Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:41]([NH:42][S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:39]=[C:38]([F:49])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]=3)[N:13]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:10]2=[N:11][CH:12]=1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:41]([NH:42][S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:39]=[C:38]([F:49])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]=3)[N:13]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:30])=[O:31])[C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCNCC2)n3S(=O)(=O)c2ccccc2)c1F
Reaction time: 2 h
Yield: 67.3 %

Procedure:
A solution of tert-butyl 4-(5-(2,6-difluoro-3-(propylsulfonamido)benzamido)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.07 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (3 mL). After 2 hours, the volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc and saturated NaHCO3. The organic layer was dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (eluting with 90:10:1 CH2Cl2/MeOH/NH4OH) to afford 2,6-difluoro-N-(1-(phenylsulfonyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (29 mg, 67%) as a solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:40])(=[O:39])[NH2:38])=[CH:27][C:26]=2[F:41])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45](O)=[O:46].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:40])(=[O:39])[NH:38][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=3[Cl:42])=[CH:27][C:26]=2[F:41])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:21])([F:20])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 86 %

Procedure:
By the procedure of Example 51, 5-n-butyl-2,4-dihydro-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-2-[5-nitro-2-(trifluoromethyl)-phenyl]-3H-1,2,4-triazol-3-one (from Step E) was reacted with 2-chlorobenzoic acid (3 equivalents), CDI (3 equiv), and DBU (3 equiv). Flash chromatography of the crude product on silica gel afforded an 86% yield of the title compound as a foam; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 732 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:55][O:56][C:57]([C:59]1[C:67]2[N:66]=[C:65]([NH2:68])[NH:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]>CN(C=O)C>[CH3:55][O:56][C:57]([C:59]1[C:67]2[N:66]=[C:65]([NH:68][C:19]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([C:12]#[C:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)[N:18]=3)=[O:21])[NH:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: CS(=O)(=O)c1cccc(C#Cc2cccc(C(=O)O)n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cccc(C#Cc4cccc(S(C)(=O)=O)c4)n3)nc12
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
To a solution of 136 mg (0.45 mmol) of 6-(3-methanesulfonyl-phenylethynyl)-pyridine-2-carboxylic acid in DMF (2 mL) was added 210 mg (0.55 mmol) of HBTU (210 mg) and DIEA (0.2 mL). The mixture was stirred for 5 min then 96 mg (0.5 mmol) of 2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) was added. The reaction mixture was stirred at 30° C. for 30 min. After usual workup as described in general procedure A, 142 mg (60%) of 2-{[6-(3-Methanesulfonyl-phenylethynyl)-pyridine-2-carbonyl]-amino}-1H-benzoimidazole-4-carboxylic acid methyl ester was obtained after column chromatography eluting with DCM/EtOAc (v/v=1:1) then EtOAc. LCMS: 475 (M+1)+. This ester was hydrolyzed as described in general procedure B to provide 135 mg (100%) of 2-{[6-(3-methanesulfonyl-phenylethynyl)-pyridine-2-carbonyl]-amino}-1H-benzoimidazole-4-carboxylic acid. LCMS: 461 (M+1)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:14][CH3:15])(=O)C.CO.[OH-].[Na+]>O>[CH2:14]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:6]=1[CH2:5][OH:4])[CH3:15]
Reactant: CCc1cccc(CC)c1COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1cccc(CC)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.4 %

Procedure:
A mixture of 2,6-diethylbenzyl acetate (2.11 g, 10.2 mmol), MeOH (20 mL), H2O (6 mL), and NaOH (1.99 g, 50 mmol, 5 eq) was stirred at RT overnight. After concentrating, the mixture was extracted with heptane (50 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to give 1.90 g of title product. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 1H, OH), 1.24 (t, 6H), 1.37 (br s, 1H), 2.79 (q, 4H), 4.75 (d, 2H), 7.09 (d, 2H), 7.21 (dd, 1H). The following compound was prepared by making appropriate substitutions to the above procedure: (2,6-Dimethylphenyl)methanol. 1H NMR (300 MHz, CDCl3) δ 1.25 (t, 1H, OH), 2.41 (s, 6H), 4.72 (d, 2H), 7.0-7.15 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[H][H]>CCOC(C)=O.CCO.[Pd]>[NH2:12][C:11]1[C:3]([NH:2][CH3:1])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CNc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1c(N)cccc1C(=O)O

Procedure:
A mixture of 2-methylamino-3-nitro-benzoic acid and 10% Pd/C (300 mg) in EtOAc (5 mL) and EtOH (5 mL) was stirred in an atmosphere of hydrogen over night. The mixture was filtered though a pad of Celite and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to provide 3-amino-2-methylamino-benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:13][CH2:12]1
Reactant: O=Cc1cccc(O)c1
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(C=O)c2)CC1
Reaction time: 3 h
Yield: 51.9 %

