Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)[NH:8][CH:7]=1)=O)C.[OH-].[K+].Cl>CCO>[CH2:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1c[nH]c2ccc(CCc3ccccc3)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(CCc2ccc3[nH]ccc3c2)cc1

Procedure:
To a solution of the 3-ethyloxycarbonyl-5-phenethylindole (0.4 g, 1.5 mmol) in EtOH 95% (10 ml) was added an excess of KOH (0.5 g) and the reaction mixture was heated at reflux for 2 h. The solution was acidified with 1N HCl (10 ml) and the precipitated material was collected by filtration. The solid was washed well with H2O (2×10 ml) to give the corresponding acid. The acid (0.3 g, 1.2 mmol) was immersed in an oil bath and then heated at about 235°-240° C. for 15 min to give a brown syrup. Distillation of the oil under high vacuum provided 5-phenethylindole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20](OC)[C:19]=2[F:27])[CH2:8]/[C:9](=[N:12]\OS(C)(=O)=O)/[C:10]=1[Br:11])=[O:4].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([Br:11])=[C:9]([NH2:12])[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:27])[N:6]=1)=[O:4]
Reactant: COC(=O)C1=C(Br)/C(=N/OS(C)(=O)=O)CC(c2ccc(Cl)c(OC)c2F)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)cc(N)c1Br
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A solution of 3-bromo-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-[(E)-methylsulfonyloximino]-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (23, 900 mg, 1.856 mmol) in glacial acetic acid (4.6 mL) was heated at 150° C. for 5 min in a Biotage microwave. After cooling to ambient temperature the reaction mixture was diluted with H2O and the pH was made neutral with a saturated solution of Na2CO3. The resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. Silica gel column chromatography (20% EtOAc/pentane) gave 4-amino-3-bromo-6-(4-chloro-2-fluorophenyl)pyridine-2-carboxylic acid methyl ester (41; 0.60 g, 83%) as a light brown solid: mp 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 7.65 (dd, J=8.6, 7.7 Hz, 1H), 7.26-7.20 (m, 1H), 7.14 (d, J=1.8 Hz, 1H), 4.91 (s, 2H), 3.99 (s, 3H), 3.97 (d, J=0.9 Hz, 3H); HRMS-ESI (m/z): calcd for C14H11BrClFN2O3, 387.962. found, 387.963.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][S:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:14])=[C:7]([CH3:13])[CH:8]=3)=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:30]([F:31])([F:32])[F:33]
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1cc(-c2ccc(CCl)cc2)ccc1Cl
Product: Cc1cc(SCc2ccc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 2C and 6B. MS m/z 481 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1(P(=[CH:37][C:38](=[O:40])[CH3:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:13]=[C:12]([CH:14]=[CH:37][C:38](=[O:40])[CH3:39])[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(Oc2cccc(C=O)n2)cc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CSc1ccc(Oc2cccc(C=CC(C)=O)n2)cc1
Yield: 221.2 %

