Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-].[C]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)OC(C)(C)C)cc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C[C@@H]2CNCCN2C(=O)OC(C)(C)C)cc1C
Yield: 90.1 %

Procedure:
A solution of (2R)-4-benzyl-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)piperazine (48.5 g) in methanol (730 ml) was hydrogenated over 20% palladium hydroxide-carbon (0.3 g) at room temperture under atmospheric pressure. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (10:1). The fractions containing the objective compound was collected and evaporated under reduced pressure to give an oil of (2R)-1-tert -butoxycarbonyl-2-(3,4-dimethylbenzyl)piperazine (33.7 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([S:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O.CCO.CCO.CCO.CCO.[Ti]>[C:2]1([CH:1]=[N:15][S:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)S(=O)N=Cc1ccccc1
Temperature: 25 °C

Procedure:
Benzaldehyde (6 mmol, 1 eq), 2-methyl-propane-2-sulfinic acid amide (1 eq) and tetraethyl orthotitanate (3 eq) are dissolved in anhydrous THF under nitrogen (J. Org. Chem. 2003, 68, 9948-9957). The mixture is stirred at room temperature over night. The mixture is poured in brine and stirred vigorously. The resulting suspension is filtered through Celite and the filter cake is extracted with ethyl acetate. The filtrate is transferred to a separatory funnel, where the aqueous layer is separated and extracted 3× with ethyl acetate. The organic layers are combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. Tert.-butane-sulfinic acid 1-phenyl-methylidene amide is obtained as a clear yellowish oil (90% yield); ES-MS (MH+)=210.2; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 8.56 (s, 1H), 7.96-7.93 (m, 2H), 7.63-7.53 (m, 3H), 1.19 (s, 9H).
Reaction SMILES: [Cl:1][P:2](Cl)[O:3][CH2:4][CH2:5][C:6]#[N:7].[CH:9]([N:12]([CH:15]([CH3:17])[CH3:16])CC)([CH3:11])[CH3:10].C(NC(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH:9]([N:12]([P:2]([Cl:1])[O:3][CH2:4][CH2:5][C:6]#[N:7])[CH:15]([CH3:17])[CH3:16])([CH3:11])[CH3:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CCCOP(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.9 mL (13.8 mmol) of dichloro(β-cyano)ethoxyphosphine in 40 mL of dichloromethane cooled in an ice-water bath was added 10 mL of diisopropylethylamine, followed by adding 2.3 mL (13.8 mmol) of diisopropylamine under Argon. The reaction mixture was warmed up to room temperature and stirred for 2 h. After adding 0.1 gm of DMAP into the solution, the reaction mixture is ready for next step reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[O:22])[CH:3]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1.C(O)=O>[O:1]([C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[O:22])[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CN2CCCC2)cc1
Reactant: Ic1ccccc1
Solvent: C1COCCO1
Solvent: O=CO
Product: O=c1cc(Oc2ccccc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 100 mg (0.34 mmol) 4-hydroxy-1-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 3) in 2.0 mL 1,4-dioxane is added 43 mg (0.39) potassium-tert-butylate and the mixture is stirred 30 min at RT. 77 μL (0.34 mmol) iodo-benzene and 21 mg (0.34 mmol) Cu-powder are added and the reaction mixture is stirred 5 h at 125° C. A few drops formic acid are added and after filtration the mixture is purified via HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1)[O:7][CH2:6]2)=O.CO.Cl.[OH:25][NH2:26].C([O-])(=O)C.[Na+]>O>[OH:25][N:26]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1)[O:7][CH2:6]2
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 5′-formyl-3′H-spiro[azetidine-3,1-isobenzofuran]-1-carboxylate (Preparation 42, 1.5 g, 5.184 mmol, 1 eq) in mixture of methanol (20 mL) and water (10 mL) was added hydroxyl amine hydrochloride (0.537 g, 7.777 mmol, 1.5 eq) followed by addition of sodium acetate (0.765 g, 9.332 mmol, 1.8 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 24 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afforded yellow colored residue, which was diluted by water (70 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellow semi solid (1.9 g, crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 24% ethyl acetate in hexane to afford title compound as yellow semi solid (1.1 g, 69.62%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.13 (d, J=9.6 Hz, 2H), 4.31 (d, J=9.84 Hz, 2H), 5.10 (s, 2H), 7.43 (s, 1H), 7.47 (d, J=7.88 Hz, 1H), 7.56 (d, J=7.92 Hz, 1H), 8.14 (s, 1H). (m/z): 303.3 (M−H).
Reaction SMILES: [C:1](=[N:16][OH:17])([C:3]1[CH:4]=[CH:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]=2[CH:15]=1)[CH3:2].[CH2:18]([OH:20])[CH3:19].Cl.NO>N1C=CC=CC=1>[OH:17][N:16]([CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]=2[CH:15]=1)[CH3:2])[C:18](=[O:20])[CH3:19]
Reactant: CC(=NO)c1ccc2c(c1)oc1ccccc12
Reactant: CCO
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Product: CC(=O)N(O)C(C)c1ccc2c(c1)oc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Acetyldibenzofuran oxime. The crude ketone prepared as described in step a, was dissolved in pyridine (50 mL) and ethanol (50 mL) and hydroxylamine hydrochloride was added. The mixture was stirred overnight at ambient temperature. The reaction was concentrated and the residue was partitioned between ethyl acetate (300 mL) and 3N HCl. The ethyl acetate layer was dried (Na2SO4), filtered and concentrated in vacuo to give a crystalline residue. The crystals were rinsed with hexane, filtered and dried to give 12.3 g of the desired product, mp 132°-135°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
A suspension of (2-amino-5-chlorophenyl) (pyridin-4-yl)methanone (156 g) in pyridine (2350 mL) was heated at 60° C. N,N-Dimethyl-4-aminopyridine (8.21 g) and 4-tert-butylbenzenesulfonyl chloride (180 g) were added, and the mixture was heated at 75° C. for 18 hr. 4-tert-Butylbenzenesulfonyl chloride (15.6 g) was further added, and the mixture was stirred for 1 hr, and this operation was repeated 6 times. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed twice with water (500 mL), and twice with saturated aqueous sodium hydrogen carbonate solution (500 mL). The organic layer was washed twice with 2N hydrochloric acid (200 mL), once with saturated aqueous sodium hydrogen carbonate solution (500 mL), and once with saturated brine (500 mL). The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, 2-propanol was added to the residue and the mixture was stirred at 50° C. for 1 hr. After cooling, the solid was washed with cold 2-propanol (600 mL) and hexane, and dried. 2-Propanol/ethyl acetate (800 mL/80 mL) was added, and the mixture was stirred at 50° C. for 1 hr. After cooling, the solid was washed with cold 2-propanol and hexane, and dried to give the object 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide (162 g, pale-yellow solid). The filtrate was purified by silica gel column chromatography (ethyl acetate/chloroform) to give the object 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide (29 g, pale-yellow solid). A total of 191 g of the object product 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Yield: 67.2 %

