Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[C:9]2[N:16]([CH3:19])[CH2:17][CH2:18][C:8]=12)(=[O:5])=[O:4].C([O-])(O)=O.[Na+]>CS(C)=O.CC(C)=O>[F:21][C:2]([F:1])([F:20])[S:3]([O:6][C:7]1[C:12]([CH:13]=[O:14])=[C:11]([CH3:15])[N:10]=[C:9]2[N:16]([CH3:19])[CH2:17][CH2:18][C:8]=12)(=[O:5])=[O:4]
Reactant: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1CO)CCN2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)CCN2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 134 mg of alcohol 30 in 2 mL of DMSO and 2 mL of acetone was added 116 mg of IBX. The reaction mixture was stirred at room temperature for 16 h then cooled to 0° C., 5 mL of a mixture of 5% NaHCO3 and 5% of NaS2O3 was added by syringe slowly. After stirred for additional 20 min the mixture was extracted with three portions of 5 mL of ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4. After the solvent was removed under diminished pressure, the residue was purified by flash chromatography on a silica gel column (15×2 cm). Elution with 1:10 EtOAc-hexanes gave product 31 as white crystal: yield 121 mg, (91%). Silica gel TLC Rf 0.20 (1:4 EtOAc-hexanes); 1H NMR (CDCl3, ppm): δ 2.70 (s, 3H), 3.09 (s, 3H), 3.18 (t, J=8.5 Hz, 2H), 3.72 (t, J=8.5 Hz, 2H), 10.09 (s, 1H). 13C NMR (CDCl3, ppm): 623.21, 24.06, 31.48, 51.19, 112.28, 112.40, 120.01, 151.18, 165.51, 166.54, 185.22; 19F NMR (CDCl3, ppm): δ−73.54 (s, 3F); HRMS (APCI+) calculated for C11H12N2O4SF3 (M+H+) 325.0470. found 325.0465.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[C:5](I)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:18]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:28][C:27]([C:5]2[C:4]([CH2:9][OH:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)([OH:29])[CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: OCc1cc(Br)cnc1I
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ncc(Br)cc2CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a stirred solution of (5-bromo-2-iodo-pyridin-3-yl)-methanol (9.5 g, 30.2 mmol, 1 eq) in dry THF (100 mL) was added i-PrMgCl.LiCl complex (1.3M in THF, 55.9 mL, 72.6 mmol, 2.4 eq) at −20° C. in drop wise manner over period of 20 minutes. Predissolved solution of N-boc-3-azetidinone (6.22 g, 36.3 mmol, 1.2 eq) in dry THF (80 mL) was added at −20° C. to above reaction mixture. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After maximum consumption of starting material, reaction mixture was cooled to 0° C. and quenched with 10% citric acid solution (20 mL), diluted with water (150 mL) and extracted with ethyl acetate (3×100 mL). Combined organic phase was washed with brine solution (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellowish sticky mass (18.2 g, crude). Crude compound was purified by column chromatography by using silica gel (100-200 mesh). Desired compound was eluted by 35% ethyl acetate in hexane to afford title compound as pale yellow thick oil (4.9 g, 45%). 1H NMR (400 MHz, CDCl3) δ: 1.43 (s, 9H), 3.12 (s, 1H), 4.13 (d, J=9.92 Hz, 2H), 4.54 (bs, 2H), 4.71-4.73 (m, 3H), 7.93 (d, J=2.12 Hz, 1H), 8.53 (d, J=3.00 Hz, 1H). LC-MS (m/z): 358.9 (M+H).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]([CH3:23])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:12]=[N-:13]>>[ClH:1].[CH3:23][C:15](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(Cc2c[nH]c(N)n2)nn1
Yield: 91.2 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.127 g, 0.809 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.168 g, 0.971 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(2-Methyl-3-phenyl-allyl)-1H [1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine hydrochloride (0.244 g, 91%) of a pale yellow solid. 1H NMR (300 MHz, D2O) δ 7.94 (s, 1H), δ 7.40-7.35 (m, 5H), δ 6.56 (s, 1H), δ 5.10 (s, 2H), δ 3.99 (s, 2H), δ 1.76 (s, 3H) ppm; 13C δ 145.8, 138.1, 136.9, 136.5, 136.4, 132.8, 128.3, 128.0, 127.6, 125.3, 123.4, 49.3, 23.8, 23.4; HRMS (ESI) calcd for C16H18N6(M+) 295.1665, found 295.1665.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:19](OCC)=[O:20].C(O)(=O)C>COCCOC>[CH:19]([CH:13]([CH2:12][C:5]1[C:4]([F:3])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[F:11])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1c(F)cc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1c(F)cc(F)cc1F
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (1.240 g, 31.0 mmol) in DME (15 mL) was added dropwise a solution of ethyl 3-(2,4,6-trifluorophenyl)propanoate (1.8 g, 7.75 mmol) and ethyl formate (3.12 mL, 38.8 mmol) in DME (15 mL) at room temperature. The reaction mixture was then stirred overnight. It was neutralized with acetic acid (1.8 mL), then extracted with EA. The organic layer was collected, washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (2.017 g, 100% yield). LCMS: rt=2.98 and 3.67 min, [M+H+]=261.0, as a mixture of ketone (RT=2.98 min) and enol (RT=3.67 min) isomer.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[C:6]([O:15][CH3:16])=[CH:5][C:3]=1[NH2:4].[C:17](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:18]>ClCCl>[F:1][C:2]1[C:3]([N:4]=[C:17]=[S:18])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[CH:8]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)c(F)cc1-n1cnc(C)n1
Solvent: ClCCl
Product: COc1cc(N=C=S)c(F)cc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
Step B (3): Dichloromethane (125 mL) was added to a flask charged with 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.07 g, 4.82 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (1.12 g, 4.82 mmol). The resulting mixture was stirred for 24 h at rt and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-5% EtOAc/chloroform, linear gradient over 36 min, flow 25 mL/min) to afford 1-(5-fluoro-4-isothiocyanato-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (950 mg, 75% yield) as a yellow solid. LC-MS (M+H)+ 265.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.74 (s, 1 H) 7.75 (d, J=10.07 Hz, 1 H) 6.84 (d, J=6.41 Hz, 1 H) 3.94 (s, 3 H) 2.48 (s, 3 H).