Procedure:
A mixture of 29.9 g (0.122 mol) of 6-(4-(methylthio)phenoxy)picolinaldehyde and 42.7 g (0.134 mol) of triphenylphosphoranylidene-2-propanone in 750 mL of benzene was heated at reflux for 2.75 hours and cooled. The solvent was removed in vacuo leaving 77 g of an oily solid which was dissolved in methylene chloride and placed on a column of dry silica gel. The column was eluted with methylene chloride and the fractions containing the desired product were combined. The solvent was removed in vacuo leaving 32.5 g (93.7 percent of theoretical) of an oily product which slowly crystallized upon standing. The above named product melted at 71°-72.5° C.; Rf -0.53, (silica gel, 50:50 ethyl acetate-hexane), 1H NMR (CDCl3) 82.25 (s, 3H, CH3C(O)--), 2.4 (s, 3H, CH3S--) 6.7-7.75 (m, 9H, ArH and --CH=CH--).
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][CH:4]([O:7][CH:8]([O:12][C@H:13]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]1)[CH2:9][CH2:10][CH3:11])[CH2:5][OH:6].[H-].[Na+].S(O[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])(=O)(=O)C>C1(C)C=CC=CC=1>[CH3:40][N:2]([CH3:1])[CH2:3][CH:4]([O:7][CH:8]([O:12][C@H:13]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:14]1)[CH2:9][CH2:10][CH3:11])[CH2:5][O:6][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CCCC(OC(CO)CN(C)C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CN(C)C)OC(CCC)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
3-Dimethylamino-2-(Cholest-5-en-3β-oxybutan-4-oxy)-1-propanol (2.6 g, 4.6 mmol) was weighed into a 200 mL round bottomed flask and co-evaporated with anhydrous toluene 2×20 mL). A stir bar was added to the flask, which was then sealed, flushed with argon and charged with anhydrous toluene (100 mL). Sodium hydride (0.7 g, 6 equiv) was added at once and the mixture was stirred, under argon, for 20 minutes. Linoleyl mesylate (4.6 g, 2.3 equiv.) was measured in a PP syringe and added slowly to the reaction mixture. The flask was fitted with a reflux condenser and the apparatus was flushed with argon. The reaction mixture was heated in an oil bath and allowed to stir at reflux overnight. The reaction mixture was then cooled to room temperature in a water bath and ethanol was added dropwise until gas evolution ceased. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with aqueous 10% sodium carbonate (2×200 mL). The aqueous phases were combined and back extracted with ethyl acetate (2×100 mL). The organic phases were combined, dried over MgSO4, filtered and concentrated. The resultant oil was purified via column chromatography (10% EtOAc/Hexanes, 3% TEA) to afford 3.0 g (81%) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=O.O.ON1C2C=CC=CC=2N=N1.[C:26](=[N:29]O)([NH2:28])[CH3:27]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]2[O:10][N:29]=[C:26]([CH3:27])[N:28]=2)[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: COCOc1cc(C(=O)O)ccc1C
Reactant: CC(N)=NO
Agent: On1nnc2ccccc21
Solvent: O
Product: COCOc1cc(-c2nc(C)no2)ccc1C
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 3-methoxymethoxy-4-methyl-benzoic acid (1.96 g, 10 mmol), 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide (1.92 g, 10 mmol, Aldrich), and 1-hydroxybenzotriazole hydrate (1.5 g, 10 mmol, Aldrich) was stirred at room temperature for 30 minutes. Acetamide oxime (0.74 g, 10 mmol) (GFS Chemicals) was added and the mixture heated at 140° C. with magnetic stirring for 2 hours. After cooling, the mixture was partitioned between ethyl acetate (2×100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). Ethyl acetate solutions were combined and concentrated to give crude 5-(3-methoxymethoxy-4-methyl-phenyl)-3-methyl-[1,2,4]oxadiazole. (Yield 1.23 g, 52.5%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[CH:5]=[CH:4][N:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ccnn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ccnn1)c1csc(N)n1)C(=O)O
Yield: 19.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,3-triazol-1-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (80 mg, 0.121 mmol), DCM (4 mL) and TFA (1 mL, 13 mmol). The crude residue was purified by reverse phase prep HPLC (T3, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (12 mg, 20%) as a white solid. LCMS: m/z=500.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.95 (s, 1H), 7.67 (s, 1H), 7.04 (s, 1H), 5.38 (d, J=5.6 Hz, 1H), 4.88-4.80 (m, 1H), 4.78-4.70 (m, 2H assumed; obscured by solvent residual peak), 1.34 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[CH:9]=[C:4]2[C@@:3]21[CH2:44][C:34]1=[N:35][CH:36]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:38]=[C:33]1[CH2:32]2.C(=O)(O)[O-].[Na+].[B-](F)(F)(F)[F:51].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S([O-])(=O)=O.[Na+].CO>CC(C)=O.[Ag-]=O>[F:51][C:8]1[CH:9]=[C:4]2[C@:3]3([CH2:44][C:34]4=[N:35][CH:36]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:38]=[C:33]4[CH2:32]3)[C:2](=[O:1])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)[C@@]1(Cc3cc(C(=O)OCC)cnc3C1)C(=O)N2COCC[Si](C)(C)C
Agent: O=[Ag-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: CO
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncc(F)cc21
Temperature: 65 °C

Procedure:
A stirred mixture of ethyl (6S)-2′-oxo-5′-(tributylstannanyl)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (1.00 g, 1.37 mmol), sodium bicarbonate (231 mg, 2.74 mmol), silver(I) oxide (32 mg, 0.137 mmol), N-chloromethyl-N′-fluorotriethylenediammonium bis(tetrafluoroborate) (972 mg, 2.74 mmol), sodium trifluoromethanesulfonate (236 mg, 1.37 mmol) and methanol (0.278 mL, 6.86 mmol) in acetone (50 mL) in a sealed vessel was heated at 65° C. for 4 h. The resulting mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc (2×75 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc 100:0 to 50:50, to give the title compound. MS: m/z=458.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]1[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a stirred mixture of 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.24 g, 10.0 mmol) in DMF (15 mL) at room temperature under argon was added K2CO3 (2.76 g, 20.0 mmol) and 3-(chloromethyl)-6-(trifluoromethyl)pyridine (2.34 g, 12.0 mmol). After stirring at room temperature for 3 d, HPLC indicated approximately 70% complete reaction. The mixture was then heated to 60° C. for 5 h, after which HPLC indicated complete reaction. The mixture was cooled to room temperature, diluted with water (100 mL), and stirred for 1 h. Solid was collected by filtration and washed with water (10 mL×5), then methanol (5 mL×2), and finally dried under vacuum. The title compound (4.4 g) was obtained as a yellow solid. HPLC/MS: retention time=3.8 min, [M+H]+=485.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10])=[N:2]1.C1C=CC=CC=1.S(Cl)([Cl:28])=O>C(N(CC)CC)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:28])=[O:10])=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccon1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1-c1ccon1

