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC[C@@H]1NC(=O)OC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC[C@H]1C(=O)OC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A solution of (4S)-4-ethyl-1,3-oxazolidine-2,5-dione (69.57 g) and benzyl chloroformate (101.1 g) in tetrahydrofuran (800 mL) was cooled to 0° C., N-methylmorpholine (81.74 g) was added dropwise, and the mixture was stirred at 0° C. for 2 hr. A 4 mol/L hydrogen chloride-ethyl acetate solution (86.9 mL) was added dropwise at 0° C. to the reaction mixture, and the precipitated morpholine hydrochloride was filtered off with celite. The filtrate was concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield: 91.58 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].CO[C:12]1C(OC)=C[C:15]2[NH:16][C:17](CCCNC)=N[C:14]=2[CH:13]=1>>[Cl:1][C:2]1[C:3]2[N:9]=[C:12]([CH2:13][CH2:14][CH2:15][NH:16][CH3:17])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1N
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2c(Cl)cccc2[nH]1

Procedure:
Prepared from 3-chloro-benzene-1,2-diamine (J. Med. Chem. 1981, 24(1), 93-101) in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1.ClCCl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(c1ccccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Reaction time: 1.25 h

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone in dichloromethane (2.5 ml) (2.7 mL, ˜0.2 mmol) containing disiopropylethylamine (17 μL, 1 mmol) was added to 4-fluoro-phenyl sulfonyl chloride (48 mg, 0.25 mmol) and diisopropylethylamine (100 μL, 0.57 mmol) and the mixture stirred for 1.25 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (72 mg). LCMS (Method D, ESI): RT 5.32 min, m+H=533.0; 1H NMR (400 MHz, CDCl3): δ 8.62-8.63 (m, 1 H); 7.85-7.86 (m, 2 H); 7.69-7.70 (m, 2 H); 7.44-7.45 (m, 3 H); 7.28 (s, 1 H); 7.14 (dt, J=12.9, 8.5 Hz, 4 H); 6.48 (d, J=2.2 Hz, 1 H); 5.51 (dd, J=12.2, 2.1 Hz, 1 H); 4.29 (d, J=16.9 Hz, 1 H); 3.82-3.86 (m, 1 H); 2.84-2.86 (m, 2 H); 2.72 (d, J=12.2 Hz, 1 H); 2.46-2.51 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=O.Cl.CN.C([O-])(=O)C.[Na+].[N+:21]([CH3:24])([O-:23])=[O:22]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[CH:24][N+:21]([O-:23])=[O:22]
Reactant: COc1cc(Cl)cc(Cl)c1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(Cl)cc(Cl)c1C=C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 2,4-dichloro-6-methoxybenzaldehyde (0.51 g; 2.5 mmol), methylamine hydrochloride (0.11 g; 1.6 mmol) and sodium acetate (0.13 g; 1.6 mmol) in 3 mL of nitromethane was stirred at ambient temperature. After stirring for 15.5 hours the mixture was diluted with 20 mL water and 40 mL DCM, and then transferred to a separatory funnel. After shaking, the organic layer was dried over sodium sulfate and evaporated to give 0.57 g of 1,5-dichloro-3-methoxy-2-(2-nitrovinyl)benzene as a light yellow solid. MS (apci, neg) m/z=247
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23]
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NCC(F)(F)F
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NCC(F)(F)F
Yield: 90 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (77 mg, 90%) which was obtained as an off white solid. MS: m/e=429.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(OCC)(=O)C.[H][H].[ClH:33]>[Pd].CO.O1CCOCC1>[ClH:33].[ClH:33].[NH2:1][C:2]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2N)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a Parr hydrogenation bottle was added 7.0 g of tert-butyl 4-(2-amino-3-nitrophenoxy)piperidine-1-carboxylate, 10% palladium on carbon (50% w/w water) (2.0 g, wet), ethyl acetate (100 mL) and MeOH (150 mL). The atmosphere of the vessel was replaced by hydrogen gas. The reaction was shaken on a Parr hydrogenator at 40 psi at room temperature, overnight. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to give a residue, which was dissolved in methanol, cooled in an ice bath and carefully acidified with 4 N hydrogen chloride in 1,4-dioxane and filtered. The resulting filtrate was concentrated under reduced pressure to give of tert-butyl 4-(2,3-diaminophenoxy)piperidine-1-carboxylate dihydrochloride (6.7 g), and was used directly in the next step without any further purification. MS (EI): 308 (MH+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:22]=[C:21]([C:23](=[O:47])[NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[C:31]([O:38][CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH:32]=[CH:33][CH:34]=3)[CH:29]=2)(=[O:27])=[O:26])[CH:20]=[CH:19][C:18]=1[N:48]1[C:52]([CH3:53])=[C:51]([Cl:54])[C:50]([C:55]([N:57]([CH2:62][CH2:63][CH2:64][CH3:65])[CH2:58][CH2:59][CH2:60][CH3:61])=[O:56])=[N:49]1)=[O:16])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[Na+].Cl>C1COCC1.O>[NH2:1][CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:22]=[C:21]([C:23](=[O:47])[NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[C:31]([O:38][CH2:39][CH2:40][N:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[CH:32]=[CH:33][CH:34]=3)[CH:29]=2)(=[O:27])=[O:26])[CH:20]=[CH:19][C:18]=1[N:48]1[C:52]([CH3:53])=[C:51]([Cl:54])[C:50]([C:55]([N:57]([CH2:62][CH2:63][CH2:64][CH3:65])[CH2:58][CH2:59][CH2:60][CH3:61])=[O:56])=[N:49]1)=[O:16]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN)c(C)c1Cl
Temperature: 50 °C
Yield: 75 %

