Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:32][C@@H:33]([CH:56]([CH3:58])[CH3:57])[C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][C@H:37]1[C:45]([NH:47][C:48]1[C:53]([F:54])=[CH:52][CH:51]=[CH:50][C:49]=1[F:55])=[O:46])=[O:35].[C:59]([O:63][C:64]([N:66]([CH3:72])[C@@H:67]([CH3:71])[C:68](O)=[O:69])=[O:65])([CH3:62])([CH3:61])[CH3:60].C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[F:55][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([F:54])[C:48]=1[NH:47][C:45]([C@@H:37]1[CH2:38][C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:36]1[C:34](=[O:35])[C@@H:33]([NH:32][C:68](=[O:69])[C@@H:67]([N:66]([CH3:72])[C:64](=[O:65])[O:63][C:59]([CH3:60])([CH3:62])[CH3:61])[CH3:71])[CH:56]([CH3:58])[CH3:57])=[O:46]
Reactant: CC(C)[C@H](N)C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
TFA (2 mL, 26.0 mmol, Eq: 76.8) was added to a solution of tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.16 g, 338 μmol, Eq: 1.00) in DCM (2 mL) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with n-heptane (20 mL) to give a viscous oil (0.16 g) which was used directly without further purification. HATU (0.21 g, 552 μmol, Eq: 1.68) was added to a solution of (S)-1-((S)-2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)indoline-2-carboxamide 2,2,2-trifluoroacetate (0.16 g, 328 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (0.1 g, 492 μmol, Eq: 1.5) and diisopropylethylamine (0.29 mL, 1.66 mmol, Eq: 5.06) in DMF (2 mL) and the reaction was stirred at rt for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with 0.1 M aqueous NaOH (10 mL) and 0.1 M aqueous HCl (10 mL). Hexanes (20 mL) were added to the organic layer and it was washed with water (3×10 mL) and brine. The organic layer was concentrated in vacuo and the resulting crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (0.15 g), m/z=559 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([Cl:33])[N:4]=1.C[N+]1([O-])CC[O:38]CC1>C1COCC1>[Cl:33][C:5]1[N:4]=[C:3]([CH:2]=[O:38])[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:6]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CBr)c12
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Bromomethyl)-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (165 mg, 0.318 mmol) was dissolved in THF (4 mL), charged with NMO (112 mg, 0.954 mmol), and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (10-50% EtOAc/hexanes) to give 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 10.41 (s, 1H), 7.31 (m, 10H), 7.20 (m, 5H), 6.08 (s, 1H), 4.00 (s, 3H).
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C(=O)([O-])[O-].[Cs+].[Cs+].[SH:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>CC(N(C)C)=O.O.CCOC(C)=O.C1COCC1>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([S:26][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:28][CH:29]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
TEA (2.30 ml) and methanesulfonyl chloride (1.22 ml) were dropwise added to a THF (40 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (3.02 g) at 0° C., followed by stirring at room temperature for 1 hour. EtOAc (50 ml) and water (50 ml) were added to the reaction solution. The organic layer was washed with aqueous 5% citric acid solution, an aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a pale orange oil. The resulting oil was dissolved in DMA (25 ml), and cesium carbonate (5.38 g) and 4-sulfanylphenol (1.89 g) were added thereto, followed by heating at 50° C. for 2 hours. The reaction solution was cooled, water was added thereto, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M hydrochloric acid solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=4:1 (v/v)) to obtain tert-butyl 4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (3.40 g) as colorless powder.
Reaction SMILES: [CH2:1]([S:8]C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11]([Cl:14])([Cl:13])[Cl:12]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.[OH-].[Na+]>[C:2]1([CH2:1][S:8][C:11]([Cl:14])([Cl:13])[Cl:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CSCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: ClC(Cl)(Cl)SCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Benzyl thiocyanate (29.8 g, 0.2 mol), chloroform (76 g, 0.6 mol) and triethylbenzylammonium chloride (0.5 g, 0.002 mol) were stirred vigorously. 40 ml of 50% aqueous sodium hydroxide were added slowly to this solution (mildly exothermic). The temperature increased to 40° C. and was maintained thereat for 4 h with efficient stirring.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccnc1NCCO
Agent: [Pd]
Solvent: CCO
Product: Nc1cccnc1NCCO
Yield: 56.4 %