Procedure:
2-Trifluoromethylbenzenesulphonyl chloride (0.195 g) was added to a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.150 g) in pyridine (1.7 ml) at room temperature and the resultant mixture was stirred for 64 hours. The solvent was removed and the residue was purified directly by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-(2-trifluoromethylbenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.194 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:26]CC>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-5-trifluoromethyl benzonitrile (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutylaluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50°-55° C. at 0.05 mm Hg. A mixture of this compound (16.24 mmoles), 1-phenylocta-1,7-diyne (19.54 mmoles, prepared as in Example 7b), cuprous iodide (0.19 mmole) and bis(triphenylphosphine) palladium (II) chloride (0.34 mmole) in triethylamine (50 ml) was refluxed under argon for 30 minutes. The reaction mixture was cooled and filtered. The filtrate was evaporated, taken up in ether (100 ml), washed with hydrochloric acid (50 ml, 3N) and sodium chloride, and treated with magnesium sulfate-charcoal. Filtration and evaporation left an oil which was purified by flash chromatography (5% ether/hexane) to yield 2-(8-phenyloctadiyn-1,7-yl)-5-trifluoromethyl benzaldehyde as an oil. A solution of this compound (13.26 mmoles) in ethyl acetate (100 ml) was treated with charcoal for 30 minutes and then filtered. The solution was then shaken under 50 psi of hydrogen with 10% palladium on charcoal (502 mg) for about 90 minutes. Thin layer chromatography of the reaction mixture indicated about 50% reduction of the aldehyde to the alcohol. To re-oxidize the alcohol, the palladium catalyst was filtered off and manganese dioxide (20 g) was added. This mixture was then stirred at room temperature under argon for 18 hours. Filtration and evaporation gave an oil which was purified by flash chromatography (2% ether/hexane) to afford the product as an oil.
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.[CH3:25][N:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N: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.C(Cl)Cl.CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:27][N:26]([CH3:25])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CN(N)c1ccccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CN(NC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1ccccn1
Yield: 16.2 %

