Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].Br[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]=[C:12]2[O:27][C@H:28]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:30]([C:40]([O:42][CH3:43])=[O:41])[CH2:29]1>CCO.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].C(Cl)Cl>[CH3:20][O:19][C:18]1[CH:17]=[C:16]2[C:11]([C:12]([O:27][C@H:28]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:30]([C:40]([O:42][CH3:43])=[O:41])[CH2:29]3)=[CH:13][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:15]2)=[CH:10][C:9]=1[CH:1]=[CH2:2]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(-c3ccccc3)nc2cc1OC
Yield: 95.9 %

Procedure:
Potassium vinyltrifluoroborate (5.05 g, 37.7 mmol), TEA (5.25 mL, 37.7 mmol) and PdCl2(dppf)-CH2Cl2 adduct (1025 mg, 1.26 mmol) were added to a solution of the product from step 5 (14.0 g, 21.5 mmol) in EtOH (300 mL). The mixture was then heated to reflux for 1.5 h, at which time LC-MS revealed the disappearance of starting material. The reaction mixture was cooled and concentrated and partitioned between EtOAc and water. The layers were separated, and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (gradient elution 10% to 80% EtOAc in hexanes) to give the title compound (10.4 g, 82% yield). LRMS (M+H)+ Calcd.: 505.2; found 505.5.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CC#N>[F:23][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH2:36][C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:39][CH:38]=2)[C@@H:4]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH2:3]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CCN2Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.6 %

Procedure:
To a solution of methyl 4-((S)-1-((R)-4,4-difluoropiperidine-2-carboxamido)ethyl)benzoate (D97) (66 mg, 0.20 mmol) in dry MeCN (4 ml), Cs2CO3 (198 mg, 0.60 mmol) and the 4-(Trifluoromethyl)benzylbromide (0.037 ml, 0.24 mmol) were added in sequence and the resulting mixture was stirred at RT for 18 hrs. The solid was filtered off, the acetonitrile was evaporated and the crude was purified by flash chromatography SNAP HP_SiO2 (10 g) eluting with a gradient DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation were purified onto reverse phase column GOLD-C18 (15 g) eluting with a gradient of H2O/MeCN (containing 0.1% Acetic acid) from 10/90 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D135) (20 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](OS(OCC)(=O)=O)[CH3:19]>CO>[CH2:18]([N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1])[CH3:19]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCn1c(CO)nc2ccccc21

Procedure:
99.2 mg (0.67 mmol) 2-hydroxymethylbenzimidazole was dissolved in 3 ml methanol. Potassium carbonate (103.1 g, 0.75 mmol) and diethylsulfate (442 μl 3.38 mmol) were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain white crystals of 1-ethyl-2-hydroxymethylbenzimidazole, 41 mg (32%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][N:16]([CH3:22])[C:17](=[O:21])[C:18]=2[CH3:20])[NH:13]C1=O.[Si]([O:31][CH2:32][CH2:33][C:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1)(C(C)(C)C)(C)C>CN(C=O)C.C1COCC1>[OH:31][CH2:32][CH2:33][C:34]1([S:37]([NH:13][C:14]2[C:19]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=3[F:3])=[C:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=2)(=[O:39])=[O:38])[CH2:36][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1c(=O)n(C)cc2[nH]c(=O)n(-c3ccc(I)cc3F)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO)CC2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60% in mineral oil) (21.8 mg, 0.544 mmol) is added to a solution of 1-(2-fluoro-4-iodophenyl)-5,7-dimethyl-1H-imidazo[4,5-c]pyridine-2,6(3H,5H)-dione (100 mg, 0.251 mmol) in dry DMF (5 mL) at 0° C. The cooling bath is removed and the solution stirred at room temperature for 1 hour. The solution is re-cooled to −5° C. in a dry-ice/acetone bath, and 1-[2-(tert-butyldimethylsilanyloxy)ethyl]-cyclopropanesulfonyl chloride (300 mg, 1 mmol) in dry THF (2 mL) is added. The mixture is warmed to room temperature and stirred for an additional 16 hours. The mixture is concentrated to give an oily residue and purified via flash chromatography (SiO2, EtOAc:MeOH=9:1) to give the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[C:14]2=[O:20])=[CH:9][CH:8]=1.C(N(CC)CC)C.C(OCC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]2=[O:20])=[CH:9][CH:8]=1
Reactant: O=C1C(CO)CCN1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2ccc(Cl)cc2)C1=O
Reaction time: 2 h
Yield: 95.4 %