Procedure:
To a stirred solution of 3-hydroxybenzaldehyde (8 g, 65 mmol), 1-methyl-4-piperidinol (7.5 g, 65 mmol), triphenylphosphine (13.1 g, 65 mmol) and THF (100 ml) was added diethylazodicarboxylate (11.4 g, 65 mmol) in THF (20 ml) over a 35 minute period. The reaction mixture was stirred in an ice bath for 3 hours, then at room temperature for 5 days. The reaction mixture was concentrated in vacuo, and partitioned between CHCl3 (300 ml) and 3N HCl (300 ml). The aqueous layer was concentrated in vacuo, the residue was treated with 10% K2CO3 and extracted with CHCl3 (2×100 ml). The solvent was removed in vacuo to afford 7.4 g of crude 3-(1-methyl-4-piperidinyloxy)benzaldehyde.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>ClCCl>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H2O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at ≈0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H2O, 0.1 NHCl (aq) (×2), saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. 1H-NMR (400 MHz, CDCl3) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); tR=1.56 min [10-99% CH3CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H)+ m/z for C9H17NO3=188.1; Found 188.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 120 °C

Procedure:
1-Fluoro-2-methyl-4-nitrobenzene (9.75 g), phenol (7.10 g), and of Cs2CO3 (41.0 g) were dissolved in 100 mL of DMF and heated to 120° C. overnight. The reaction mixture was taken up in EtOAc and washed with water and brine, and dried over Na2SO4. The solution was concentrated to provide 2-methyl-4-nitro-1-phenoxybenzene as an oil, which was used in Step B without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].[C:39]([O:42][CH:43](Cl)[CH3:44])(=[O:41])[CH3:40].O>CN(C=O)C>[C:39]([O:42][CH:43]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:10])[CH3:44])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)Cl
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
To a suspension of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (0.743 mmol, 340 mg) and sodium bicarbonate (5.94 mmol, 499 mg) in DMF (3.0 mL) was added 1-chloroethyl acetate (5.94 mmol, 0.73 g) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (50 mL) and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine solution (80 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 265 mg (66% yield) of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H27F2N3O7 (M+Na) 566.1709, found 566.1710.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[N:13]=[CH:12]1>N1CCCCC1.CCO>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2[nH]cnc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]cnc2c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
Indolin-2-one (80 mg, 0.60 mmol), 1H-benzo[d]imidazole-5-carbaldehyde (97 mg, 0.66 mmol) and piperidine (2 drops) in EtOH (2 mL) were heated with stirring in a sealed tube under microwave irradiation at 90° C. for 15 min. A yellow precipitate was filtered and rinsed with EtOH. Recrystallization from EtOH afforded the title compound as a yellow powder (15.5 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (br. s., 1H), 10.59 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.65-7.75 (m, 2H), 7.59 (d, J=8.34 Hz, 1H), 7.22 (t, J=7.58 Hz, 1H), 6.82-6.91 (m, 2H); MS ESI [M+H]+ 262.0, calcd for [C16H11N3O+H]+ 262.3.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: BrCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 61.5 %