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][N:11]=1.O>O1CCCC1>[N+:16]([C:15]1[C:10]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:11][CH:12]=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CCS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 54.5 %

Procedure:
3.1 g of ethanesulfonamide was dissolved in 50 ml of dry tetrahydrofuran, and 1.2 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 5.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and then the mixture was reacted for 7 hours under reflux. After completion of the reaction, the reaction product was poured into 200 ml of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 3.6 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 160° to 163° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[O:20]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][C:30]1[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:33][CH:32]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(N)cccc2c1Nc1ccc(Oc2ccccc2)cc1

Procedure:
The compound prepared in Example 3 was reacted with 4-phenoxyaniline according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:18]([O-])=O)[C:8]([O:16][CH3:17])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:18][C:7]1[C:8]([O:16][CH3:17])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=1
Reactant: COc1c(NS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
To a 5 L hydrogenator was charged the product from step (viii) above (209.4 g, 0.693 mol), methanol (1675 mL, 8 volumes) and 10% Pd/C (10.2 g). The vessel was purged with 3×N2 and 3×H2 and then stirred under 0.3447 MPa (50 psi) H2 until no further exotherm was observed, with HPLC indicating 96.35% product and 1.10% starting material. The reaction was diluted with THF (314 mL) and the catalyst was removed via vacuum filtration (Cuno filter), before being washed with THF (1000 mL). The solvents were concentrated to isolate a light brown solid, which was dried under vacuum at 40° C. overnight. Yield=167.0 g (88.5%). HPLC purity 96.7%. Purity >95% by 1H NMR.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][N:51]([CH2:53][C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH:52]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:56]1[CH:57]=[CH:58][CH:59]=[C:54]([CH2:53][N:51]2[CH:52]=[C:48]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[C:8]([C:11]5[CH:16]=[CH:15][C:14]([N:17]6[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]6)=[CH:13][CH:12]=5)[CH:9]=4)[N:4]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:3]=3)[CH:49]=[N:50]2)[CH:55]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccnc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccnc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 72.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (150 mg, 0.22 mmol) was coupled with 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (intermediate 64) (130 mg, 0.45 mmol) using sodium carbonate (70 mg, 0.66 mmol) and Pd(PPh3)2Cl2 (7.7 mg, 0.011 mmol) in toluene/ethanol/water (10/10/2 ml) to give 110 mg (70% yield) of the titled compound after purification by column (Silica gel 60/120) using 35% ethyl acetate in hexane as eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.Cl.[CH2:29]([N:31]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:30]>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:45]5[CH2:44][CH2:43][CH:42]([N:31]([CH2:29][CH3:30])[C:32](=[O:41])[O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH2:47][CH2:46]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Agent: Cl
Product: CCOc1cc(N2CCC(N(CC)C(=O)OCc3ccccc3)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 47 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and benzyl ethyl(4-piperidinyl)carbamate monohydrochloride was used in place of N-methylpiperazine. In this manner, 134 mg (47%) of the captioned compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Cl)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]([F:24])[C:11]([F:23])=[C:12]3[O:17][CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18]4)[N:14]([CH:22]=1)[C:13]=23)=[O:5])C>C(O)(=O)C.O.OS(O)(=O)=O>[F:24][C:10]1[C:11]([F:23])=[C:12]2[O:17][CH2:16][C:15]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]3[CH:22]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:25])[C:8]([CH:9]=1)=[C:13]23
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCCC1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
A solution of ethyl-9′,10′-difluoro-7′-oxospiro[cyclopentane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (13.2 g, 38 mmol) in a mixture of acetic acid/water/H2SO4 (8:6:1 v/v, 75 mL) was heated under reflux for 2 h. The reaction mixture was poured into ice water. A precipitate formed and was collected by filtration, washed with water and then dried to give the title compound (10.5 g, 32.7 mmol, 86%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=1)=[O:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:33])=[CH:30][CH:31]=1)=[O:26]