Procedure:
To 0.55 g of 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 10 ml of benzene, then 0.17 ml of thionyl chloride and a drop of triethylamine to heat at reflux for 2 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]([F:13])[C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19]>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([OH:15])[CH:17]=2)(=[O:10])=[O:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: COc1ccc(N)cc1O
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)c(F)c1F
Product: COc1ccc(NS(=O)(=O)c2cc(Br)c(F)c(F)c2F)cc1O

Procedure:
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)amino-sulfonyl]benzene and 1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)amino-sulfonyl]benzne were prepared in a manner similar to that described above, beginning with a mixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example B) and2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example C) and 3-hydroxy4-methoxyaniline. The two isomeric compounds were separated by column chromatography (silica gel; ethyl acetate:hexanes, 1:4). 1H-NMR (CDCl3): δ 7.79 (1H, m), 6.72-6.62 (4H, m), 5.65 (1H, s), 3.85 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:29]3[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC(C)(C)O)cc1
Yield: 64.5 %

Procedure:
The product from Example 471C (12.79 g, 32.86 mmol) was coupled to 4-(methylthio)phenylboronic acid (6.07 g, 36.15 mmol) with K2CO3 (10 g, 72.3 mmol) and PdCl2(PPh3)2 (1.15 g, 1.64 mmol) in ethanol (200 mL) at 60-65° C. for 40-70 minutes to provide the title intermediate (yield: 9.16 g, 64.5%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: Cc1oc(C2(C)CCCCC2)nc1CC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(C2(C)CCCCC2)nc1CC(=O)O
Temperature: 90 °C

Procedure:
Benzyl 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetate (1.0 g) was dissolved in ethanol (3 ml), and 2N sodium hydroxide (3 ml) was added. The mixture was heated on a water bath at 90° C. for 5 minutes, diluted with water and washed with ethyl ether. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl ether. The ethyl ether extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from hexane to give 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetic acid as crystals; yield 0.41 g (56.9%). Mp 66°-67° C. The IR and NMR spectra of this product were in good agreement with those of the compound obtained in Example 15.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH:4]1[NH:8]C(=O)N[C:5]1=[O:10].[OH-:19].[Na+]>>[NH2:8][CH:4]([CH2:3][C:2]([CH3:18])([CH3:1])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:19])=[O:10]
Reactant: [OH-]
Reactant: CC(C)(Cc1ccccc1)CC1NC(=O)NC1=O
Agent: [Na+]
Product: CC(C)(Cc1ccccc1)CC(N)C(=O)O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of (RS)-5-(2,2-dimethyl-3-phenyl-propyl)-imidazolidine-2,4-dione (2.04 g) in 4 N NaOH was heated under an argon atmosphere to 120° C. (oil bath temperature). After 30 min strong foaming was observed. More 4 N NaOH (20 ml) was added. The suspension was heated to 120° C. for 2 days, turning into a clear solution. The mixture was cooled to r.t. and the insoluble material was filtered off The filtrate was cooled in an ice bath and concentrated HCl was carefully added until pH ˜6 was reached. The solid that had precipitated out was collected by filtration, washed with plenty of H2O and with Et2O, and dried to give (RS)-2-amino-4,4-dimethyl-5-phenyl-pentanoic acid (5.39 g, product contains large amount of salt) as white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([Cl:34])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:34])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccnc(Cl)c2)cc(C(=O)Nc2ccnc(Cl)c2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-chloropyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=359.1, 361.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:52](Cl)[CH2:53]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:52][CH3:53])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCCCl
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccc(F)c(F)c3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccc(F)c(F)c2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 1.50 g 4-((S)-4-Carboxy-2-{[5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3,4-difluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 25 ml dichloromethane were added 481 mg EDC, 306 mg DMAP and 617 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 520 mg MS (ES+): m/e=746.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)(=O)=[O:25].C(O)C>C(Cl)Cl>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccc3)ccc2N1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
3.3 gm of 6-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril were dissolved in 50 ml of methylene chloride, the solution cooled to -70° C., and a solution of 1.5 gm of sulfuryl chloride in 5 ml of methylene chloride was added dropwise. After 15 hours, 20 ml of 95% ethanol were added, and the mixture was heated to room temperature by removing the cooling bath, neutralized with an aqueous sodium carbonate solution. The methylene chloride phase was dried with sodium sulfate, and the solvent was evaporated. The residue was recrystallized from toluene.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[O:55][C:35]3=[CH:36][N:37]=[C:38]([C:40]4[O:44][C:43]([Si](C(C)C)(C(C)C)C(C)C)=[N:42][CH:41]=4)[CH:39]=[C:34]3[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[O:55][C:35]3=[CH:36][N:37]=[C:38]([C:40]4[O:44][CH:43]=[N:42][CH:41]=4)[CH:39]=[C:34]3[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[Si](c1ncc(-c2cc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)oc3cn2)o1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4cnco4)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1 mol/L in tetrahydrofuran; 1.5 mL) is added to a solution of 4-[5-(2-triisopropylsilanyl-oxazol-5-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.31 g) in tetrahydrofuran (6 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature for 2 h. Water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. LC (method 4): tR=1.66 min; Mass spectrum (ESI+): m/z=370 [M+H]+.