Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([N:19](S(C)(=O)=O)[S:20]([CH3:23])(=[O:22])=[O:21])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CS(=O)(=O)N(c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl)S(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 53.4 %

Procedure:
A solution of 3.6 g (7.78 mmol) of 3-chloro-2-[4-chloro-3-bis-(methylsulfonyl)aminophenyl]-5-trifluoromethylpyridine (prepared as in Example 13) and 100 mg of sodium methoxide in 100 ml of methanol were stirred at 20°-25° C. for three hours. Then most of the methanol was distilled off under reduced pressure. The residue was taken up in dilute hydrochloric acid, after which the product was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The oily residue was treated with ether/petroleum ether to afford 1.6 g (53%) of colorless crystals of melting point 133°-134° C.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)=[O:32])[CH:25]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)=[O:32])[CH:27]=[CH:28][CH:29]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(NC(=O)c2cnccn2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)NS(=O)(=O)C3CC3)c2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (182 mg, 1.5 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (57 mg, 1.43 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-{3-[(pyrazine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (65 mg, 0.15 mmol) and 1,1′-carbonyldiimidazole (49 mg, 0.3 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h, the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded pyrazine-2-carboxylic acid [3-(6-chloro-8-cyclopropanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (40 mg, 49%) as a white solid: LC/MS m/e calcd for C26H26ClN5O4S (M+H)+: 541.05, observed: 540.0.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH:3]=[CH2:4].N1C=CN=C1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([Si:15]([CH3:17])([CH3:16])[O:5][CH:2]([CH3:1])[CH:3]=[CH2:4])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC(C)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of but-3-en-2-ol (5.0 g, 69.34 mmol) in CH2Cl2 (100 mL) at 0° C. was added imidazole (5.66 g, 1.2 eq) and TBSCl (10.45 g, 1.0 eq). The reaction mixture was stirred at 0° C. to rt for 3 h. Solid was filtered off, the filtrate was concentrated and passed through a short silica gel column by eluting with hexane to give tert-butyl-dimethyl-(1-methyl-allyloxy)-silane (10.86 g, 85%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (8.8 g, 47.5 mmol) in MeCN (100 ml) was added K2CO3 (7.9 g, 57.0 mmol) followed by 4-methoxybenzyl chloride (7.1 ml, 52.3 mmol) and the mixture stirred at ambient temperature for 20 hours. The mixture was evaporated in vacuo, the residue partitioned between EtOAc and 2M aqueous hydrochloric acid and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:4)] to give 1-(4-methoxy-benzyl)-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (11 g) as a colourless gum.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.Cl>[O:11]=[CH:12][C:13]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(NCC(CO)(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC(CNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To a solution of oxalyl chloride (5.39 mL, 61.53 mmol) in dichloromethane (100 mL) was added dropwise dry DMSO (6.83 mL, 96.15 mmol) at −78° C. After 10 minutes at this temperature, a solution of benzyl 3-hydroxy-2,2-diphenylpropylcarbamate (13.9 g, 38.46 mmol) in dichloromethane (100 mL) was slowly added and stirred at −78° C. The reaction was stirred for 1 hour and triethylamine (26.8 mL, 192.3 mmol) was added and the reaction stirred at −78° C. for 10 more minutes then warmed to room 23° C. The reaction was diluted with 1N HCl and the phases were separated. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude title material (12.09 g, 87%) as an oil which was used as such in the next reaction. HPLC ret. time (Condition A): 2.093 min. LC/MS (M+H)+: 360. 1H NMR (400 MHz, CDCl3) δ ppm: 4.18 (2H, d, J=6.57 Hz), 4.98 (2H, s), 5.00 (1H, t, J=5.81 Hz), 7.17-7.42 (15H, 2 m), 9.90 (1H, s).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][S:9]([C:12]1[S:13][C:14]([Sn](C)(C)C)=[CH:15][CH:16]=1)(=[O:11])=[O:10])[C@@H:4]([CH3:7])[CH2:5][CH3:6].[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCOC(C)=O.CCCCCC>C(#N)C>[F:22][C:14]1[S:13][C:12]([S:9]([NH:8][C@H:3]([CH2:2][OH:1])[C@@H:4]([CH3:7])[CH2:5][CH3:6])(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: F[B-](F)(F)F
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc([Sn](C)(C)C)s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(F)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.5 %