Procedure:
2-(2-Hydroxyethylamino)-3-nitropyridine (8.9 g) was dissolved in ethanol (200 ml) and hydrogenated over 5% palladium on charcoal (400 mg) at 50 p.s.i. (3.45 bar) for 21/2 hours. The reaction mixture was filtered and the ethanol removed under reduced pressure, yielding the title compound (4.2 g, 56%) as a dark oil which was used without purification in 1(b) below.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: CN1CCN(C(=O)Cl)CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)N3CCN(C)CC3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 4-methylpiperazine-1-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (79% yield). 1H NMR (300 MHz, CDCl3) δ 8.01, 7.83, 6.96, 3.77-3.73, 3.51-3.44, 3.42-3.38, 3.36-3.33, 2.44-2.41, 2.31, 1.75-1.62, 1.48, 0.92. MS (ES+) m/z 404.4 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[O:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[Mg]Br)[CH3:18]>C1COCC1>[OH:2][CH:1]([C:23]1[CH:24]=[C:19]([O:17][CH3:18])[CH:20]=[CH:21][C:22]=1[O:25][CH3:26])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: COc1ccc(OC)c([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(O)c2cnccc2-c2cccc(C#N)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 2,5-dimethoxylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2,5-dimethoxy-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([NH2:32])[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:32][CH2:30][CH3:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 82.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (41.2 mg, 0.100 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 70% aqueous ethylamine-solution (0.192 mL, 2.42 mmol), acetic acid (0.345 mL, 6.03 mmol) and sodium triacetoxyborohydride (170 mg, 0.802 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium hydrogen carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(ethylaminomethyl)indol-2-yl]isoindolinone (36.4 mg, yield 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[N:6][CH:7]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:15]1[C:11]2([CH2:16][CH2:17][CH:8]([C:5]3[N:6]=[CH:7][C:2]([N:32]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:3][C:4]=3[CH3:18])[CH2:9][CH2:10]2)[O:12][CH2:13][CH2:14]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)cnc1C1=CCC2(CC1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(N=C(c2ccccc2)c2ccccc2)cnc1C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
A suspension of 5-bromo-2-(1,4-dioxaspiro[4.5]decan-7-en-8-yl)-3-methylpyridine (22.5 g) in Reference Example 105, benzophenone imine (13.9 g), palladium acetate (204 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (567 mg) and sodium tert-butoxide (10.5 g) in toluene (150 ml) was stirred for 6 hours under heating to reflux. After completion of the reaction, the mixture was allowed to cool, ice water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to give 6-(1,4-dioxaspiro[4.5]decan-8-yl)-N-(diphenylmethylene)-5-methylpyridin-3-amine (28 g) as a brown oil. MS (ESI) m/z: 411 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][CH:8]([NH2:16])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])(C)(C)C.[ClH:18]>>[ClH:18].[NH2:16][C@@H:8]([CH2:9][C:10]([CH3:14])([CH3:15])[CH2:11][CH2:12][CH3:13])[CH2:7][C:6]([OH:17])=[O:5]
Reactant: CCCC(C)(C)CC(N)CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCC(C)(C)C[C@H](N)CC(=O)O

Procedure:
According to example 1, 3-amino-5,5-dimethyl-octanoic acid tert-butyl ester was treated with 3N HCl to provide 286 mg of the title compound as a solid. MS (APCl), m/z: 188.1 (M+1)+. 186.1 (M−1)+. Anal. Calc'd for C10H21NO2.HCl.0.12H2O: C: 53.17; H, 9.92; N, 6.20; Cl: 15.69; Found: C: 53.19; H, 10.00; N, 6.08; Cl: 15.25. α=+20° (MeOH). MP: 194.2-195.2° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1)=[O:7].[Li+].[OH-].Cl>O1CCOCC1>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A solution of 1.42 g (4.3 mmol) N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine methyl ester in 17 ml of dioxane was treated with 17.3 ml of 0.50M aqueous LiOH. The resulting solution was stirred at ambient temperature for 30 min, treated with 8.7 ml of 1M HCl, and concentrated in vacuo. The residue was taken up in dichloromethane, washed with water, dried over Na2SO4, and concentrated in vacuo to provide 1.1 g (81%) of the desired compound. Mass spectrum: (M+H)+ =314.
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[NH:9][CH:8]([CH2:10][CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1>CCO.[Pd]>[ClH:1].[NH:2]=[C:3]1[NH:9][CH:8]([CH2:10][CH2:11][CH2:12][C:13]2[O:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(C=CCC2CCCCC(=N)N2)o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(CCCC2CCCCC(=N)N2)o1

Procedure:
The title material of Example 179 in EtOH is hydrogenated over 10% Pd on carbon catalyst in a standard Parr apparatus by the method of Example 35 to generate the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][OH:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccccc3)nc2CO[Si](C)(C)C(C)(C)C)cc1
Yield: 90 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-hydroxymethyl-4-phenylimidazole (1.68 g, 5.71 mmol) in CH2Cl2 (35 mL) with N,N-diisopropylethylamine (3.2 mL, 18.4 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.46 g, 9.69 mmol) at room temperature for 60 hours. Quench with H2O (40 mL), extract with CH2Cl2 (100 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 20:1→9:1) to provide 2.09 g (90% yield). MS (ES+): m/z=409 (M+H)+
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]1[CH2:29][N:28]2[C:12]3[C:13](C[CH2:26][CH2:27]2)=[C:14]2[O:21][C:19](=[O:20])[C:18]([C:22](O)=O)=[CH:17][C:15]2=[CH:16][C:11]=3C1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:9][CH2:29][N:28]([C:12]1[CH:11]=[CH:16][C:15]2[CH:17]=[C:18]([C:22]3[NH:8][C:1]4[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:7]=3)[C:19]([O:21][C:14]=2[CH:13]=1)=[O:20])[CH2:27][CH3:26]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1ccc2cc(-c3nc4ccccc4[nH]3)c(=O)oc2c1
Reaction time: 8 h