Procedure:
Under ice-cooling, 14.0 g of methanesulfonyl chloride was added dropwise to a solution of 23.2 g of 1-(4-chlorophenyl)-3-hydroxymethyl-2-pyrrolidinone and 12.5 g of triethylamine in 200 mL of dichloromethane. After 2 hours, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals. The crystals were sludged with diethyl ether and collected by filtration. The crystals were washed with diethyl ether and dried in vacuo to give 29.8 g of the title compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:39]=[CH:40][CH:41]=[CH:42][C:21]=3[N:20]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:19]2=[O:49])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:39]=[CH:40][CH:41]=[CH:42][C:21]=3[N:20]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:19]2=[O:49])=[N:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 6 h
Yield: 70.8 %

Procedure:
400 mg of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide, prepared as in Intermediate 68, is dissolved in 10 mL of CHCl3 and 5 mL of TFA is added. The reaction mixture is stirred for 6 h and the solvents were removed in vacuo and the residue is purified by flash column chromatography on silica gel (MeOH 1%:CHCl3 99%) to afford 240 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ7.93 (d, 1H, J=8.4), 7.51-7.19 (m, 16H), 6.99 (m, 1H), 5.03 (m,1H, J=6.8), 4.29 (d, 1, J=16.4), 4.26 (d, 1H, J=16.4), 4.14 (m, 1H), 3.89 (dd, 1H, J=16.5, 6.4), 3.82 (dd 1H,J=16.5, 6.4,), 1.08 (t, 6H, J=6.8); LOW RESOLUTION MS (FAB) m/e 558 (MH+); Tr =9.90 min. (HPLC Column: Dynamax C-8 2 mL/min., 50-90% Acetonitrile in aqueous TFA (0.1% v/v) over 15 min.).
Reaction SMILES: Cl[C:2]([C:16]([F:19])([F:18])[F:17])=[C:3]([C:6]1[CH:14]=[C:13]([Cl:15])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)[C:4]#[N:5].[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[NH:26][NH2:27].C(N(CC)CC)C>C(O)C>[Cl:15][C:13]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=[C:6]([C:3]2[C:2]([C:16]([F:18])([F:17])[F:19])=[N:27][N:26]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[C:4]=2[NH2:5])[CH:14]=1
Reactant: NNc1ncccn1
Reactant: N#CC(=C(Cl)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Yield: 43.8 %