Procedure:
A solution of N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-5-(trimethylstannyl)-2-thiophene sulfonamide (1.0 g, 2.34 mmol) in dry acetonitrile (20 mL) was stirred under nitrogen at 25° C. Selectfluor (0.850 g, 2.40 mL) was added in one portion and the solution stirred for 19 h at 25° C. After 3 h a white precipitate began to appear. An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was not complete. Mainly, starting material was present. The reaction was heated to 80° C. for 6 h. An aliquot was taken and TLC (1.1 EtOAc-hexane) indicated that reaction was complete. The slurry was then filtered and the solvent removed in vacuo to obtain a crude yellow oil (0.6 g). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluent: 1:2 EtOAc-hexane to obtain 5-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methyl-butyl]-2-thiophenesulfonamide as an amorphous white solid (0.102 g, 15.49%). Mass Spectrum (−ESI): 280 (M−H)−. Anal. Calc'd for C10H16NFO4S2: C, 42.69; H, 5.73; N, 4.98. Found: C, 42.47; H, 5.74; N, 4.87.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].C[C:25]([N:27](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:25]#[N:27])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccc(F)cc3)sc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2nc(-c3ccc(F)cc3)sc2c1O
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-bromo-2-(4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (157 mg, 0.40 mmole), tris(dibenzylideneacetone)-dipalladium(0)(18 mg, 0.02 mmole), 1,1′-bis(diphenylphosphino)ferrocene (22 mg, 0.04 mmole), zinc cyanide (28 mg, 0.24 mmole) and zinc (3 mg, 0.05 mmole) in dimethylacetamide (0.8 ml) was stirred at 120° C. for 4.5 h before it was cooled to room temperature, partitioned between ethyl acetate and water, filtered. The filtrate washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane to give the title compound as a yellow solid (64 mg). MS: (+) m/z 344.26 (M+1), MS: (−) m/z 342.27 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23](C)([CH3:25])[CH3:24])=[O:21])[CH2:18][CH:19]=3)[N:10]=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1>Cl>[Cl:1][C:2]1[C:7]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:18][CH:19]=3)[N:10]=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1cccnc1Cl
Agent: Cl
Product: Cc1c(C2=CCN(C(=O)OC(C)C)CC2)nnn1-c1cccnc1Cl
Reaction time: 2.5 h

Procedure:
tert-Butyl 4-[1-(2-chloropyridin-3-yl)-5-methyl-1H-[1,2,3]-triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (265 mg) prepared in Example 12 was dissolved in 4.0 ml of a 10% methanolic hydrochloric acid and stirred for 2.5 hours and the solvent was evaporated in vacuo to give the title compound as a mixture.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][C:33]([O:37][CH3:38])=[CH:32][C:31]=1[Cl:39]>C1COCC1.O.CCOCC>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:29][C:30]1[C:31]([Cl:39])=[CH:32][C:33]([O:37][CH3:38])=[CH:34][C:35]=1[Cl:36])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -60 °C
Yield: 76 %