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 (0.43 g), 2-(1-methylhydrazinyl)pyridine (0.15 g, 1.0 eq.) in EtOAc (10 mL). T3P (50% in EtOAc; 1.1 g, 1.5 eq.) and DIPEA (0.40 g, 2.5 eq.) were added under nitrogen atmosphere at −60° C. and the progress of the reaction was monitored by TLC (using 10% MeOH:CH2Cl2 as mobile phase and visualization with UV light). The reaction mixture was concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.65 g of crude solid. Purification was performed on Combi-Flash Column chromatography in CH2Cl2 and MeOH (desired compound started eluting at 3.3% MeOH in CH2Cl2). The fractions containing the desired compound were combined and concentrated under reduced pressure (35° C., 20 mm Hg) to afford 90.0 mg (yield: 18%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-methyl-N′-(pyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.79 (brs, 1H), 8.57-8.62 (d, 2H), 7.92-7.94 (d, J=11.2 Hz, 1H), 7.59-7.64 (m, 1H), 7.19-7.25 (q, 1H), 6.75-6.89 (m, 2H), 5.85-5.88 (d, J=10.8 Hz, 1H), 3.46 (d, 3H); LCMS for C19H15F6N6O [M+H]+ 457.35; found 456.26 (RT 2.52 min, purity: 100.0%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClCCl.CO.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of tert-butyl (trans)-4-aminocyclohexylcarbamate (1.0 g, 4.67 mmol) in dichloromethane (30 mL) was treated with 4-methoxybenzaldehyde (0.568 mL, 4.67 mmol) and magnesium perchlorate (0.052 g, 0.233 mmol) and stirred at room temperature overnight. A large excess of solid Na2SO4 was added, and the reaction mixture was stirred for 1 h., filtered, and the filter cake was rinsed with MeOH. The filtrate and rinse were combined and concentrated to yield a white solid, which was dissolved in MeOH (10 mL). This solution was treated with NaBH4 (0.265 g, 7.00 mmol) in a single portion. The reaction mixture became a light yellow solution which was stirred at room temperature for 1.5 h. The reaction was quenched with 1.0N NaOH, diluted with water (150 mL), and stirred for 30 min. The resulting white solid was collected by filtration, washed with water, and air dried to provide 15A (1.26 g, 81% yield). MS (ES): m/z=335 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (d, 2H, J=8.5 Hz); 6.83 (d, 2H, J=8.5 Hz); 6.63 (d, 1H, J=8.0 Hz); 3.70 (s, 2H); 3.60 (br. s, 1H); 3.31 (s, 3H); 3.08-3.18 (m, 1H); 2.06-2.25 (m, 1H); 1.65-1.88 (m, 4H); 1.34 (s, 9H); 0.93-1.12 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][CH3:78])([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([NH:65][CH2:66][C:67]5[CH:68]=[CH:69][C:70]6[C:74]([CH2:75][CH3:76])([CH2:77][CH3:78])[O:73][B:72]([OH:79])[C:71]=6[CH:80]=5)=[O:26])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(F)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.23 mmol) and DIPEA (118 mg, 0.92 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (175 mg, 0.46 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]-oxaborol-1(3H)-ol hydrochloride (118 mg, 0.46 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:19])(=[O:18])[N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30]
Reactant: COC(=O)c1cccnc1S(=O)(=O)Nc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccnc1S(=O)(=O)N(COCC[Si](C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenylsulfamoylnicotinic acid methyl ester (1.1 g), N,N-diisopropylethylamine (1.9 mL) and dichloromethane at 0° C. was treated with 2-(trimethylsilyl)ethoxymethyl chloride (0.67 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0° C., treated with additional (trimethylsilyl)ethoxymethyl chloride (0.30 mL), and stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (0:1 to 1:0 by volume) to afford the title compound (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[C:8]([C:14](OC)=[O:15])#[C:9][C:10]([O:12][CH3:13])=[O:11]>C(O)C>[OH:15][C:14]1[N:6]2[C:5]([SH:7])=[N:4][N:3]=[C:2]2[N:1]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1n[nH]c(S)n1
Solvent: CCO
Product: COC(=O)c1cc(O)n2c(S)nnc2n1
Yield: 98.6 %

Procedure:
A mixture of 15.1 g of 3-amino-5-mercapto-s-triazole, 18.9 g of dimethyl acetylenedicarboxylate and 100 ml of ethanol was refluxed for 90 minutes. The objective compound (29 g) was obtained by collecting the crystals separated out upon cooling the reaction mixture.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35](O)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH2:16][N:17]([C:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[C:26]5[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=5)=[O:36])[CH2:18][CH:19]4[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1-c1ccc(C(F)(F)F)cc1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 4′-trifluoromethyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C30H53F3N4O, 514.56; m/z found 515.3 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[O-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl.O>CO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1S
Reactant: COc1cccc(CCl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(CSc2ncccc2C(=O)O)c1
Reaction time: 14 h

Procedure:
A suspension of 4.65 g (0.03 mole) of 2-mercaptonicotinic acid in 100 ml of methanol was cooled in ice as 3.24 g (0.06 mole) of sodium methoxide was added. The resulting solution was left at ice-temperature as 4.68 g (0.03 mole) of 3-methoxybenzyl chloride was added over 5 minutes. The reaction mixture was stirred for 14 hours and the reaction set solid. The addition of 50 ml of water caused solution and an excess of acetic acid precipitated 7.55 g (92% of theory) of 2-(3-methoxybenzylthio)nicotinic acid. Recrystallization was effected from ethyl acetate; m.p. 156°-157° C.