Procedure:
3-chloro-2-(7-chloro-1,3-benzodioxol-5-yl)-4,4,4-trifluoro-but-2-enenitrile (20.2 g, 65.4 mmol) was dissolved in ethanol (200 mL) and treated with pyrimidin-2-yl-hydrazine (7.20 g, 65.4 mmol) and triethylamine (6.60 g, 65.4 mmol). The reaction mixture was heated to reflux for 10 h. The solvent was removed in vacuo, to the residue was added water, extracted with EtOAc, then the organic layer was combined, washed with water and brine, dried, filtered and concentrated to give crude product. The crude product was washed with DCM to give the title compound (11.0 g; 44%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[C:9]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:10]=3[CH2:11][C:5]2=[N:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:28][C:3]1[N:4]=[C:5]2[CH2:11][C:10]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:9]=3[C:8]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:7][N:6]2[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc3c(cc1C2)OCO3
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)nc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc3c(cc1C2)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
900 mg of 8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is mixed in 10 ml of dimethylformamide with 441 mg of N-bromosuccinimide and stirred for 1.5 hours at room temperature. After dilution with 40 ml of water, the precipitated product is suctioned off, and 900 mg of 9-bromo-8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][CH2:15]/[CH:16]=[CH:17]/[CH2:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20](O)=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC/C=C/C[C@@H](C(C)C)C(Cl)=O)C1C=CC=CC=1.[CH3:45][NH:46][CH3:47]>C(Cl)Cl.CN(C)C=O.C(O)(C)(C)C.O1CCCC1>[CH3:45][N:46]([CH3:47])[C:20](=[O:21])[C@H:19]([CH:23]([CH3:25])[CH3:24])[CH2:18]/[CH:17]=[CH:16]/[CH2:15][O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[C@H](C/C=C/COCc1ccccc1)C(=O)O
Reactant: CNC
Agent: CC(C)[C@H](C/C=C/COCc1ccccc1)C(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](C/C=C/COCc1ccccc1)C(=O)N(C)C
Reaction time: 1 h
Yield: 101 %

Procedure:
7.75 ml of oxalyl chloride (87 mmol) and 0.11 ml of N,N-dimethylformamide (1.4 mmol) were added to a solution of 19.02 g of (2S,4E)-6-(benzyloxy)-2-isopropylhex-4-enoic acid obtained in Example (1b) (72.5 mmol) in methylene chloride (180 ml) at room temperature. The mixture was stirred at the same temperature for one hour to prepare a solution of (2S,4E)-6-(benzyloxy)-2-isopropylhex-4-enoic acid chloride in methylene chloride. The solution of acid chloride in methylene chloride above was added to a solution of 76 ml of a 50% dimethylamine aqueous solution (725 mmol) in a mixed solvent of tetrahydrofuran (180 ml) and t-butanol under ice-cooling over one hour, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure to about ⅕ of the volume and diluted with 150 ml of water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 21.20 g of the crude title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH2:17]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: CCCCc1ccc2c(c1)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-butyl-2-oxindole to give 0.3 g of 5-butyl-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH3:22])=[C:17]([N+:19]([O-])=O)[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1>CO.[Ni]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH3:22])=[C:17]([NH2:19])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1N
Yield: 93.9 %

Procedure:
Sponge nickel (0.7 g water wet) was added to a solution of 5-methyl-4-nitro-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide (0.72 g, 2.2 mmol) in methanol (50 mL), and the mixture was hydrogenated at room temperature under a hydrogen atmosphere at a starting pressure of 50 psi. After a reaction time of 1.77 hours, the pressure was released, and the mixture was filtered. The slurry was rinsed with methanol, and the filtrate was stripped of solvent under reduced pressure to afford 0.6 g of 5-methyl-4-amino-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide as an oil.
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11](=O)[CH3:12])[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(OC(=O)[N:20]([CH2:31][CH2:32][NH2:33])[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)(C)(C)C>>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][NH:20][CH2:31][CH2:32][NH:33][CH:11]([C:9]3[N:10]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[S:7][CH:8]=3)[CH3:12])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(=O)c1csc(-n2ccnc2)n1
Reactant: CC(C)(C)OC(=O)N(CCN)Cc1ccc2c(c1)OCO2
Product: CC(NCCNCc1ccc2c(c1)OCO2)c1csc(-n2ccnc2)n1

Procedure:
N-Benzo[1,3]dioxol-5-ylmethyl-N′-[1-(2-imidazol-1-yl-thiazol-4-yl)-ethyl]-ethane-1,2-diamine was prepared following the procedures described in the preparation of Example 64 using 1-(2-imidazol-1-yl-thiazol-4-yl)-ethanone and (2-amino-ethyl)-benzo[1,3]dioxol-5-ylmethyl-carbamic acid tert-butyl ester. [M+H]+ 372.01; 1H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.82 (d, 1H), 7.31 (s, 1H), 7.18 (d, 1H), 6.92 (d, 1H), 6.84 (d, 1H), 6.77 (dd, 1H), 6.00 (s, 2H), 4.14 (br s, 2H), 3.82 (q, 1H), 3.60 (s, 2H), 3.21 (s, 2H), 2.57 (s, 2H), 1.34 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[I:18]C1C=CC=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: Oc1ccccc1I
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccccc1I