Procedure:
To a solution of (S)-1-(2-(3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(8-(2-morpholinoethoxy)naphthalen-2-ylsulfonylcarbamoyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (45 mg, 0.049 mmol) and PPh3 (38 mg, 0.15 mmol) in THF (4.0 mL) and water (0.4 mL) was added 1N aq. NaOH solution (0.2 mL, 0.20 mmol). The resulting reaction mixture was heated at 50° C. for 3 h and then acidified (pH=1) with 1N aq. HCl solution. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to give the title compound (33 mg, 72%) as a white solid. 1H NMR (CD3OD, mixture of amide rotamers) δ 9.16 (s, 1H), 8.29-7.88 (m, 4H), 7.83-7.58 (m, 3H), 7.40-7.08 (m, 4H), 6.99 (br s, 1H), 5.04 (br s, 0.5H), 4.76-4.41 (m, 4H), 4.27-2.66 (m, 18.5H), 2.42-2.20 (m, 3H), 1.64-0.72 (m, 13H), 0.60 (br s, 1H); MS(ESI+) m/z 898.1 (M+H)+.
Reaction SMILES: BrCCCCCCCCCCC(O)=O.[N-]=[N+]=[N-].[Na+].[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=O)=[N+:20]=[N-:21].C(Cl)(=O)C([Cl:38])=O>CN(C=O)C.[Cl-].[Na+].O.C1C=CC=CC=1.CCOCC>[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([Cl:38])=[O:34])=[N+:20]=[N-:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=NCCCCCCCCCCC(=O)O
Agent: O=C(O)CCCCCCCCCCBr
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCCCCCCCCC(=O)Cl
Temperature: 80 °C