Procedure:
Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (5.0 g, 19.3 mmol) and tetrahydrofuran (75 mL) in a 250 mL round bottom flask at −75° C. Transfer 2 M LDA (14.5 mL) to the flask via syringe and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point, add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene (7.76 g, 28.96 mmol) in THF (25 mL). After the addition is complete, the reaction vessel is allowed to slowly warm up to 0° C., and maintain the internal reaction temperature at 0° C. for 4 hr. Quench the reaction with 30 mL aqueous 1N hydrochloric acid. Transfer the mixture to a 500 mL separatory funnel and dilute with 100 mL water and 100 mL ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous sodium sulfate, filter and concentrate to give a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 6.65 g, (76%) of a pale yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[C:18](OCC)(OCC)([O:21][CH2:22][CH3:23])[CH2:19][CH3:20].C(OC(=O)C)(=O)C>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][CH3:20])[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)N(C(C)=O)C(=O)C2
Reactant: CCOC(CC)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-5,6-dimethoxy-2-indolinone, triethyl orthopropionate and acetic anhydride
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-].[Na+]>>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: C(#Cc1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
Following General Procedure C (120° C., 30 hours), phenylacetylene (84 μL, 1.5 mmol) was coupled with bromobenzene (106 μL, 1.0 mmol), in the presence of sodium iodide (NaI; 0.5 eq.; 0.5 mmol). The crude brown oil was purified by flash chromatography on silica gel to provide 90% 1,1′-ethyne-1,2-diyldibenzene.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].Br[CH2:8][CH2:9][CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:5][C:2]([N:1]1[CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:6])[CH2:3][OH:4]
Reactant: CC(C)(N)CO
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CO)N1CCCC1
Temperature: 25 °C

Procedure:
A solution of 2-amino-2-methyl-1-propanol (15 g, 168.3 mmol), 1,4-dibromobutane (18.2 g, 84.1 mmol), and K2CO3 (48.8 g, 353.4 mmol) in 1 L of THF was heated at 60° C. for 4.5 days. After cooling to ambient temperature, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (SiO2; 94:4:2 EtOAc/MeOH/TEA) afforded 8.21 g (57.3 mmol; 34%) of the title product as a pale yellow oil. A small sample was dissolved in EtOAc and treated with one equivalent of oxalic acid in a method similar to Example 1, Part C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][Br:11]
Reactant: COc1cccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cl)c1CBr
Yield: 96.4 %

Procedure:
A mixture of 3-chloro-2-methylanisole (2 g), N-bromosuccinimide (2.39 g) and 2,2′-azobis(2-methylpropionitrile) (32 mg) in carbon tetrachloride (15 mL) was heated at reflux for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (2.9 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:7]([F:23])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-:25].[K+].[K+].OO.O>CS(C)=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=2)[C:7]([F:23])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:25]
Reactant: N#Cc1cc(F)c(OCc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(OCc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a suspension of 2,5-difluoro-4-[4-chloro-3-(trifluoromethyl)phenylmethoxy]-benzonitrile (Preparation 61, 0.2 g, 0.5 mmol) and potassium carbonate (0.39 g, 2.5 mmol) in DMSO (3 mL), was added hydrogen peroxide (30% solution in water, 0.6 mL, 5 mmol) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. Water (30 mL) was then added and the precipitate formed was filtered. The filtrate was extracted twice with EtOAc and combined with the solid. The resulting organic solution was dried over magnesium sulphate, filtered and evaporated to afford the title compound as a white solid (160 mg, 76%).
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([O:41][CH3:42])[C:33]=4[C:34]=3[CH3:35])=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH3:42][O:41][C:36]1[C:33]2[C:34]([CH3:35])=[C:30]([C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([C:18]4[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:43])=[O:5])(=[O:13])=[O:14])=[CH:16][CH:17]=4)=[CH:22][CH:23]=3)=[O:29])[O:31][C:32]=2[CH:39]=[CH:38][C:37]=1[CH3:40]
Reactant: COc1c(C)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To 80 mg of (S)-2-{4′-[(4-methoxy-3,5-dimethyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester was added 2 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 3 h. When the reaction was done, the solvent was removed under vacuum and the residue was triturated with acetonitrile. Filtration of the suspension gave 64 mg of (S)-2-{4′-[(4-methoxy-3,5-dimethyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.3 (s, 3 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 5.8 Hz, 1 H) 3.8 (s, 3 H) 7.4 (m, 2 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.3 Hz, 1 H) 10.5 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=1[C:26]([F:29])([F:28])[F:27]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:20]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Reactant: COc1ccc(CCl)cc1C(F)(F)F
Product: COc1ccc(CSc2nnc(-c3ccc4occc4c3)o2)cc1C(F)(F)F
Yield: 100 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 100%) was obtained as colorless crystals.
Reaction SMILES: [I-:1].[Na+].Cl[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[Na+]>CC(C)=O>[I:1][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(Cl)c1ccccc1
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C(I)c1ccccc1
Temperature: 25 °C