Procedure:
The diphenyl analog of coumarin 7 was prepared by the dehydration/condensation (J. B. Hendrickson, M. S. Hussoin, J. Org. Chem. 1987, 52, 4139-4140) of o-phenylenediamine with the diphenyl analog of coumarin 343. A solution of 7.9 ml of triflic anhydride in 150 ml methylene chloride was added to a solution of 26.16 g triphenylphosphine oxide in 150 ml methylene chloride at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to come to room temperature and a solution of 2.54 g o-phenylenediamine and 7 g diphenyl analog of coumarin 343 prepared according to the method of Example 2 in 80 ml methylene chloride was added dropwise. The slurry was stirred overnight. The reaction mixture was washed with 5% sodium bicarbonate, water and brine, dried of magnesium sulfate, filtered, and rotary evaporated to remove the solvent. The product was isolated by flash column chromatography in methylene chloride.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CC2
Solvent: CC(=O)O
Product: O=C1CCc2ccc(C(=O)CBr)cc2N1
Temperature: 20 °C

Procedure:
9.45 Grams of 7-acetyl-3,4-dihydrocarbostyril was dissolved in 30 ml of glacial acetic acid with stirring at 20° C., then a mixture of 2.6 ml of bromine with 10 ml of glacial acetic acid was added dropwise at a room temperature for 30 minutes with stirring. The reaction mixture was ice-cooled to precipitate crystals, and recrystalized from 50%-ethanol aqueous solution to obtain 7-α-bromoacetyl-3,4-dihydrocarbostyril. Yield: 9.4 g. Melting point: 202°-203° C. Colorless needle-like crystals
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:16])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Sn](=O)CCCC)CCC.[C:29]1([CH3:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:35]([O:15][CH2:14][C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[OH:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OC[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1
Agent: CCCC[Sn](=O)CCCC
Product: O[C@H](COCc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
(S)-1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1,2-diol (11.45 g) and di-n-butyltin oxide (10.40 g) were dissolved in toluene (200 ml) and refluxed in a Dean and Stark apparatus for 16 hours. The toluene was removed under reduced pressure, cesium fluoride (12.70 g) suspended in N,N-dimethylformamide (200 ml) was added and the reaction stirred for 1 hour. The reaction was diluted with water and filtered through Hyflo™ before concentrating under reduced pressure and extracting into ethyl acetate. The organic phase was dried (brine, MgSO4) and concentrated under reduced pressure to give a crude brown oil. This was purified on silica eluting with 20% ethyl acetate/iso-hexane to afford the title compound as a pale yellow oil.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[O:15]=[C:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH:11]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1CNCCC1=O
Yield: 95.6 %

Procedure:
10% palladium/active carbon (2 g) was added to a solution of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride (30 g) in methanol (500 ml) and the resultant mixture was stirred at room temperature under hydrogen atmosphere for a day. After filtering the reaction mixture through celite, the filtrate was concentrated under reduced pressure to give the title compound (20.0 g) as a white powder (yield: 97%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:11][CH:12]=[CH2:13])=[CH:5][CH:4]=1.[NH:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N:23]=[CH:22]1>>[CH:14]1([CH:10]([CH2:11][CH:12]=[CH2:13])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:26]3[CH:27]=[CH:28][C:29]4=[N:21][CH:22]=[N:23][C:24]4=[CH:25]3)=[CH:4][CH:5]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1cc2[nH]cnc2cn1
Reactant: C=CCC(C(=O)c1ccc(CCl)cc1)C1CCCCC1
Product: C=CCC(C(=O)c1ccc(Cn2ccc3ncnc-3c2)cc1)C1CCCCC1
Yield: 60 %

Procedure:
Following the procedure of Example 1, 85mg (0.00029 moles) of the product of Example Q was reacted with 35mgs of 1H-imidazo[4,5-c]pyridine. The crude product was chromatographed on silica gel using MeOH/CH2Cl2/ NH4OH (5/94/1) as eluent to give 65 mg (60% yield) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7](C(C)C)[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=[C:27]1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][CH2:7][C:6]([OH:39])=[O:5])(=[O:10])=[O:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-valine t-butyl ester (60 mg) was dissolved in a 95% solution of TFA in methylene chloride (5 mL). The solution was stirred at room temperature for 4 h and the solvent was removed under vacuum. The crude product was triturated with hexane/ethyl acetate (95:5) three times. The product was lyophilized with benzene to give 36 mg of N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)glycine. LCMS MH+ (m/z) 493. 1H NMR (300 MHz, DMSO-d6): δ 10.53 ppm (s, 1H), 7.81-7.54 ppm (m, 11H), 7.34 ppm (dd, 1H, J1=8.4 Hz, J2=8.4 Hz), 7.20 ppm (dd, 1H, J1=8.4 Hz, J2=8.4 Hz), 3.35 ppm (d, 1H J=6.0 Hz), 1.79 ppm (m, 1H), 0.63 ppm (dd, 6H, J1=13.8 Hz, J2=6.6 Hz).