Procedure:
In a glass reaction vessel, 10.6 grams (40 mmol) of 11-Bromoundecanoic acid was dissolved in 225 milliliters DMF and 26 grams (400 mmol) sodium azide was added. The resulting stirred mixture was heated to 80° C. for 16 h, and then the reaction mixture was worked up with ether and brine. The ether layer was dried (MgSO4), filtered, and concentrated to 9.5 grams of N3(CH2)10C(O)OH as a pale yellow oil which was used without purification. In a glass reaction vessel, the N3(CH2)10C(O)OH was dissolved in 120 milliliters benzene and 12.7 grams (100 mmol) oxalyl chloride was added. The reaction was allowed to stir for 20 h, at which time the volatiles were removed in vacuo. The resulting residue was dissolved in pentane and filtered in a nitrogen atmosphere to remove solids. Concentration of the filtrate afforded N3(CH2)10C(O)Cl as a clear, yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([OH:20])=O)[C:13]2[C:8](=[CH:9][C:10]([CH3:21])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O.[CH:45]1([NH:49][C:50]([C@@H:52]2[CH2:56][CH2:55][CH2:54][NH:53]2)=[O:51])[CH2:48][CH2:47][CH2:46]1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:53]2[CH2:54][CH2:55][CH2:56][C@H:52]2[C:50](=[O:51])[NH:49][CH:45]2[CH2:46][CH2:47][CH2:48]2)=[O:20])[C:13]2[C:8](=[CH:9][C:10]([CH3:21])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2 g of 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 30 ml of DCM, 3.6 g of EDC, 3.4 g of pentafluorophenol, 2.2 g of NEM was added and the reaction mixture was stirred at RT for 2 h. Then, 5.3 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 2.1 g of NEM in 10 ml of DCM was added. After 16 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.5 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH2:12][CH2:13][C:14]#[N:15])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].CO>C1COCC1.O>[C:14]([CH2:13][CH2:12][N:9]1[C:8]2[CH:16]=[CH:17][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)#[N:15]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCC#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#CCCn1cnc2cc(C(=O)O)ccc21
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 1-(2-cyanoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (4.0 g, 17.4 mmol) in THF (30 mL) was added LiOH (1.67 g, 69.79 mmol) in water (8 mL) followed by MeOH (2 mL). Stirring continued at the ambient temperature for 1 h. It was then concentrated and acidified with 2N HCl. The solids formed were filtered and dried which afforded 1-(2-cyanoethyl)-1H-benzoimidazole-5-carboxylic acid (3.5 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 3.1 (t, 2H), 4.6 (t, 2H), 7.8 (d, 1H), 7.9 (dd, 1H), 8.25 (d, 1H), 8.42 (s, 1H)
Reaction SMILES: [CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:26][CH2:35][C:36]([NH2:38])=[O:37])=[CH:25][C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)CBr
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C(O)c2ccccc21
Yield: 73.6 %

Procedure:
A solution of the product of Example 5E (69 mg, 0.15 mmol), 2-bromoacetamide (80 mg, 0.58 mmol), cesium carbonate (96 mg, 0.58 mmol), and tetrabutylammonium iodide (26 mg, 0.08 mmol) in N,N-dimethylformamide (2.4 mL) was stirred at 25° C. for 48 hours, diluted with ethyl acetate and treated with saturated ammonium chloride solution (2 mL). The organic layer was washed with water (3×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (58 mg, 76%). 1H NMR (300 MHz, DMSO-d6): δ 13.73 (s, 1 H), 8.17 (d, J=7.72 Hz, 1 H), 7.74 (m, 3 H), 7.55 (m, 1 H), 7.40 (m, 2 H), 4.59 (s, 2 H), 2.19 (m, 2 H), 2.02 (d, 2 H), 1-06 (m, 4 H), 0.90 (m, 2H), 0.69 (q, J=7.60 Hz, 6 H), 0.52 (m, 2 H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([N:9]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2=[O:16])=[N:5][N:6]([CH3:8])[CH:7]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:15][C:11]1([CH3:14])[CH2:12][CH2:13][N:9]([C:4]2[C:3]([NH:2][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([S:22]([C:18]4[S:17][CH:21]=[CH:20][N:19]=4)(=[O:24])=[O:23])[CH:26]=3)=[CH:7][N:6]([CH3:8])[N:5]=2)[C:10]1=[O:16]
Reactant: O=C(O)c1cccc(S(=O)(=O)c2nccs2)c1
Reactant: Cn1cc(N)c(N2CCC(C)(C)C2=O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2cccc(S(=O)(=O)c3nccs3)c2)c(N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 1-(4-amino-1-methyl-1H-pyrazol-3-yl)-3,3-dimethylpyrrolidin-2-one hydrochloride (30 mg) and 3-(1,3-thiazol-2-ylsulfonyl)benzoic acid (33.0 mg) in DMF (0.61 mL) were added HATU (56 mg) and diisopropylethylamine (43 μL). The reaction mixture was stirred overnight at room temperature, and poured into water, and the precipitate was collected by filtration, purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (40 mg).