Procedure:
Sodium iodide (7.5 g, 0.05 mol) dissolved in analar acetone (25 ml) was stirred at room temperature and to it added methyl α-chlorophenylacetate (9.32 g, 0.05 mol). Stirred for 15 minutes. The precipitate sodium chloride was allowed to settle.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH3:29][CH2:30][N:31](C(C)C)C(C)C.CN(C=O)C.BrCC#N.N>CO>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]#[N:31])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: N
Agent: N#CCBr
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(CC#N)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), DIPEA (16.5 μL, 0.0947 mmol) and DMF (1.00 mL, 12.9 mmol) were mixed. Bromoacetonitrile (1.7 μL, 0.026 mmol) was added at last at 0° C. The mixture was stirred at 0° C. for 2 hours. Crude was passed through SCX-2 SPE, and the product was released by 2 M NH3 in methanol and purified on the MDPS. MS (ES+): m/z 461.03/463.05 (100/81) [MH+]. HPLC: tR=0.83 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, DMSO-d6): δ=1.82 (d, J=6.8 Hz, 3H), 2.46 (br. s., 2H), 2.65-2.74 (m, 2H), 3.19-3.22 (m, 2H), 3.85 (s, 2H), 5.60 (s, 2H), 6.21 (q, J=6.6 Hz, 1H), 6.31 (br. s., 1H), 7.45 (t, J=8.7 Hz, 1H), 7.52 (dd, J=9.0, 5.2 Hz, 1H), 7.78 (s, 1H), 8.30 (s, 1H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:16]([C@@H:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH2:15].CI>O1CCCC1>[CH3:1][C@@H:18]([C@@H:17]([N:16]([C@@H:32]([CH3:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH:14]=[CH2:15])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: C=CCN([C@H](CC(=O)OC(C)(C)C)c1ccccc1)[C@@H](C)c1ccccc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: C=CCN([C@@H](C)c1ccccc1)[C@@H](c1ccccc1)[C@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (0.691 ml, 4.93 mmol) in anhydrous tetrahydrofuran (10 ml) was cooled to -78° C. prior to the dropwise addition of 1.6M butyllithium (2.57 ml, 4.11 mmol) via a syringe. The solution was warmed to 0° C. and then immediately recooled to -78° C., whereupon a solution of compound (8) from Example 2 (600 mg, 1.64 mmol) in tetrahydrofuran (10 ml) was added dropwise via a cannula. Stirring was continued for 1 hour at -78° C. followed by the rapid injection of methyl iodide (0.512 ml, 8.22 mmol). The reaction mixture was allowed to warm slowly to room temperature overnight (16 hours) after which the solvent was evaporated. The residue was partitioned between ethyl acetate (50 ml) and brine (25 ml) and the organic layer was dried (magnesium sulphate), filtered and evaporated to yield a yellow oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:49)] affording the title compound (51) in 94% diastereoisomeric excess (Rf 0.25) as a colourless oil (406 mg, 65%). δH (300 MHz, CDCl3) 7.41-7.17 (10H, m, Ph), 5.93-5.79 (1H, m, NCH2CH=CH2), 5.11 (1H, app. dd, J=17.3 and 1.3, trans CH=CH2), 5.08 (1H, app. dd, J=10.1 and 1.1, cis CH=CH2), 4.18 (1H, d, J=11.4, PhCHCH3), 3.29 (1H, app. ddt, J=14.7, 5.0 and 1.9, NCH2), 3.19 (1H, dq, J=11.4 and 6.9, CHCHCH3), 3.10 (1H, dd, J=14.7 and 8.0, NCH2), 1.50 (9H, s, (CH3)3C), 0.94 (3H, d, J=6.7, PhCHCH3), 0.90 (3H, d, J=6.9, CHCHCH3).