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-iodophenol and tert-butyl bromoacetate (Aldrich), the title compound was obtained as a yellow liquid in quantitative yield.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2.[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][NH:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][N:43]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[S:23]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[CH:22][C:13]=2[CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:18]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A round-bottom flask was charged with perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (0.234 g, 0.420 mmol), N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.126 g, 0.504 mmol), and THF (4.20 ml) to give a clear solution. The flask was cooled in an dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.924 ml, 0.924 mmol) was added dropwise over 30 seconds. The reaction was stirred for 30 minutes, then the cooling bath was removed and the reaction was stirred for 30 minutes. The mixture was diluted with saturated aq. ammonium chloride solution, then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g, 0 to 10% MeOH/DCM) to give N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as a white foam. (ESI) 510.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH2:11].[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]
Reactant: Cn1c(N)nc2ccccc21
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cn1c(NC(=S)n2ccnc2)nc2ccccc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
To 1-methyl-1H-benzo[d]imidazol-2-amine (1.28 g, 8.7 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (2.015 g, 11.31 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1H-imidazole-1-carbothioamide (1.6 g, 6.22 mmol, 71.5% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:22][CH2:21][C@@H:20]([OH:23])[C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=[C:11]2[CH2:10]1>CO.[Pd]>[NH2:17][C:15]1[CH:16]=[C:11]2[CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:22][CH2:21][C@@H:20]([OH:23])[C:12]2=[N:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2O
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2O
Reaction time: 4 h

Procedure:
The mixture of Pd/C (37 mg, 0.035 mmol) and (6R,9R)-6-(2,3-difluorophenyl)-3-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (300 mg, 0.937 mmol) in methanol (10 mL) was hydrogenated under H2 (balloon) for 4 h. LCMS showed the reaction was over. The reaction was filtered through a celite plug. The filtrate was concentrated to give the crude product. MS(ESI)[M+H+]=291.29; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84 (br.s., 1H) 7.02 (br.s., 3H) 6.79 (br.s, 1H) 5.90 (br.s, 1H) 4.74 (d, J=10.32 Hz, 1H) 3.87 (br.s., 2H) 3.06 (t, J=12.34 Hz, 1H) 2.86 (br.s., 1H) 2.62 (d, J=13.85 Hz, 1H) 2.26 (d, J=12.34 Hz,1H) 1.96-2.12 (m, 3H) 1.52 (br.s., 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:19])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCC(=O)Nc1ccccc1C(F)(F)F
Product: CCCCC(Cl)=Nc1ccccc1C(F)(F)F
Yield: 102.5 %

Procedure:
Using the procedure of Step B of Example 6, 20 g of the product of Step A and 19 g of phosphorus pentachloride were reacted to form 22.05 g of N-(2-trifluoromethylphenyl)-pentanimidoyl chloride as an oil which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@@H:28]([CH3:31])[CH2:29][OH:30])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-2-amino-1-propanol via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-hydroxypropan-2-yl)terephthalamide. MS (Q1) 445 (M)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([OH:14])[CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([OH:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(N)c(O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.5 %

Procedure:
To a solution of 3-hydroxy-4-nitrophenyl acetate (3.0 g) in ethyl acetate (50 mL), 300 mg of palladium/carbon (10%) was added under nitrogen atmosphere. The resulting mixture was stirred under hydrogen atmosphere for 10 h at room temperature. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by the column chromatography over silica gel using hexane/ethyl acetate(1:1) to give the title compound (2.48 g).