Procedure:
A mixture of 2,4,5-triphenylimidazole (11.5 g), 1,7-dibromo-heptane (50 g) and potassium carbonate (27 g) in dry butanone (250 ml) was heated at reflux for 20 hours. The mixture was filtered and the flitrate evaporated to an oil. Chromatography on silica gel (hexane/ethyl acetate) and recrystallisation from hexane gave 1-(7-bromoheptyl)-2,4,5-triphenylimidazole (11.3 g, 61.4%) as a colourless solid, m.p. 69°-71°.
Reaction SMILES: [H-].[Na+].[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:4].[CH3:18]I>C1COCC1>[C:3](=[O:17])([S:5][CH2:6][CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:18])[CH3:4]
Reactant: CI
Reactant: CC(=O)SCCCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of NaH (0.57 g, 60%, 14.25 mmol) in 20 ml of THF at 0° C. was added S-3-(tert-butoxycarbonylamino)propyl ethanethioate (1.25 g, 5.36 mmol) under Ar. After stirring at 0° C. for 30 min, MeI (1.0 ml, 16.06 mmol) was added to the mixture. Stirring was continued at 0° C. for 2 h then RT overnight. The mixture was concentrated, redissolved in 120 ml of EtAc/Hexane (1:2), washed with 1 M NaH2PO4 NaCl (conc.), dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (1:7) to afford 1.121 g (85%) of the title compound. 1H NMR (CDCl3) 3.69 (t, 2H, J=7.3 Hz), 2.41 (t, 2H, J=7.3 Hz), 2.39 (s, 3H), 2.03 (s, 3H), 1.76 (m, 2H), 1.47 (s, 9H); 13C NMR 173.21, 153.39, 83.28, 43.67, 31.84, 28.26, 28.19, 27.11, 15.65; MS m/z+270.0 (M+Na).
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20](O)=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[NH:28][NH2:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH:29][NH:28][C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:21])[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NNC(=O)OCc1ccccc1)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of 1.9 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-4-methylvaleric acid in 3 ml of dry dimethylformamide was cooled to 0° C. under a nitrogen atmosphere and treated with 2.61 g of benzyl carbazate and 1.20 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and then stirred overnight. The mixture was diluted with ethyl acetate and washed in sequence with water, 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave 2.68 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-2′-benzyloxycarbonyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14]([OH:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.CN1C=CN=C1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:17][C@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of (3aR,4R,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-ol (3.2 g, 11.75 mmol) from Example 30 in dichloromethane (15 mL) was added triethylamine (4.10 mL, 29.4 mmol) followed by 1-methylimidazole (0.281 mL, 3.53 mmol). The solution was cooled to 0° C. and 4-bromobenzene-1-sulfonyl chloride (4.50 g, 17.63 mmol) was added. The solution was warmed to room temperature (solution turned cloudy) and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (12 mL) and washed with aqueous hydrogen chloride (0.1 N, 2×10 mL) and water (10 mL). The organic phase was dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography using 0-60% dichloromethane/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.99-7.90 (m, 2H), 7.77-7.67 (m, 2H), 7.51 (t, J=7.9, 1H), 6.99 (d, J=7.3, 1H), 6.45 (d, J=8.6, 1H), 5.17 (q, J=6.1, 1H), 3.69 (dd, J=11.4, 4.6, 1H), 3.57-3.47 (m, 1H), 3.37 (dd, J=11.4, 8.9, 1H), 3.23 (dd, J=10.7, 4.5, 1H), 2.90-2.78 (m, 1H), 2.67-2.54 (m, 1H), 2.02-1.88 (m, 1H), 1.80 (dq, J=8.2, 6.0, 1H), 1.70 (dtd, J=13.5, 8.6, 7.0, 1H), 1.51-1.37 (m, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:34])=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].I[CH3:36].[OH-].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:34])=[C:22]4[C:26]=3[N:25]([CH3:36])[CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CI
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D47) (450 mg) and iodomethane (0.91 mL) in dimethyl sulfoxide (DMSO) (15 mL) at room temperature was added potassium hydroxide (218 mg). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated ammonium chloride, extracted with EtOAc for 3 times. The organic phase was washed with brine, dried over anhydrous sodium sulphate and evaporated in vacuo to afford the crude product. Purification by column chromatography affords ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoate (D130) (349 mg). MS (ES): C26H25FN4O4 requires 476; found 477.3 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:14])[CH2:10][S:11]([CH3:13])=[O:12].[N:15]([O-])=O.[Na+].ClC1C=C2C(=CC=1)NN=C(S(C)=O)C2=O>Cl>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][N:15]=[C:10]([S:11]([CH3:13])=[O:12])[C:9]2=[O:14]
Reactant: Cc1ccc(N)c(C(=O)CS(C)=O)c1
Reactant: O=N[O-]
Agent: CS(=O)c1n[nH]c2ccc(Cl)cc2c1=O
Agent: Cl
Agent: [Na+]
Product: Cc1ccc2[nH]nc(S(C)=O)c(=O)c2c1

Procedure:
This compound was prepared by diazotizing a solution of 18.5 g of 2'-amino-5'-methyl-2-(methylsulfinyl)acetophenone in 500 ml of 1N HCl with 6.3 g of NaNO2 in analogous fashion to 6-chloro-3-(methylsulfinyl)-4(1H)-cinnolinone. The material was recrystallized from DMF, m.p. 265°-67°; yield 15 g (77%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[NH2:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:27][NH:26][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1ccncc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1ccncc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and EtOAc (10.0 mL). 4-Hydrazinylpyridine hydrochloride (0.16 g, 1.2 eq.) was added at −40° C. followed by the simultaneous addition of T3P (50% in EtOAc, 0.85 mL, 2.0 eq.) and DIPEA (0.49 mL, 4.0 eq.). The reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.35 g of crude material. Purification by column chromatography using MeOH:CH2Cl2 as a mobile phase (compound was eluted with 4% MeOH in CH2Cl2) afforded 80 mg (yield: 29.85%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-4-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.53 (br s, NH exchangeable, 1H), 9.58 (s, 1H), 8.88 (br s, NH exchangeable, 1H), 8.84 (s, 2H), 8.29 (s, 1H), 8.09-8.11 (d, 2H), 7.52-7.54 (d, J=10.4 Hz, 1H), 6.66-6.69 (m, 2H), 6.06-6.10 (d, J=14.4 Hz, H); LCMS for C18H13F6N6O [M+H]+ 443.33; found 443.24 (RT 2.241 min, purity: 90.17%).