Reactant: NNC(=O)c1ccc(C(=O)NCC2CCCO2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NCC2CCCO2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 64.4 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (22 mg, 0.075 mmol) in isopropanol (2.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid (tetrahydrofuran-2-ylmethyl)amide (20 mg, 0.075 mmol) prepared in Reference Synthetic Example 2 and 3 mg of p-toluenesulfonic acid monohydrate at 105° C. for 17 hours and allowed to cool to room temperature. The precipitated solid was collected by filtration, washed with 1 mL of isopropanol and 1 mL of chloroform and dried to give 26 mg of the desired product (yield 72%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C1C(=O)N([Br:34])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:1][C:2]1[NH:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[N:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ethyl 6-methyl-4-(2-nitrophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (7.45 g, 20 mmol) in carbon tetrachloride (100 mL) was added NBS (3.74 g, 21 mmol) under N2 at 60° C. The mixture was stirred at 60° C. for 10 minutes, and cooled to 25° C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a yellow solid (6.32 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:33]=[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]1[C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([NH:25][C:44](=[O:45])[C:43]2[CH:42]=[CH:41][C:40]([N:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]3=[O:33])=[CH:48][CH:47]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Reactant: O=C(Cl)c1ccc(-n2ccccc2=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Cis-3-amino-4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (332.1 mg, 0.95 mmol), from Example 112 Part F, was mixed with 10 mL of CH2Cl2 and 96 mg (0.95 mmol) of triethylamine. The resulting solution was cooled with an ice-water bath. Freshly prepared 4-(2-oxopyridin-1(2H)-yl)benzoyl chloride (222 mg, 0.95 mmol), from part A, was added portion wise. Stirring was continued at rt overnight. CH2Cl2 (10 mL) was added, and the solution was washed with water (3×3 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield cis-4-Benzyloxycarbonylamino-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (343.2 mg) as a crude oil, which was further purified by flash chromatography (ISCO system; 10 g cartridge Eluent AcOEt/Hexane 20%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.4 Hz, 2H), 7.42–7.24 (m, 8H), 7.06 (d, J=6.5 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 6.27 (t, 1H), 5.06 (s, 2H), 4.34 (bs, 1H), 4.08 (bs, 1H), 3.87 (m, 1H), 3.16 (d, J=13.4 Hz, 1H), 2.98 (t, 1H), 1.85 (bs, 1H), 1.65 (m, 1H), 1.39 (m, 9H), ppm. LC-MS (ESI) 569.24 [M+Na]+, tR=6.331 min (Shimadzu Phenomenex S5 ODS 4.6 ×50 mm Luna flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:23]([NH2:25])[CH3:24].O.C(OCC)(=O)C>O1CCCC1>[CH2:23]([NH:25][CH2:2][C:3]1[CH:4]=[C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:24]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)c1cc(CBr)cc(C(=O)OC(C)(C)C)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNCc1cc(C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of di-tert-butyl 5-(bromomethyl)isophthalate (1.00 g) in tetrahydrofuran (10.0 mL) were added a 70% aqueous ethylamine solution (2.21 mL), followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, and subsequently chloroform-methanol) to obtain di-tert-butyl 5-[ethylamino(methyl)]isophthalate (558 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:3]3[CH:7]=[CH:6][CH:5]=[CH:4]3)(=[O:29])=[O:30])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: c1cc[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cccc3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Sodium hydride (139 mg, 60%, 3.5 mmol) was added to a solution of pyrrole (200 uL, 194 mg, 2.9 mmol) in THF (10 mL). Stirring for 3 h at room temperature, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (185 mg, 0.5 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with NH4Cl (5 mL), diluted with EtOAc (50 mL), washed with NaCl (2×20 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 70 mg (35%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.36-1.53 (m, 4 H), 1.55 (s, 9 H), 2.18-2.38 (m, 1 H), 3.22-3.35 (m, 2 H), 3.88 (m, 2 H), 4.33 (d, J=7.42 Hz, 2 H), 6.22-6.31 (m, 2 H), 7.13-7.29 (m, 2 H), 7.71 (d, J=8.8 Hz, 1 H), 7.77 (dd, J=8.6, 1.8 Hz, 1 H), 8.13 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=401.8; Anal. Calcd for C21H27N3O3S+0.30H2O (406.94): C, 61.98; H, 6.84; N, 10.33. Found: C, 62.10; H, 6.90; N, 10.43.